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Клеточная терапия и трансплантация
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Early studies

Some of the most compelling evidence for the absolute requirement of a competent microenvironment (ME) to support engraftment comes from early studies in mutant mice. In particular, unequivocal studies show that both the SL/SL, or “Steel” mutant mouse which dies of anemia spontaneously, and the more viable SL/SLd  mouse, which succumbs following very low doses of irradiation, cannot be rescued with an infusion of normal bone marrow cells [<38]. However, the animals could be rescued by transplantation of intact spleen tissue, which becomes the site of hematopoiesis [29]. These studies not only established the importance of the ME for stem cell engraftment, but also advanced the concept that at least some components of the ME cannot be transplanted by an intra-venous infusion of aspirated marrow cells. More recently the mutated gene product that gives rise to the Steel phenotype was shown to be kit ligand, also known as “stem cell factor” (SCF) expressed by stromal cells [12, 19].

Early seminal work by Wolf and Trentin illustrated that the ME is also critical for inducing lineage commitment. In these experiments, a section of bone with intact marrow was implanted within the spleen of a mouse prior to irradiation. After stem cell transplantation, the resulting spleen colonies that bridged the two different MEs were mixed such that there was mostly erythroid differentiation on the splenic side while myeloid differentiation predominated on the marrow side [51].

Although these early studies highlighted the important role of the ME in normal hematopoiesis, identifying the cells and secreted products that are involved in this process remains unfinished work. Specifically, the components that can support the expansion of stem cells without loss of their potential have not been defined. This may be due in part to the fact that more than one cell type and gene product participate in this regulation. In addition, even though the hematopoietic system is a liquid tissue, some ME components appear to be "fixed" stromal elements that contribute to the architecture and may have critical spatial relationships with each other that are difficult to reproduce in vitro.

For several decades in vitro studies of the ME have relied heavily on the Dexter long term culture (LTC) in which many cell types are evident [13]. LTC that are established from aspirated marrow and cultured under appropriate conditions will generate in 2-4 weeks an adherent layer that supports hematopoiesis for several months. Figure 1 shows an example of an LTC.

Figure1. Dexter Long-Term Culture (LTC): Panel A depicts a schematic representation of a typical LTC. A complex adherent layer composed of fibroblasts, endothelium, adipocytes, and macrophages which supports the production of hematopoietic cells. As hematopoietic cells mature, they are released from the adherent layer into the media. Panel B depicts a phase-contrast photomicrograph of a typical human LTC.  

Ramakrishnan-Figure1-A-B_01.png

The adherent stromal layer in the LTC consists of fibroblasts, endothelial cells, macrophages, adipocytes, osteoclasts, and extracellular matrix. LTC, if done properly, appear to approximate the in vivo ME since the functional ramifications of the Steel defect are apparent in cultures established from SL/SLd marrow [14]. However there are limitations to this system as myeloid cell production is generally favored over erythroid, and the ever-increasing proportion of monocyte-derived macrophages, is eventually associated with the termination of cell production [10].

Stromal component of the ME

There has been considerable debate concerning the origin of the ME stromal cells. Many reports have suggested that hematopoietic cells and stromal cells have a common precursor, and in agreement with this, several reports have claimed that stromal fibroblasts as well as hematopoietic cells are replaced by donor cells after hematopoietic stem cell transplantation [23, 43]. However, many of these studies typically looked at LTC established from sex mismatched transplants and detected donor cells using standard cytogenetics or fluorescent in-situ hybridization (FISH) for sex chromatin [23]. While it is clear that adherent cells of donor origin were detected in these LTC, these reports were flawed, as they did not properly account for the macrophage component of the adherent layer. This is an important consideration, since studies have shown that even after weekly passage of adherent cells, macrophages can represent a significant proportion of the cells in a 12 week LTC (see Table 1) [5].

Table 1: Percentage of NSE + cells in LTC of normal donors

Weeks in culture

2wk

4wk

6wk

8wk

10wk

12wk

Donor

1

15.5

17.7

44.0

28.0

23.0

8.2

2

13.9

24.9

17.4

5.8

2.1

1.9

3

32.8

22.3

29.6

31.7

29.5

22.0

4

25.1

21.4

27.6

41.1

16.5

3.3

NSE=nonspecific esterase; LTC=long term culture

LTCs were established from 4 normal donors and evaluated at various time points for the presence of monocytes/macrophages using NSE staining. As shown in the table, even after 12 weeks there can be a considerable proportion of macrophages in LTC.


Using histochemistry to identify and exclude the donor-derived macrophage component, our lab has determined that even after decades following successful stem cell transplantation, with 100% donor-derived hematopoietic cells, the stromal cells detected in an LTC from a transplanted patient remain of host origin, as predicted by the Steel mouse [5, 42].

The stromal component of the ME remains relatively constant and is quite resistant to currently used conditioning regimens. Therefore, after transplantation, the ME as a whole becomes chimeric; the stromal fibroblasts and endothelial cells remain host-derived while the macrophages are donor-derived [42, 48]. There are several possible explanations for this: First, unlike hematopoietic cells, the stromal fibroblasts and endothelial cells that are harvested from marrow and detectable in the transplanted product are not equipped with the surface molecules needed for trans-migrating the endothelium and homing to the ME. Pre-clinical animal studies suggest that when stromal cells are infused intravenously, they get trapped primarily in the lung and spleen (M. Mielcarek, personal communication). Second, because stromal cells are relatively resistant to chemotherapy and irradiation, the stromal cell compartment is not depleted by standard conditioning; as a result there may not be a demand for stromal cell replacement.

ME niches

After conditioning, the resident stromal cells express or secrete molecules that attract hematopoietic stem and progenitor cells, provide cell surface receptors which allow for the attachment of these cells, and secrete activities for the induction and support of various cell fates. Recently there has been considerable interest in identifying the specific cellular components that make up the stem cell niche, the specific ME unit where the hematopoietic stem cell resides and self-renews. Over the past two decades, the mouse model has been used to identify various chemokines, cell surface adhesion molecules, and cell types that contribute to this niche. There is general agreement that a number of signaling pathways including c-kit/SCF, CXCR4/CXCL12, VCAM1/VLA-4, Tie2/angipoietin, c-mpl/thrombopoietin, notch/jagged-1, and osteopontin play important roles in maintaining the stem cell niche [6, 30, 3, 16, 22, 32, 4, 27, 31, 44, 25, 35, 52, 9]. However, there is less agreement on the exact identity of the cells that make up the stem cell niche.

Compelling evidence from mouse studies suggest that the endosteal region is critical for the maintenance of hematopoietic stem and precursor cells. One prevalent model proposes that stem cell maintenance critically depends on N-cadherin-mediated binding to osteoblasts [9, 53]. This “osteoblastic niche” model was based on experiments which showed that N-cadherin-positive cells in the endosteal region are associated with cells expressing stem cell markers [9] . However, there are also reports that ablation of osteoblasts does not result in an immediate loss of stem cells, suggesting that while the stem cells may be spatially associated with osteoblasts, the osteoblasts may not be playing a significant role in their support [50, 54]. Furthermore, a recent study demonstrated that only CD146-positive mesenchymal progenitors and not osteoblasts can transfer a ME when transplanted into immunodeficient mice [39] .

Another equally compelling model proposes that hematopoietic stem cells localize close to marrow sinusoids. Evidence for this “endothelial niche” comes from experiments where cells expressing the SLAM family of surface receptors, which are highly expressed in hematopoietic stem cells, were detected in close association with vascular endothelium [24] . A third study suggested that reticular cells that express high levels of CXCL12/SDF1 (CAR cells) essentially define the stem cell niche, and these cells could be detected in both the perivascular and endosteal regions [45] .

The macrophage component of the ME

It is obvious that in vivo, stromal cells do not function in isolation, but do so in the context of other cells. One cell type that is clearly conspicuous both in vivo and in vitro (see Figure 2) is the monocyte-derived macrophage [34, 33].

Figure 2. Panel A shows a normal human bone marrow biopsy stained with macrophage-specific CD68 antibody. Panel B depicts a marrow LTC from an inducible transgenic mouse where GFP is under the control of the human CD68 promoter and is expressed exclusively in macrophages. As illustrated in the photomicrographs, CD68 positive macrophages have a significant presence in the marrow and have numerous cell processes which interact with many cell types, suggesting a crucial role in the regulation of hematopoiesis.

Ramakrishnan-Figure2-A-B.png

In vivo, monocytes are recruited from the circulation into tissues, where they can differentiate into macrophages and perform functions that are relevant to that particular tissue ME. It has long been known that macrophages play a critical role in hematopoiesis. Bessis first described the “nurse cell”, a specialized macrophage that is an important component of the erythroblast island, thought to provide structure and nutrients to developing erythroid cells [7, 11]. Osteoclasts, another specialized type of monocyte-derived macrophages, are critical in Ca+ homeostasis in the bone, which is also important for the maintenance of hematopoietic stem cells [1]. However, there is little known or even speculated about the role macrophages may play in the stem cell niche.

Available data suggest that stromal cells play a direct role in the stem cell niche by influencing cell fate decisions through the expression of proteins, such as SDF1 and Jagged, which bind progenitor surface determinants CXCR4 and Notch, respectively. While SDF1 facilitates homing and retention of cells in the marrow, Jagged transduces a signal through Notch that renders early progenitors resistant to differentiation signals [30, 3, 27, 9]. However, since the stromal cell compartment appears constant, with little turnover, it is unclear how interactions between stroma and stem cells can be modulated to allow for the dynamic range of cell production that is characteristic of hematopoiesis. In particular, the mechanisms that regulate gene expression in stromal cells have not been well defined. However, in theory the influence of a constant level of a stroma-expressed genes, e.g. Jagged, could be modulated to some extent indirectly, by down-regulating the level of its receptor, Notch, expressed by progenitors. In vitro studies using cloned human stromal cell lines suggest that this may occur.

Recent data from our laboratory indicates that functionally distinct stromal cell lines isolated from the same LTC can induce different gene expression profiles in monocytes. Specifically, the cloned stromal cell line HS27a, which expresses a number of genes associated with the stem cell niche including CXCL12, angiopoietin, Jagged 1, VCAM, induces the secretion of osteopontin by monocytes [37, 15, 20]. The osteopontin in turn down-regulates Notch expression on progenitors. It is reasonable to conclude that the reduced expression of Notch on progenitors can limit Jagged-Notch signaling, thereby making the progenitors more responsive to differentiation signals [20]. Interestingly, we also showed that the second functionally distinct stromal line, designated HS5, secretes activities that increase the production of matrix metalloproteinase 9 (MMP9) by monocytes, which would facilitate egress of the newly matured cells [21]. Since monocytes circulate and can be recruited from the blood, changes in their number and gene expression within an ME could significantly modulate stromal function.

ME and disease

Since stroma-monocyte interactions likely participate at many levels in the regulation of hematopoiesis, it would be reasonable to conclude that abnormal monocytes may contribute to the pathophysiology of hematologic malignancies. One example that we reported shows that monocytes from patients with myelodysplastic syndrome (MDS) fail to respond appropriately to stromal signals [21]. Specifically, clonally derived monocytes from patients with MDS fail to upregulate MMP-9 gene expression in response to stromal signals (see Figure 3).

Figure 3. Combined Immunohistochemistry for MMP-9 and FISH for chromosome 7. Monocytes from a healthy donor and from an MDS patient with monosomy seven were isolated and exposed to stromal signals. Cytospins were prepared and IHC for MMP-9 and FISH for chromosome 7 were performed. Panel A depicts monocytes from a healthy control which upregulate MMP-9 expression in response to stromal signals (green cytoplasmic staining) and have two copies of chromosome 7 detected by FISH (see white arrows). Panel B depicts clonal MDS monocytes identified by monosomy 7 which fail to upregulate MMP-9 expression in response to stromal signals.

Ramakrishnan-Figure3-A-B_01.png

The potential clinical relevance of this finding was suggested by a significant negative correlation between the proportion of abnormal monocytes and degree of marrow cellularity [21]. Given the role of MMP-9 in facilitating the egress of cells from marrow, it is reasonable to conclude that as the proportion of non-responsive monocytes increases, inducible levels of MMP-9 decline, resulting in hypercellularity. We also determined that the stromal signal from HS5 that induced MMP-9 is most likely MCP-1; however, we have not as yet identified the compromised monocyte signaling pathway that fails to respond [21]. Clearly a better delineation of signaling pathways that are responsible for normal responses between stromal cells and monocytes as well as the activities that trigger these pathways are needed.

These data suggest that macrophages can play a significant role in altering the hematopoietic ME to support the malignant/dysplastic process. This has clear implications for the success of hematopoietic stem cell transplantation, especially with the introduction of reduced intensity and so-called non-myeloablative conditioning regimens. Most of these conditioning regimens are of insufficient intensity to eliminate residual clonal host macrophages. Thus, when allogeneic stem cells are infused, they encounter a ME that remains dysregulated. This may explain the high rates of graft rejection and relapse seen in MDS patients after reduced intensity and non-myeloablative transplantation [21, 2, 28, 40, 26].

Finally, appreciating the critical role that monocyte-derived macrophages may play in the hematopoietic ME sheds new light on the “seed versus soil” debate as to the cause of hematopoietic dysplasias and aplasias, as well as graft failures. Clearly, the ME (soil) may appear abnormal, yet the defect may reside in the hematopoietic stem cell (seed)- derived monocyte, which upon entering the ME, fails to respond appropriately to stromal signals and thereby contributes to abnormal ME function. This would explain why “defective” MEs appear to be corrected by transplantation; the transplant is actually replacing the abnormal monocytes, not the stromal cells. This is not to suggest that primary stromal failures do not exist. Two examples of such failures have been observed following transplantation: one involves CMV infection and destruction of stromal cells [41, 47, 36, 46, 8], the other involves GVH-mediated anti-stroma activities [49, 18, 17]. In both cases the recipients could not be rescued by the infusion of additional stem cells, even after the anti-stroma mechanism had been eliminated.  

Summary

Over the past several decades, studies have revealed the hematopoietic ME to be a complex tissue that consists of both hematopoietic and non-hematopoietic cells, extra-cellular matrix, as well as soluble and membrane bound factors, all of which act in concert to support normal hematopoiesis.

• The ME consists of both hematopoietic stem cell derived and non-hematopoietic cells.

• A viable host ME is required for successful stem cell transplantation.

• Graft failure ensues when the ME is damaged/destroyed.

• After transplantation, the ME becomes chimeric. The stromal elements of the ME remain host-derived, whereas the monocyte/macrophage component is replaced by donor cells.

• Distinct niches or “ME units” exist that are responsible for the regulation of stem cell quiescence as well as differentiation.

• The hematopoietic stem cell derived monocyte/macrophage is a critical component of the ME.

• Stromal cells activate monocytes to assume different fates, which subsequently secrete activities that regulate hematopoiesis.

• In hematologic malignancies, clonally derived monocytes contribute to the dysregulation of the ME.

Data from our lab suggest that monocyte-derived macrophages play a significant role within the ME, and that abnormal monocytes derived from a clone of malignant hematopoietic cells, can compromise ME function. Importantly, following reduced intensity conditioning, recipient macrophages can be retained, and the dysregulated ME can persist and fail to support engraftment. Clearly, further investigation is necessary to completely understand how stroma and monocytes interact to regulate normal hematopoiesis, and how these pathways are altered by abnormal cells. As our knowledge increases we will be able to develop strategies to identify and correct abnormal signaling within the ME.

Acknowledgements

This work was supported in part by PHS grants DK082783, HL099993, DK056465 from the National Institutes of Health. We thank Bonnie Larson, Helen Crawford and Sue Carbonneau for assistance with the preparation and editing of the manuscript. The authors indicate no potential conflict of interest.

References

1. Adams, G. B., K. T. Chabner, I. R. Alley, D. P. Olson, Z. M. Szczepiorkowski, M. C. Poznansky, C. H. Kos, M. R. Pollak, E. M. Brown, and D. T. Scadden. 2006. Stem cell engraftment at the endosteal niche is specified by the calcium-sensing receptor. Nature 439, (7076) (Feb 2): 599-603. 

2. Alyea, E. P., H. T. Kim, V. Ho, C. Cutler, D. J. DeAngelo, R. Stone, J. Ritz, J. H. Antin, and R. J. Soiffer. 2006. Impact of conditioning regimen intensity on outcome of allogeneic hematopoietic cell transplantation for advanced acute myelogenous leukemia and myelodysplastic syndrome. Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation 12, (10) (Oct): 1047-55.

3. Ara, T., K. Tokoyoda, T. Sugiyama, T. Egawa, K. Kawabata, and T. Nagasawa. 2003. Long-term hematopoietic stem cells require stromal cell-derived factor-1 for colonizing bone marrow during ontogeny. Immunity 19, (2) (Aug): 257-67.

4. Arai, F., A. Hirao, M. Ohmura, H. Sato, S. Matsuoka, K. Takubo, K. Ito, G. Y. Koh, and T. Suda. 2004. Tie2/angiopoietin-1 signaling regulates hematopoietic stem cell quiescence in the bone marrow niche. Cell 118, (2) (Jul 23): 149-61.

5. Awaya, N., K. Rupert, E. Bryant, and B. Torok-Storb. 2002. Failure of adult marrow-derived stem cells to generate marrow stroma after successful hematopoietic stem cell transplantation. Experimental Hematology 30, (8) (Aug): 937-42.

6. Barker, J. E. 1994. Sl/Sld hematopoietic progenitors are deficient in situ. Experimental Hematology 22, (2) (Feb): 174-7.

7. Bessis, M. 1958. Erythroblastic island, functional unity of bone marrow. Revue d'Hematologie 13, (1) (Jan-Mar): 8-11.

8. Boeckh, M., C. Hoy, and B. Torok-Storb. 1998. Occult cytomegalovirus infection of marrow stroma. Clinical Infectious Diseases : An Official Publication of the Infectious Diseases Society of America 26, (1) (Jan): 209-10.

9. Calvi, L. M., G. B. Adams, K. W. Weibrecht, J. M. Weber, D. P. Olson, M. C. Knight, R. P. Martin, et al. 2003. Osteoblastic cells regulate the haematopoietic stem cell niche. Nature 425, (6960) (Oct 23): 841-6.

10. Chabannon, C., and B. Torok-Storb. 1992. Stem cell-stromal cell interactions. Current Topics in Microbiology and Immunology 177, : 123-36.

11. Chasis, J. A., and N. Mohandas. 2008. Erythroblastic islands: Niches for erythropoiesis. Blood 112, (3) (Aug 1): 470-8.

12. Copeland, N. G., D. J. Gilbert, B. C. Cho, P. J. Donovan, N. A. Jenkins, D. Cosman, D. Anderson, S. D. Lyman, and D. E. Williams. 1990. Mast cell growth factor maps near the steel locus on mouse chromosome 10 and is deleted in a number of steel alleles. Cell 63, (1) (Oct 5): 175-83.

13. Dexter, T. M., T. D. Allen, and L. G. Lajtha. 1977. Conditions controlling the proliferation of haemopoietic stem cells in vitro. Journal of Cellular Physiology 91, (3) (Jun): 335-44.

14. Dexter, T. M., and M. A. Moore. 1977. In vitro duplication and "cure" of haemopoietic defects in genetically anaemic mice. Nature 269, (5627) (Sep 29): 412-4.

15. Graf, L., M. Iwata, and B. Torok-Storb. 2002. Gene expression profiling of the functionally distinct human bone marrow stromal cell lines HS-5 and HS-27a. Blood 100, (4) (Aug 15): 1509-11.

16. Heissig, B., K. Hattori, S. Dias, M. Friedrich, B. Ferris, N. R. Hackett, R. G. Crystal, et al. 2002. Recruitment of stem and progenitor cells from the bone marrow niche requires MMP-9 mediated release of kit-ligand. Cell 109, (5) (May 31): 625-37.

17. Hirabayashi, N. 1981. Studies on graft versus host (GvH) reactions. I. impairment of hemopoietic stroma in mice suffering from GvH disease. Experimental Hematology 9, (2) (Feb): 101-10.

18. Hows, J. M. 1991. Mechanisms of graft failure after human marrow transplantation: A review. Immunology Letters 29, (1-2) (Jul): 77-80.

19. Huang, E., K. Nocka, D. R. Beier, T. Y. Chu, J. Buck, H. W. Lahm, D. Wellner, P. Leder, and P. Besmer. 1990. The hematopoietic growth factor KL is encoded by the sl locus and is the ligand of the c-kit receptor, the gene product of the W locus. Cell 63, (1) (Oct 5): 225-33.

20. Iwata, M., N. Awaya, L. Graf, C. Kahl, and B. Torok-Storb. 2004. Human marrow stromal cells activate monocytes to secrete osteopontin, which down-regulates Notch1 gene expression in CD34+ cells. Blood 103, (12) (Jun 15): 4496-502.

21. Iwata, M., M. Pillai, A. Ramakrishnan, R. C. Hackman, H. Joachim Deeg, G. Opdenakker, and B. Torok-Storb. 2007. Reduced expression of inducible gelatinase B/matrix metalloproteinase-9 in monocytes from patients with myelodysplastic syndrome: Correlation of inducible levels with the percentage of cytogenetically marked cells and with marrow cellularity. Blood 109, (1) (Jan 1): 85-92.

22. Jiang, Y., H. Bonig, T. Ulyanova, K. Chang, and T. Papayannopoulou. 2009. On the adaptation of endosteal stem cell niche function in response to stress. Blood 114, (18) (Oct 29): 3773-82.

23. Keating, A., J. W. Singer, P. D. Killen, G. E. Striker, A. C. Salo, J. Sanders, E. D. Thomas, D. Thorning, and P. J. Fialkow. 1982. Donor origin of the in vitro haematopoietic microenvironment after marrow transplantation in man. Nature 298, (5871) (Jul 15): 280-3.

24. Kiel, M. J., O. H. Yilmaz, T. Iwashita, O. H. Yilmaz, C. Terhorst, and S. J. Morrison. 2005. SLAM family receptors distinguish hematopoietic stem and progenitor cells and reveal endothelial niches for stem cells. Cell 121, (7) (Jul 1): 1109-21.

25. Kimura, S., A. W. Roberts, D. Metcalf, and W. S. Alexander. 1998. Hematopoietic stem cell deficiencies in mice lacking c-mpl, the receptor for thrombopoietin. Proceedings of the National Academy of Sciences of the United States of America 95, (3) (Feb 3): 1195-200.

26. Laport, G. G., B. M. Sandmaier, B. E. Storer, B. L. Scott, M. J. Stuart, T. Lange, M. B. Maris, et al. 2008. Reduced-intensity conditioning followed by allogeneic hematopoietic cell transplantation for adult patients with myelodysplastic syndrome and myeloproliferative disorders. Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation 14, (2) (Feb): 246-55.

27. Li, L., L. A. Milner, Y. Deng, M. Iwata, A. Banta, L. Graf, S. Marcovina, et al. 1998. The human homolog of rat Jagged1 expressed by marrow stroma inhibits differentiation of 32D cells through interaction with Notch1. Immunity 8, (1) (Jan): 43-55.

28. Martino, R., S. Iacobelli, R. Brand, T. Jansen, A. van Biezen, J. Finke, A. Bacigalupo, et al. 2006. Retrospective comparison of reduced-intensity conditioning and conventional high-dose conditioning for allogeneic hematopoietic stem cell transplantation using HLA-identical sibling donors in myelodysplastic syndromes. Blood 108, (3) (Aug 1): 836-46.

29. McCulloch, E. A., L. Siminovitch, J. E. Till, E. S. Russell, and S. E. Bernstein. 1965. The cellular basis of the genetically determined hemopoietic defect in anemic mice of genotype sl-sld. Blood 26, (4) (Oct): 399-410.

30. Nagasawa, T. 2000. A chemokine, SDF-1/PBSF, and its receptor, CXC chemokine receptor 4, as mediators of hematopoiesis. International Journal of Hematology 72, (4) (Dec): 408-11.

31. Nilsson, S. K., H. M. Johnston, G. A. Whitty, B. Williams, R. J. Webb, D. T. Denhardt, I. Bertoncello, L. J. Bendall, P. J. Simmons, and D. N. Haylock. 2005. Osteopontin, a key component of the hematopoietic stem cell niche and regulator of primitive hematopoietic progenitor cells. Blood 106, (4) (Aug 15): 1232-9.

32. Papayannopoulou, T., C. Craddock, B. Nakamoto, G. V. Priestley, and N. S. Wolf. 1995. The VLA4/VCAM-1 adhesion pathway defines contrasting mechanisms of lodgement of transplanted murine hemopoietic progenitors between bone marrow and spleen. Proceedings of the National Academy of Sciences of the United States of America 92, (21) (Oct 10): 9647-51.

33. Pillai, M. M., B. Hayes, and B. Torok-Storb. 2009. Inducible transgenes under the control of the hCD68 promoter identifies mouse macrophages with a distribution that differs from the F4/80 - and CSF-1R-expressing populations. Experimental Hematology 37, (12) (Dec): 1387-92.

34. Pillai, M. M., M. Iwata, N. Awaya, L. Graf, and B. Torok-Storb. 2006. Monocyte-derived CXCL7 peptides in the marrow microenvironment. Blood 107, (9) (May 1): 3520-6.

35. Qian, H., N. Buza-Vidas, C. D. Hyland, C. T. Jensen, J. Antonchuk, R. Mansson, L. A. Thoren, M. Ekblom, W. S. Alexander, and S. E. Jacobsen. 2007. Critical role of thrombopoietin in maintaining adult quiescent hematopoietic stem cells. Cell Stem Cell 1, (6) (Dec 13): 671-84.

36. Randolph-Habecker, J., M. Iwata, and B. Torok-Storb. 2002. Cytomegalovirus mediated myelosuppression. Journal of Clinical Virology : The Official Publication of the Pan American Society for Clinical Virology 25 Suppl 2, (Aug): S51-6.

37. Roecklein, B. A., and B. Torok-Storb. 1995. Functionally distinct human marrow stromal cell lines immortalized by transduction with the human papilloma virus E6/E7 genes. Blood 85, (4) (Feb 15): 997-1005.

38. Russell, E. S. 1979. Hereditary anemias of the mouse: A review for geneticists. Advances in Genetics 20, : 357-459.

39. Sacchetti, B., A. Funari, S. Michienzi, S. Di Cesare, S. Piersanti, I. Saggio, E. Tagliafico, et al. 2007. Self-renewing osteoprogenitors in bone marrow sinusoids can organize a hematopoietic microenvironment. Cell 131, (2) (Oct 19): 324-36.

40. Scott, B. L., B. M. Sandmaier, B. Storer, M. B. Maris, M. L. Sorror, D. G. Maloney, T. R. Chauncey, R. Storb, and H. J. Deeg. 2006. Myeloablative vs nonmyeloablative allogeneic transplantation for patients with myelodysplastic syndrome or acute myelogenous leukemia with multilineage dysplasia: A retrospective analysis. Leukemia : Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K 20, (1) (Jan): 128-35.

41. Simmons, P., K. Kaushansky, and B. Torok-Storb. 1990. Mechanisms of cytomegalovirus-mediated myelosuppression: Perturbation of stromal cell function versus direct infection of myeloid cells. Proceedings of the National Academy of Sciences of the United States of America 87, (4) (Feb): 1386-90.

42. Simmons, P. J., D. Przepiorka, E. D. Thomas, and B. Torok-Storb. 1987. Host origin of marrow stromal cells following allogeneic bone marrow transplantation. Nature 328, (6129) (Jul 30-Aug 5): 429-32.

43. Singer, J. W., A. Keating, J. Cuttner, A. M. Gown, R. Jacobson, P. D. Killen, J. W. Moohr, V. Najfeld, J. Powell, and J. Sanders. 1984. Evidence for a stem cell common to hematopoiesis and its in vitro microenvironment: Studies of patients with clonal hematopoietic neoplasia. Leukemia Research 8, (4): 535-45.

44. Stier, S., Y. Ko, R. Forkert, C. Lutz, T. Neuhaus, E. Grunewald, T. Cheng, et al. 2005. Osteopontin is a hematopoietic stem cell niche component that negatively regulates stem cell pool size. The Journal of Experimental Medicine 201, (11) (Jun 6): 1781-91.

45. Sugiyama, T., H. Kohara, M. Noda, and T. Nagasawa. 2006. Maintenance of the hematopoietic stem cell pool by CXCL12-CXCR4 chemokine signaling in bone marrow stromal cell niches. Immunity 25, (6) (Dec): 977-88.

46. Torok-Storb, B., M. Boeckh, C. Hoy, W. Leisenring, D. Myerson, and T. Gooley. 1997. Association of specific cytomegalovirus genotypes with death from myelosuppression after marrow transplantation. Blood 90, (5) (Sep 1): 2097-102.

47. Torok-Storb, B., L. Bolles, M. Iwata, K. Doney, G. E. Sale, T. A. Gooley, and R. Storb. 2001. Increased prevalence of CMV gB3 in marrow of patients with aplastic anemia. Blood 98, (3) (Aug 1): 891-2.

48. Torok-Storb, B., and L. Holmberg. 1994. Role of marrow microenvironment in engraftment and maintenance of allogeneic hematopoietic stem cells. Bone Marrow Transplantation 14 Suppl 4, : S71-3.

49. Torok-Storb, B., P. Simmons, and D. Przepiorka. 1987. Impairment of hemopoiesis in human allografts. Transplantation Proceedings 19, (6 Suppl 7) (Dec): 33-7.

50. Visnjic, D., Z. Kalajzic, D. W. Rowe, V. Katavic, J. Lorenzo, and H. L. Aguila. 2004. Hematopoiesis is severely altered in mice with an induced osteoblast deficiency. Blood 103, (9) (May 1): 3258-64.

51. Wolf, N. S., and J. J. Trentin. 1968. Hemopoietic colony studies. V. effect of hemopoietic organ stroma on differentiation of pluripotent stem cells. The Journal of Experimental Medicine 127, (1) (Jan 1): 205-14.

52. Yoshihara, H., F. Arai, K. Hosokawa, T. Hagiwara, K. Takubo, Y. Nakamura, Y. Gomei, et al. 2007. Thrombopoietin/MPL signaling regulates hematopoietic stem cell quiescence and interaction with the osteoblastic niche. Cell Stem Cell 1, (6) (Dec 13): 685-97.

53. Zhang, J., C. Niu, L. Ye, H. Huang, X. He, W. G. Tong, J. Ross, et al. 2003. Identification of the haematopoietic stem cell niche and control of the niche size. Nature 425, (6960) (Oct 23): 836-41.

54. Zhu, J., R. Garrett, Y. Jung, Y. Zhang, N. Kim, J. Wang, G. J. Joe, et al. 2007. Osteoblasts support B-lymphocyte commitment and differentiation from hematopoietic stem cells. Blood 109, (9) (May 1): 3706-12.

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Early studies

Some of the most compelling evidence for the absolute requirement of a competent microenvironment (ME) to support engraftment comes from early studies in mutant mice. In particular, unequivocal studies show that both the SL/SL, or “Steel” mutant mouse which dies of anemia spontaneously, and the more viable SL/SLd  mouse, which succumbs following very low doses of irradiation, cannot be rescued with an infusion of normal bone marrow cells [<38]. However, the animals could be rescued by transplantation of intact spleen tissue, which becomes the site of hematopoiesis [29]. These studies not only established the importance of the ME for stem cell engraftment, but also advanced the concept that at least some components of the ME cannot be transplanted by an intra-venous infusion of aspirated marrow cells. More recently the mutated gene product that gives rise to the Steel phenotype was shown to be kit ligand, also known as “stem cell factor” (SCF) expressed by stromal cells [12, 19].

Early seminal work by Wolf and Trentin illustrated that the ME is also critical for inducing lineage commitment. In these experiments, a section of bone with intact marrow was implanted within the spleen of a mouse prior to irradiation. After stem cell transplantation, the resulting spleen colonies that bridged the two different MEs were mixed such that there was mostly erythroid differentiation on the splenic side while myeloid differentiation predominated on the marrow side [51].

Although these early studies highlighted the important role of the ME in normal hematopoiesis, identifying the cells and secreted products that are involved in this process remains unfinished work. Specifically, the components that can support the expansion of stem cells without loss of their potential have not been defined. This may be due in part to the fact that more than one cell type and gene product participate in this regulation. In addition, even though the hematopoietic system is a liquid tissue, some ME components appear to be "fixed" stromal elements that contribute to the architecture and may have critical spatial relationships with each other that are difficult to reproduce in vitro.

For several decades in vitro studies of the ME have relied heavily on the Dexter long term culture (LTC) in which many cell types are evident [13]. LTC that are established from aspirated marrow and cultured under appropriate conditions will generate in 2-4 weeks an adherent layer that supports hematopoiesis for several months. Figure 1 shows an example of an LTC.

Figure1. Dexter Long-Term Culture (LTC): Panel A depicts a schematic representation of a typical LTC. A complex adherent layer composed of fibroblasts, endothelium, adipocytes, and macrophages which supports the production of hematopoietic cells. As hematopoietic cells mature, they are released from the adherent layer into the media. Panel B depicts a phase-contrast photomicrograph of a typical human LTC.  

Ramakrishnan-Figure1-A-B_01.png

The adherent stromal layer in the LTC consists of fibroblasts, endothelial cells, macrophages, adipocytes, osteoclasts, and extracellular matrix. LTC, if done properly, appear to approximate the in vivo ME since the functional ramifications of the Steel defect are apparent in cultures established from SL/SLd marrow [14]. However there are limitations to this system as myeloid cell production is generally favored over erythroid, and the ever-increasing proportion of monocyte-derived macrophages, is eventually associated with the termination of cell production [10].

Stromal component of the ME

There has been considerable debate concerning the origin of the ME stromal cells. Many reports have suggested that hematopoietic cells and stromal cells have a common precursor, and in agreement with this, several reports have claimed that stromal fibroblasts as well as hematopoietic cells are replaced by donor cells after hematopoietic stem cell transplantation [23, 43]. However, many of these studies typically looked at LTC established from sex mismatched transplants and detected donor cells using standard cytogenetics or fluorescent in-situ hybridization (FISH) for sex chromatin [23]. While it is clear that adherent cells of donor origin were detected in these LTC, these reports were flawed, as they did not properly account for the macrophage component of the adherent layer. This is an important consideration, since studies have shown that even after weekly passage of adherent cells, macrophages can represent a significant proportion of the cells in a 12 week LTC (see Table 1) [5].

Table 1: Percentage of NSE + cells in LTC of normal donors

Weeks in culture

2wk

4wk

6wk

8wk

10wk

12wk

Donor

1

15.5

17.7

44.0

28.0

23.0

8.2

2

13.9

24.9

17.4

5.8

2.1

1.9

3

32.8

22.3

29.6

31.7

29.5

22.0

4

25.1

21.4

27.6

41.1

16.5

3.3

NSE=nonspecific esterase; LTC=long term culture

LTCs were established from 4 normal donors and evaluated at various time points for the presence of monocytes/macrophages using NSE staining. As shown in the table, even after 12 weeks there can be a considerable proportion of macrophages in LTC.


Using histochemistry to identify and exclude the donor-derived macrophage component, our lab has determined that even after decades following successful stem cell transplantation, with 100% donor-derived hematopoietic cells, the stromal cells detected in an LTC from a transplanted patient remain of host origin, as predicted by the Steel mouse [5, 42].

The stromal component of the ME remains relatively constant and is quite resistant to currently used conditioning regimens. Therefore, after transplantation, the ME as a whole becomes chimeric; the stromal fibroblasts and endothelial cells remain host-derived while the macrophages are donor-derived [42, 48]. There are several possible explanations for this: First, unlike hematopoietic cells, the stromal fibroblasts and endothelial cells that are harvested from marrow and detectable in the transplanted product are not equipped with the surface molecules needed for trans-migrating the endothelium and homing to the ME. Pre-clinical animal studies suggest that when stromal cells are infused intravenously, they get trapped primarily in the lung and spleen (M. Mielcarek, personal communication). Second, because stromal cells are relatively resistant to chemotherapy and irradiation, the stromal cell compartment is not depleted by standard conditioning; as a result there may not be a demand for stromal cell replacement.

ME niches

After conditioning, the resident stromal cells express or secrete molecules that attract hematopoietic stem and progenitor cells, provide cell surface receptors which allow for the attachment of these cells, and secrete activities for the induction and support of various cell fates. Recently there has been considerable interest in identifying the specific cellular components that make up the stem cell niche, the specific ME unit where the hematopoietic stem cell resides and self-renews. Over the past two decades, the mouse model has been used to identify various chemokines, cell surface adhesion molecules, and cell types that contribute to this niche. There is general agreement that a number of signaling pathways including c-kit/SCF, CXCR4/CXCL12, VCAM1/VLA-4, Tie2/angipoietin, c-mpl/thrombopoietin, notch/jagged-1, and osteopontin play important roles in maintaining the stem cell niche [6, 30, 3, 16, 22, 32, 4, 27, 31, 44, 25, 35, 52, 9]. However, there is less agreement on the exact identity of the cells that make up the stem cell niche.

Compelling evidence from mouse studies suggest that the endosteal region is critical for the maintenance of hematopoietic stem and precursor cells. One prevalent model proposes that stem cell maintenance critically depends on N-cadherin-mediated binding to osteoblasts [9, 53]. This “osteoblastic niche” model was based on experiments which showed that N-cadherin-positive cells in the endosteal region are associated with cells expressing stem cell markers [9] . However, there are also reports that ablation of osteoblasts does not result in an immediate loss of stem cells, suggesting that while the stem cells may be spatially associated with osteoblasts, the osteoblasts may not be playing a significant role in their support [50, 54]. Furthermore, a recent study demonstrated that only CD146-positive mesenchymal progenitors and not osteoblasts can transfer a ME when transplanted into immunodeficient mice [39] .

Another equally compelling model proposes that hematopoietic stem cells localize close to marrow sinusoids. Evidence for this “endothelial niche” comes from experiments where cells expressing the SLAM family of surface receptors, which are highly expressed in hematopoietic stem cells, were detected in close association with vascular endothelium [24] . A third study suggested that reticular cells that express high levels of CXCL12/SDF1 (CAR cells) essentially define the stem cell niche, and these cells could be detected in both the perivascular and endosteal regions [45] .

The macrophage component of the ME

It is obvious that in vivo, stromal cells do not function in isolation, but do so in the context of other cells. One cell type that is clearly conspicuous both in vivo and in vitro (see Figure 2) is the monocyte-derived macrophage [34, 33].

Figure 2. Panel A shows a normal human bone marrow biopsy stained with macrophage-specific CD68 antibody. Panel B depicts a marrow LTC from an inducible transgenic mouse where GFP is under the control of the human CD68 promoter and is expressed exclusively in macrophages. As illustrated in the photomicrographs, CD68 positive macrophages have a significant presence in the marrow and have numerous cell processes which interact with many cell types, suggesting a crucial role in the regulation of hematopoiesis.

Ramakrishnan-Figure2-A-B.png

In vivo, monocytes are recruited from the circulation into tissues, where they can differentiate into macrophages and perform functions that are relevant to that particular tissue ME. It has long been known that macrophages play a critical role in hematopoiesis. Bessis first described the “nurse cell”, a specialized macrophage that is an important component of the erythroblast island, thought to provide structure and nutrients to developing erythroid cells [7, 11]. Osteoclasts, another specialized type of monocyte-derived macrophages, are critical in Ca+ homeostasis in the bone, which is also important for the maintenance of hematopoietic stem cells [1]. However, there is little known or even speculated about the role macrophages may play in the stem cell niche.

Available data suggest that stromal cells play a direct role in the stem cell niche by influencing cell fate decisions through the expression of proteins, such as SDF1 and Jagged, which bind progenitor surface determinants CXCR4 and Notch, respectively. While SDF1 facilitates homing and retention of cells in the marrow, Jagged transduces a signal through Notch that renders early progenitors resistant to differentiation signals [30, 3, 27, 9]. However, since the stromal cell compartment appears constant, with little turnover, it is unclear how interactions between stroma and stem cells can be modulated to allow for the dynamic range of cell production that is characteristic of hematopoiesis. In particular, the mechanisms that regulate gene expression in stromal cells have not been well defined. However, in theory the influence of a constant level of a stroma-expressed genes, e.g. Jagged, could be modulated to some extent indirectly, by down-regulating the level of its receptor, Notch, expressed by progenitors. In vitro studies using cloned human stromal cell lines suggest that this may occur.

Recent data from our laboratory indicates that functionally distinct stromal cell lines isolated from the same LTC can induce different gene expression profiles in monocytes. Specifically, the cloned stromal cell line HS27a, which expresses a number of genes associated with the stem cell niche including CXCL12, angiopoietin, Jagged 1, VCAM, induces the secretion of osteopontin by monocytes [37, 15, 20]. The osteopontin in turn down-regulates Notch expression on progenitors. It is reasonable to conclude that the reduced expression of Notch on progenitors can limit Jagged-Notch signaling, thereby making the progenitors more responsive to differentiation signals [20]. Interestingly, we also showed that the second functionally distinct stromal line, designated HS5, secretes activities that increase the production of matrix metalloproteinase 9 (MMP9) by monocytes, which would facilitate egress of the newly matured cells [21]. Since monocytes circulate and can be recruited from the blood, changes in their number and gene expression within an ME could significantly modulate stromal function.

ME and disease

Since stroma-monocyte interactions likely participate at many levels in the regulation of hematopoiesis, it would be reasonable to conclude that abnormal monocytes may contribute to the pathophysiology of hematologic malignancies. One example that we reported shows that monocytes from patients with myelodysplastic syndrome (MDS) fail to respond appropriately to stromal signals [21]. Specifically, clonally derived monocytes from patients with MDS fail to upregulate MMP-9 gene expression in response to stromal signals (see Figure 3).

Figure 3. Combined Immunohistochemistry for MMP-9 and FISH for chromosome 7. Monocytes from a healthy donor and from an MDS patient with monosomy seven were isolated and exposed to stromal signals. Cytospins were prepared and IHC for MMP-9 and FISH for chromosome 7 were performed. Panel A depicts monocytes from a healthy control which upregulate MMP-9 expression in response to stromal signals (green cytoplasmic staining) and have two copies of chromosome 7 detected by FISH (see white arrows). Panel B depicts clonal MDS monocytes identified by monosomy 7 which fail to upregulate MMP-9 expression in response to stromal signals.

Ramakrishnan-Figure3-A-B_01.png

The potential clinical relevance of this finding was suggested by a significant negative correlation between the proportion of abnormal monocytes and degree of marrow cellularity [21]. Given the role of MMP-9 in facilitating the egress of cells from marrow, it is reasonable to conclude that as the proportion of non-responsive monocytes increases, inducible levels of MMP-9 decline, resulting in hypercellularity. We also determined that the stromal signal from HS5 that induced MMP-9 is most likely MCP-1; however, we have not as yet identified the compromised monocyte signaling pathway that fails to respond [21]. Clearly a better delineation of signaling pathways that are responsible for normal responses between stromal cells and monocytes as well as the activities that trigger these pathways are needed.

These data suggest that macrophages can play a significant role in altering the hematopoietic ME to support the malignant/dysplastic process. This has clear implications for the success of hematopoietic stem cell transplantation, especially with the introduction of reduced intensity and so-called non-myeloablative conditioning regimens. Most of these conditioning regimens are of insufficient intensity to eliminate residual clonal host macrophages. Thus, when allogeneic stem cells are infused, they encounter a ME that remains dysregulated. This may explain the high rates of graft rejection and relapse seen in MDS patients after reduced intensity and non-myeloablative transplantation [21, 2, 28, 40, 26].

Finally, appreciating the critical role that monocyte-derived macrophages may play in the hematopoietic ME sheds new light on the “seed versus soil” debate as to the cause of hematopoietic dysplasias and aplasias, as well as graft failures. Clearly, the ME (soil) may appear abnormal, yet the defect may reside in the hematopoietic stem cell (seed)- derived monocyte, which upon entering the ME, fails to respond appropriately to stromal signals and thereby contributes to abnormal ME function. This would explain why “defective” MEs appear to be corrected by transplantation; the transplant is actually replacing the abnormal monocytes, not the stromal cells. This is not to suggest that primary stromal failures do not exist. Two examples of such failures have been observed following transplantation: one involves CMV infection and destruction of stromal cells [41, 47, 36, 46, 8], the other involves GVH-mediated anti-stroma activities [49, 18, 17]. In both cases the recipients could not be rescued by the infusion of additional stem cells, even after the anti-stroma mechanism had been eliminated.  

Summary

Over the past several decades, studies have revealed the hematopoietic ME to be a complex tissue that consists of both hematopoietic and non-hematopoietic cells, extra-cellular matrix, as well as soluble and membrane bound factors, all of which act in concert to support normal hematopoiesis.

• The ME consists of both hematopoietic stem cell derived and non-hematopoietic cells.

• A viable host ME is required for successful stem cell transplantation.

• Graft failure ensues when the ME is damaged/destroyed.

• After transplantation, the ME becomes chimeric. The stromal elements of the ME remain host-derived, whereas the monocyte/macrophage component is replaced by donor cells.

• Distinct niches or “ME units” exist that are responsible for the regulation of stem cell quiescence as well as differentiation.

• The hematopoietic stem cell derived monocyte/macrophage is a critical component of the ME.

• Stromal cells activate monocytes to assume different fates, which subsequently secrete activities that regulate hematopoiesis.

• In hematologic malignancies, clonally derived monocytes contribute to the dysregulation of the ME.

Data from our lab suggest that monocyte-derived macrophages play a significant role within the ME, and that abnormal monocytes derived from a clone of malignant hematopoietic cells, can compromise ME function. Importantly, following reduced intensity conditioning, recipient macrophages can be retained, and the dysregulated ME can persist and fail to support engraftment. Clearly, further investigation is necessary to completely understand how stroma and monocytes interact to regulate normal hematopoiesis, and how these pathways are altered by abnormal cells. As our knowledge increases we will be able to develop strategies to identify and correct abnormal signaling within the ME.

Acknowledgements

This work was supported in part by PHS grants DK082783, HL099993, DK056465 from the National Institutes of Health. We thank Bonnie Larson, Helen Crawford and Sue Carbonneau for assistance with the preparation and editing of the manuscript. The authors indicate no potential conflict of interest.

References

1. Adams, G. B., K. T. Chabner, I. R. Alley, D. P. Olson, Z. M. Szczepiorkowski, M. C. Poznansky, C. H. Kos, M. R. Pollak, E. M. Brown, and D. T. Scadden. 2006. Stem cell engraftment at the endosteal niche is specified by the calcium-sensing receptor. Nature 439, (7076) (Feb 2): 599-603. 

2. Alyea, E. P., H. T. Kim, V. Ho, C. Cutler, D. J. DeAngelo, R. Stone, J. Ritz, J. H. Antin, and R. J. Soiffer. 2006. Impact of conditioning regimen intensity on outcome of allogeneic hematopoietic cell transplantation for advanced acute myelogenous leukemia and myelodysplastic syndrome. Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation 12, (10) (Oct): 1047-55.

3. Ara, T., K. Tokoyoda, T. Sugiyama, T. Egawa, K. Kawabata, and T. Nagasawa. 2003. Long-term hematopoietic stem cells require stromal cell-derived factor-1 for colonizing bone marrow during ontogeny. Immunity 19, (2) (Aug): 257-67.

4. Arai, F., A. Hirao, M. Ohmura, H. Sato, S. Matsuoka, K. Takubo, K. Ito, G. Y. Koh, and T. Suda. 2004. Tie2/angiopoietin-1 signaling regulates hematopoietic stem cell quiescence in the bone marrow niche. Cell 118, (2) (Jul 23): 149-61.

5. Awaya, N., K. Rupert, E. Bryant, and B. Torok-Storb. 2002. Failure of adult marrow-derived stem cells to generate marrow stroma after successful hematopoietic stem cell transplantation. Experimental Hematology 30, (8) (Aug): 937-42.

6. Barker, J. E. 1994. Sl/Sld hematopoietic progenitors are deficient in situ. Experimental Hematology 22, (2) (Feb): 174-7.

7. Bessis, M. 1958. Erythroblastic island, functional unity of bone marrow. Revue d'Hematologie 13, (1) (Jan-Mar): 8-11.

8. Boeckh, M., C. Hoy, and B. Torok-Storb. 1998. Occult cytomegalovirus infection of marrow stroma. Clinical Infectious Diseases : An Official Publication of the Infectious Diseases Society of America 26, (1) (Jan): 209-10.

9. Calvi, L. M., G. B. Adams, K. W. Weibrecht, J. M. Weber, D. P. Olson, M. C. Knight, R. P. Martin, et al. 2003. Osteoblastic cells regulate the haematopoietic stem cell niche. Nature 425, (6960) (Oct 23): 841-6.

10. Chabannon, C., and B. Torok-Storb. 1992. Stem cell-stromal cell interactions. Current Topics in Microbiology and Immunology 177, : 123-36.

11. Chasis, J. A., and N. Mohandas. 2008. Erythroblastic islands: Niches for erythropoiesis. Blood 112, (3) (Aug 1): 470-8.

12. Copeland, N. G., D. J. Gilbert, B. C. Cho, P. J. Donovan, N. A. Jenkins, D. Cosman, D. Anderson, S. D. Lyman, and D. E. Williams. 1990. Mast cell growth factor maps near the steel locus on mouse chromosome 10 and is deleted in a number of steel alleles. Cell 63, (1) (Oct 5): 175-83.

13. Dexter, T. M., T. D. Allen, and L. G. Lajtha. 1977. Conditions controlling the proliferation of haemopoietic stem cells in vitro. Journal of Cellular Physiology 91, (3) (Jun): 335-44.

14. Dexter, T. M., and M. A. Moore. 1977. In vitro duplication and "cure" of haemopoietic defects in genetically anaemic mice. Nature 269, (5627) (Sep 29): 412-4.

15. Graf, L., M. Iwata, and B. Torok-Storb. 2002. Gene expression profiling of the functionally distinct human bone marrow stromal cell lines HS-5 and HS-27a. Blood 100, (4) (Aug 15): 1509-11.

16. Heissig, B., K. Hattori, S. Dias, M. Friedrich, B. Ferris, N. R. Hackett, R. G. Crystal, et al. 2002. Recruitment of stem and progenitor cells from the bone marrow niche requires MMP-9 mediated release of kit-ligand. Cell 109, (5) (May 31): 625-37.

17. Hirabayashi, N. 1981. Studies on graft versus host (GvH) reactions. I. impairment of hemopoietic stroma in mice suffering from GvH disease. Experimental Hematology 9, (2) (Feb): 101-10.

18. Hows, J. M. 1991. Mechanisms of graft failure after human marrow transplantation: A review. Immunology Letters 29, (1-2) (Jul): 77-80.

19. Huang, E., K. Nocka, D. R. Beier, T. Y. Chu, J. Buck, H. W. Lahm, D. Wellner, P. Leder, and P. Besmer. 1990. The hematopoietic growth factor KL is encoded by the sl locus and is the ligand of the c-kit receptor, the gene product of the W locus. Cell 63, (1) (Oct 5): 225-33.

20. Iwata, M., N. Awaya, L. Graf, C. Kahl, and B. Torok-Storb. 2004. Human marrow stromal cells activate monocytes to secrete osteopontin, which down-regulates Notch1 gene expression in CD34+ cells. Blood 103, (12) (Jun 15): 4496-502.

21. Iwata, M., M. Pillai, A. Ramakrishnan, R. C. Hackman, H. Joachim Deeg, G. Opdenakker, and B. Torok-Storb. 2007. Reduced expression of inducible gelatinase B/matrix metalloproteinase-9 in monocytes from patients with myelodysplastic syndrome: Correlation of inducible levels with the percentage of cytogenetically marked cells and with marrow cellularity. Blood 109, (1) (Jan 1): 85-92.

22. Jiang, Y., H. Bonig, T. Ulyanova, K. Chang, and T. Papayannopoulou. 2009. On the adaptation of endosteal stem cell niche function in response to stress. Blood 114, (18) (Oct 29): 3773-82.

23. Keating, A., J. W. Singer, P. D. Killen, G. E. Striker, A. C. Salo, J. Sanders, E. D. Thomas, D. Thorning, and P. J. Fialkow. 1982. Donor origin of the in vitro haematopoietic microenvironment after marrow transplantation in man. Nature 298, (5871) (Jul 15): 280-3.

24. Kiel, M. J., O. H. Yilmaz, T. Iwashita, O. H. Yilmaz, C. Terhorst, and S. J. Morrison. 2005. SLAM family receptors distinguish hematopoietic stem and progenitor cells and reveal endothelial niches for stem cells. Cell 121, (7) (Jul 1): 1109-21.

25. Kimura, S., A. W. Roberts, D. Metcalf, and W. S. Alexander. 1998. Hematopoietic stem cell deficiencies in mice lacking c-mpl, the receptor for thrombopoietin. Proceedings of the National Academy of Sciences of the United States of America 95, (3) (Feb 3): 1195-200.

26. Laport, G. G., B. M. Sandmaier, B. E. Storer, B. L. Scott, M. J. Stuart, T. Lange, M. B. Maris, et al. 2008. Reduced-intensity conditioning followed by allogeneic hematopoietic cell transplantation for adult patients with myelodysplastic syndrome and myeloproliferative disorders. Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation 14, (2) (Feb): 246-55.

27. Li, L., L. A. Milner, Y. Deng, M. Iwata, A. Banta, L. Graf, S. Marcovina, et al. 1998. The human homolog of rat Jagged1 expressed by marrow stroma inhibits differentiation of 32D cells through interaction with Notch1. Immunity 8, (1) (Jan): 43-55.

28. Martino, R., S. Iacobelli, R. Brand, T. Jansen, A. van Biezen, J. Finke, A. Bacigalupo, et al. 2006. Retrospective comparison of reduced-intensity conditioning and conventional high-dose conditioning for allogeneic hematopoietic stem cell transplantation using HLA-identical sibling donors in myelodysplastic syndromes. Blood 108, (3) (Aug 1): 836-46.

29. McCulloch, E. A., L. Siminovitch, J. E. Till, E. S. Russell, and S. E. Bernstein. 1965. The cellular basis of the genetically determined hemopoietic defect in anemic mice of genotype sl-sld. Blood 26, (4) (Oct): 399-410.

30. Nagasawa, T. 2000. A chemokine, SDF-1/PBSF, and its receptor, CXC chemokine receptor 4, as mediators of hematopoiesis. International Journal of Hematology 72, (4) (Dec): 408-11.

31. Nilsson, S. K., H. M. Johnston, G. A. Whitty, B. Williams, R. J. Webb, D. T. Denhardt, I. Bertoncello, L. J. Bendall, P. J. Simmons, and D. N. Haylock. 2005. Osteopontin, a key component of the hematopoietic stem cell niche and regulator of primitive hematopoietic progenitor cells. Blood 106, (4) (Aug 15): 1232-9.

32. Papayannopoulou, T., C. Craddock, B. Nakamoto, G. V. Priestley, and N. S. Wolf. 1995. The VLA4/VCAM-1 adhesion pathway defines contrasting mechanisms of lodgement of transplanted murine hemopoietic progenitors between bone marrow and spleen. Proceedings of the National Academy of Sciences of the United States of America 92, (21) (Oct 10): 9647-51.

33. Pillai, M. M., B. Hayes, and B. Torok-Storb. 2009. Inducible transgenes under the control of the hCD68 promoter identifies mouse macrophages with a distribution that differs from the F4/80 - and CSF-1R-expressing populations. Experimental Hematology 37, (12) (Dec): 1387-92.

34. Pillai, M. M., M. Iwata, N. Awaya, L. Graf, and B. Torok-Storb. 2006. Monocyte-derived CXCL7 peptides in the marrow microenvironment. Blood 107, (9) (May 1): 3520-6.

35. Qian, H., N. Buza-Vidas, C. D. Hyland, C. T. Jensen, J. Antonchuk, R. Mansson, L. A. Thoren, M. Ekblom, W. S. Alexander, and S. E. Jacobsen. 2007. Critical role of thrombopoietin in maintaining adult quiescent hematopoietic stem cells. Cell Stem Cell 1, (6) (Dec 13): 671-84.

36. Randolph-Habecker, J., M. Iwata, and B. Torok-Storb. 2002. Cytomegalovirus mediated myelosuppression. Journal of Clinical Virology : The Official Publication of the Pan American Society for Clinical Virology 25 Suppl 2, (Aug): S51-6.

37. Roecklein, B. A., and B. Torok-Storb. 1995. Functionally distinct human marrow stromal cell lines immortalized by transduction with the human papilloma virus E6/E7 genes. Blood 85, (4) (Feb 15): 997-1005.

38. Russell, E. S. 1979. Hereditary anemias of the mouse: A review for geneticists. Advances in Genetics 20, : 357-459.

39. Sacchetti, B., A. Funari, S. Michienzi, S. Di Cesare, S. Piersanti, I. Saggio, E. Tagliafico, et al. 2007. Self-renewing osteoprogenitors in bone marrow sinusoids can organize a hematopoietic microenvironment. Cell 131, (2) (Oct 19): 324-36.

40. Scott, B. L., B. M. Sandmaier, B. Storer, M. B. Maris, M. L. Sorror, D. G. Maloney, T. R. Chauncey, R. Storb, and H. J. Deeg. 2006. Myeloablative vs nonmyeloablative allogeneic transplantation for patients with myelodysplastic syndrome or acute myelogenous leukemia with multilineage dysplasia: A retrospective analysis. Leukemia : Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K 20, (1) (Jan): 128-35.

41. Simmons, P., K. Kaushansky, and B. Torok-Storb. 1990. Mechanisms of cytomegalovirus-mediated myelosuppression: Perturbation of stromal cell function versus direct infection of myeloid cells. Proceedings of the National Academy of Sciences of the United States of America 87, (4) (Feb): 1386-90.

42. Simmons, P. J., D. Przepiorka, E. D. Thomas, and B. Torok-Storb. 1987. Host origin of marrow stromal cells following allogeneic bone marrow transplantation. Nature 328, (6129) (Jul 30-Aug 5): 429-32.

43. Singer, J. W., A. Keating, J. Cuttner, A. M. Gown, R. Jacobson, P. D. Killen, J. W. Moohr, V. Najfeld, J. Powell, and J. Sanders. 1984. Evidence for a stem cell common to hematopoiesis and its in vitro microenvironment: Studies of patients with clonal hematopoietic neoplasia. Leukemia Research 8, (4): 535-45.

44. Stier, S., Y. Ko, R. Forkert, C. Lutz, T. Neuhaus, E. Grunewald, T. Cheng, et al. 2005. Osteopontin is a hematopoietic stem cell niche component that negatively regulates stem cell pool size. The Journal of Experimental Medicine 201, (11) (Jun 6): 1781-91.

45. Sugiyama, T., H. Kohara, M. Noda, and T. Nagasawa. 2006. Maintenance of the hematopoietic stem cell pool by CXCL12-CXCR4 chemokine signaling in bone marrow stromal cell niches. Immunity 25, (6) (Dec): 977-88.

46. Torok-Storb, B., M. Boeckh, C. Hoy, W. Leisenring, D. Myerson, and T. Gooley. 1997. Association of specific cytomegalovirus genotypes with death from myelosuppression after marrow transplantation. Blood 90, (5) (Sep 1): 2097-102.

47. Torok-Storb, B., L. Bolles, M. Iwata, K. Doney, G. E. Sale, T. A. Gooley, and R. Storb. 2001. Increased prevalence of CMV gB3 in marrow of patients with aplastic anemia. Blood 98, (3) (Aug 1): 891-2.

48. Torok-Storb, B., and L. Holmberg. 1994. Role of marrow microenvironment in engraftment and maintenance of allogeneic hematopoietic stem cells. Bone Marrow Transplantation 14 Suppl 4, : S71-3.

49. Torok-Storb, B., P. Simmons, and D. Przepiorka. 1987. Impairment of hemopoiesis in human allografts. Transplantation Proceedings 19, (6 Suppl 7) (Dec): 33-7.

50. Visnjic, D., Z. Kalajzic, D. W. Rowe, V. Katavic, J. Lorenzo, and H. L. Aguila. 2004. Hematopoiesis is severely altered in mice with an induced osteoblast deficiency. Blood 103, (9) (May 1): 3258-64.

51. Wolf, N. S., and J. J. Trentin. 1968. Hemopoietic colony studies. V. effect of hemopoietic organ stroma on differentiation of pluripotent stem cells. The Journal of Experimental Medicine 127, (1) (Jan 1): 205-14.

52. Yoshihara, H., F. Arai, K. Hosokawa, T. Hagiwara, K. Takubo, Y. Nakamura, Y. Gomei, et al. 2007. Thrombopoietin/MPL signaling regulates hematopoietic stem cell quiescence and interaction with the osteoblastic niche. Cell Stem Cell 1, (6) (Dec 13): 685-97.

53. Zhang, J., C. Niu, L. Ye, H. Huang, X. He, W. G. Tong, J. Ross, et al. 2003. Identification of the haematopoietic stem cell niche and control of the niche size. Nature 425, (6960) (Oct 23): 836-41.

54. Zhu, J., R. Garrett, Y. Jung, Y. Zhang, N. Kim, J. Wang, G. J. Joe, et al. 2007. Osteoblasts support B-lymphocyte commitment and differentiation from hematopoietic stem cells. Blood 109, (9) (May 1): 3706-12.

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Аравинд Рамакришнан, Биверли Дж.Торок-Шторб

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Успешность трансплантации гемопоэтических стволовых клеток зависит от приживления плюрипотентных гемопоэтических стволовых клеток (ГСК) и регулируемой пролиферации и созревания коммитированных родоначальных клеток. В целом, существует согласие в том, что эти процессы не могут возникать без соответствующей среды, которую обеспечивает компетентное микроокружение костного мозга. Оно состоит как из негемопоэтических клеток, так и клеток гемопоэтического происхождения, и  впоследствии, после аллогенной трансплантации ГСК, становится химерным,  содержащим стромальные клетки реципиента и макрофаги донора.

Ключевые слова

гемопоэтическое микроокружение, стромальные клетки, трансплантация, ниша стволовых клеток, единицы микроокружения, моноцит/макрофаг

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Aravind Ramakrishnan (MD), Beverly J. Torok-Storb (Ph.D.)

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Fred Hutchinson Cancer Research Center and the University of Washington, Seattle, USA

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The success of hematopoietic stem cell transplantation depends on the engraftment of pluripotent hematopoietic stem cells and the regulated proliferation and maturation of committed progenitor cells. It is generally agreed that these processes cannot occur without an appropriate milieu provided by a competent marrow microenvironment (ME). The ME is composed of both non-hematopoietic and hematopoietic stem cell derived cells and consequently is chimeric following allogeneic stem cell transplantation, containing recipient stromal cells and donor macrophages.

Keywords

hematopoietic microenvironment, stromal cell, transplantation, stem cell niche, ME units, monocyte/macrophage

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Aravind Ramakrishnan (MD), Beverly J. Torok-Storb (Ph.D.)

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Aravind Ramakrishnan (MD), Beverly J. Torok-Storb (Ph.D.)

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The success of hematopoietic stem cell transplantation depends on the engraftment of pluripotent hematopoietic stem cells and the regulated proliferation and maturation of committed progenitor cells. It is generally agreed that these processes cannot occur without an appropriate milieu provided by a competent marrow microenvironment (ME). The ME is composed of both non-hematopoietic and hematopoietic stem cell derived cells and consequently is chimeric following allogeneic stem cell transplantation, containing recipient stromal cells and donor macrophages.

Keywords

hematopoietic microenvironment, stromal cell, transplantation, stem cell niche, ME units, monocyte/macrophage

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The success of hematopoietic stem cell transplantation depends on the engraftment of pluripotent hematopoietic stem cells and the regulated proliferation and maturation of committed progenitor cells. It is generally agreed that these processes cannot occur without an appropriate milieu provided by a competent marrow microenvironment (ME). The ME is composed of both non-hematopoietic and hematopoietic stem cell derived cells and consequently is chimeric following allogeneic stem cell transplantation, containing recipient stromal cells and donor macrophages.

Keywords

hematopoietic microenvironment, stromal cell, transplantation, stem cell niche, ME units, monocyte/macrophage

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Fred Hutchinson Cancer Research Center and the University of Washington, Seattle, USA

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Fred Hutchinson Cancer Research Center and the University of Washington, Seattle, USA

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Аравинд Рамакришнан, Биверли Дж.Торок-Шторб

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Аравинд Рамакришнан, Биверли Дж.Торок-Шторб

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["PROPERTY_VALUE_ID"]=> string(5) "18960" ["VALUE"]=> array(2) { ["TEXT"]=> string(1534) "<p class="bodytext"><span lang="RU">Успешность трансплантации гемопоэтических стволовых клеток зависит от приживления плюрипотентных гемопоэтических стволовых клеток (ГСК) и регулируемой пролиферации и созревания коммитированных родоначальных клеток. В целом, существует согласие в том, что эти процессы не могут возникать без соответствующей среды, которую обеспечивает компетентное микроокружение костного мозга. Оно состоит как из негемопоэтических клеток, так и клеток гемопоэтического происхождения, и  впоследствии, после аллогенной трансплантации ГСК, становится химерным,  содержащим стромальные клетки реципиента и макрофаги донора.</p> <h3>Ключевые слова</h3> <p> гемопоэтическое микроокружение, стромальные клетки, трансплантация, ниша стволовых клеток, единицы микроокружения, моноцит/макрофаг</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(1472) "

Успешность трансплантации гемопоэтических стволовых клеток зависит от приживления плюрипотентных гемопоэтических стволовых клеток (ГСК) и регулируемой пролиферации и созревания коммитированных родоначальных клеток. В целом, существует согласие в том, что эти процессы не могут возникать без соответствующей среды, которую обеспечивает компетентное микроокружение костного мозга. Оно состоит как из негемопоэтических клеток, так и клеток гемопоэтического происхождения, и  впоследствии, после аллогенной трансплантации ГСК, становится химерным,  содержащим стромальные клетки реципиента и макрофаги донора.

Ключевые слова

гемопоэтическое микроокружение, стромальные клетки, трансплантация, ниша стволовых клеток, единицы микроокружения, моноцит/макрофаг

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(29) "Описание/Резюме" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(1472) "

Успешность трансплантации гемопоэтических стволовых клеток зависит от приживления плюрипотентных гемопоэтических стволовых клеток (ГСК) и регулируемой пролиферации и созревания коммитированных родоначальных клеток. В целом, существует согласие в том, что эти процессы не могут возникать без соответствующей среды, которую обеспечивает компетентное микроокружение костного мозга. Оно состоит как из негемопоэтических клеток, так и клеток гемопоэтического происхождения, и  впоследствии, после аллогенной трансплантации ГСК, становится химерным,  содержащим стромальные клетки реципиента и макрофаги донора.

Ключевые слова

гемопоэтическое микроокружение, стромальные клетки, трансплантация, ниша стволовых клеток, единицы микроокружения, моноцит/макрофаг

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Since the first related donor umbilical cord blood (UCB) transplant in 1988 for a patient with Fanconi anemia, and the first successful unrelated donor UCB transplant in 1993, an estimated 15,000 UCB transplantations have been performed [23]. Today, this approach is being applied to patients of all ages with a variety of diseases, including nonmalignant hematologic disorders and congenital metabolic disorders, as well as hematologic malignancies [2, 15, 16]. Between 2004 and 2007, the Center for International Blood and Marrow Transplant Research (CIBMTR) reported that for patients under age 20 years, 40% of unrelated donor stem cell grafts were collected from the bone marrow, 40% from umbilical cord blood, and 20% from peripheral blood. In contrast, for patients over age 20 years, only 7% of unrelated stem cell grafts were derived from UCB during the same time period. There are a number of factors contributing to increased usage of UCB stem cells. The most important factor is that results with UCB have improved progressively. 

Furthermore, the cord blood banking infrastructure has improved, allowing for increased availability of high quality unrelated UCB. Compared to stem cell grafts obtained from unrelated adult donors, UCB stem cells can be procured more quickly, without risk or inconvenience to the donor. Finally, there is the possibility that contained within the UCB are totipotential stem cells with regenerative potential for non-hematopoietic tissues [23, 38]. This is particularly relevant when treating inborn errors of metabolism, which can result in damage to neuronal tissue.

This review will focus on the use of UCB transplantation to treat inherited or acquired hematopoietic disorders. Included are inborn errors of metabolism, in which promising outcomes have been demonstrated with allogeneic stem cell transplantation. As a group, bone marrow failure and congenital immunodeficiency disorders, as well as inborn errors of metabolism are rare. As a result, the worldwide experience with UCB transplantation is limited. Despite this, it is clear that UCB has proven to be a viable and effective stem cell source that will continue to play a major role in allogeneic stem cell therapy.

Use of UCB stem cell grafts for allogeneic transplantation; historical perspective

The 1988 report of successful engraftment and outcome of a patient with Fanconi anemia who was transplanted with cord blood from a new-born HLA-identical sibling, generated considerable interest in further development of this novel transplant approach [15]. From 1988 until 1993, UCB transplants were limited to grafts collected from HLA-identical related donors. This early experience was important in that it confirmed the pre-clinical observation that contained within the UCB graft were true pluripotent long-term repopulating cells. What also became apparent from the early experience was that the graft vs host disease (GvHD)-inducing potential of HLA-matched related cord blood T-cells was less than been observed with similarly matched bone marrow grafts [37,47]. The encouraging results in matched related donor cord blood transplantation prompted Kurtzberg and colleagues to perform the first mismatched cord blood transplantation [24]. This series of three patients and the larger series later reported by Wagner and colleagues were notable for the engraftment potential and low GvHD potential of these unrelated, cryopreserved cells [24, 48]. Due to the limited number of stem cells contained within the cord blood graft, early experience was restricted primarily to children where the UCB cell dose relative to body weight was more favorable.  However, as promising outcome data began to emerge from large UCB bank and international registry studies, the experience in adult patients began to grow.
 
In recent years, great strides have been made in identifying factors predictive of successful outcome.  The two most important characteristics of an UCB graft are the cellular content and donor-recipient HLA-matching. It is generally accepted that a total nucleated cell dose under 2 x 107/kg recipient body weight results in an unacceptably high rate of graft failure. CD34+ cell content and colony forming unit potential of the donor graft have also proven to be predictive of donor cell engraftment [25]. However, practical issues surrounding accurate characterization of prospective units for their progenitor cell content remain to be worked out. For example, while CD34+ cell content is often enumerated by individual cord blood banks prior to cryopreservation, there remains considerable concern that inter-bank comparison of these values is not valid due to subtle differences in CD34+ quantification techniques. Therefore, choosing cord blood units based on CD34+ cell content as measured by different banks is not yet realistic.

As the outcome data are presented in this review, it is important to remember that earlier results were significantly compromised by lack of a clear understanding of the many factors that contribute to successful UCB transplantation. While advances in supportive care, patient selection, and transplantation techniques have improved outcomes of allogeneic stem cell transplantation as a whole, the advances are more pronounced with UCB transplantation.

Umbilical cord blood transplantation for inherited immunodeficiency disorders

Lymphoid immunodeficiency disorders

Severe Combined Immunodeficiency Disorders (SCID)

Included in this discussion of UCB transplantation for SCID will be the classical form of SCID characterized by an X-linked mutation of the common gamma-chain, adenosine deaminase deficient SCID, autosomal recessive SCID, and Omenn syndrome. Data on cord blood transplantation for treatment of these disorders remain scant. The largest single center series comes from Diaz de Heredia and colleagues who report the outcomes of 12 SCID patients (median age 11.6 months) transplanted with UCB at three Spanish hospitals between 1996 and 2002 [10]. All but 2 patients received a high dose busulfan/cyclophosphamide preparative regimen. Two patients received a reduced intensity melphalan/fludarabine preparative regimen. All patients achieved donor stem cell engraftment. The 5-year overall survival (which includes 3 additional patients with non-SCID immunodeficiency disorders) was 73%, with 3 patients dying from graft versus host disease, and one from progressive interstitial lung disease. Importantly, all surviving children had normal age-adjusted levels of T-cells, B-cells and NK cells by 24 months following transplantation.  In contrast to what has been observed following stem cell transplantation without conditioning, quantitative and qualitative T-cell and B-cell functions are durable following UCB transplantation using high intensity transplant conditioning. 

The outcomes of 16 children transplanted with UCB for treatment of SCID are reported in three separate retrospective reports [5, 22, 45]. One of 16 failed to engraft, and 13 of 16 are long-term survivors with normalization of immune function.

Wiscott-Aldrich Syndrome

Wiscott-Aldrich Syndrome (WAS) is due to an X-linked mutation in the WASP gene, with an incidence of 4 per million live male births. The role of stem cell transplantation for treatment of this disorder has been firmly established. The initial reports demonstrated cure rates as high as 89% when matched unrelated donor transplantation is performed before the age of 5 years [13]. The published experience of UCB transplantation for WAS has grown significantly in the past few years. In 2003, Knutsen and colleagues were among the first to demonstrate feasibility of UCB transplantation for WAS with successful treatment of 3 children age 2–8 yrs [21]. More recently, the Duke University group reported the outcome of 15 patients transplanted with UCB between 1998 and 2007 [42]. All patients achieved donor cell engraftment following a conditioning regimen consisting of busulfan, cyclophosphamide, +/- ATG. Six of 15 patients died from transplant-related complications, resulting in an overall survival of 60%. Chronic GvHD was observed in 11 of 12 surviving patients (limited in 10, extensive in 1). The authors found this incidence of chronic GvHD to be in excess of what has been observed in other patients with congenital immunodeficiency disorders transplanted with UCB. They postulate a potential link to pre-existing eczema, which is commonly seen in patients with WAS. 

A recent review of registry data collected by the CIBMTR (unpublished) compared 113 WAS recipients of unrelated bone marrow with 65 WAS recipients of unrelated cord blood transplants carried out between 1995 and 2005. This analysis showed equivalent 3-year survival for recipients age <5 years at the time of transplantation (73% vs 75%). Taken together, these data support the use of UCB for stem cell transplantation of WAS.

The CIBMTR has received registration reports of UCB transplantation for other rare lymphoid immunodeficiency disorders. These include Cartilage Hair Hypoplasia, X-linked Lymphoproliferative syndrome, Common Variable Immunodeficiency, Reticular dysgenesis and Bare Lymphocyte syndrome. Unfortunately, the outcomes of these transplants are not available for review.

Myeloid immunodeficiency disorders

Chronic Granulomatous Disease (CGD)

CGD is a congenital neutrophil disorder that is a consequence of an X-linked or autosomal recessive mutation in the NADPH-oxidase complex. The curative potential of stem cell transplantation has been clearly demonstrated [17, 40]. There are 8 reported cases of UCB transplantation for CGD [4, 31, 32, 35, 43]. Reduced intensity conditioning was successfully used in the oldest patient of this compilation of reports (age 20 yrs). The others were conditioned with high intensity regimen; 2 experienced primary graft failure. Six of 8 patients are long-term survivors.

Leukocyte adhesion deficiency is another life-threatening myeloid immune disorder. To date, there are no published reports of UCB transplantation for treatment of this disorder.

Immune/Inflammatory disorders

Hemophagocytic Lymphohistiocytosis (HLH)

The familial or inherited form of HLH as well as the EBV-associated HLH will be considered together in this review. In general, the outcomes of allogeneic stem cell transplantation following high dose conditioning, regardless of the stem cell source, are not as favorable as that observed for other inherited immunodeficiencies. This has prompted a movement toward the use of reduced intensity preparative regimens for this disorder [8]. Ohga and colleagues recently reviewed data from the Japanese Society of Pediatric Hematology [34]. Outcomes of 57 patients (familial HLA-43, EBV-associated HLH-14), 21 of whom received UCB grafts, are reported. The overall survival by log-rank analysis of the UCB transplant recipients was 66%, which did not differ from recipients of related or unrelated bone marrow or peripheral blood stem cell transplantation.

Chediak-Higashi

The team from the University of California at Los Angeles has reported in abstract form successful UCB transplantation of 3 patients with Chediak-Higashi. Limited information is available on long-term outcome [50].

Umbilical cord blood transplantation for inborn errors of metabolism

Current data supports the use of allogeneic stem cell transplantation for the treatment of lysosomal and peroxisomal storage disorders. Enzyme replacement therapies are currently available, but questions remain as to the long-term efficacy of these therapies and their ability to positively impact the natural history of the disorder. Stem cell transplantation provides the opportunity for enzyme replacement via “cross correction” of enzyme-deficient cells by neighboring donor derived, enzyme-replete cells [9, 20]. Furthermore, stem cell transplantation (and UCB transplantation in particular) provides the potential for repair of damaged non-hematopoietic tissue such as microglial cells in the brain and Kupffer cells in the liver via differentiation of tissue-specific progenitor cells or transdifferentiation.

Lysosomal and peroxisomal storage diseases affect multiple organ systems, with the central and peripheral nervous system particularly impacted. Depending on the extent of damage at the time of stem cell transplantation, the impact of allogeneic SCT may require extensive and sophisticated neurocognitive testing to objectively measure response. It is clear that many of the neurocognitive deficits incurred by the patients will not be corrected by stem cell transplantation. However, a plateau in survival appears to be evident from a large, single center series of UCB transplants for inherited metabolic disorders [36, Fig. 3]. Longer follow-up and more experience will be required to optimize the timing and impact of this treatment modality.

Krabbe’s disease

The potential for UCB transplantation to favorably impact on the natural history of inborn errors of metabolism was elegantly demonstrated by Escolar and colleagues in patients with Krabbe’s disease [11]. Children born with Krabbe’s disease are deficient of the lysosomal enzyme galactocerebrosidase. As a result, the children experience rapidly progressive neurologic deterioration and death at an early age. Escolar et al found that when children undergo UCB transplantation prior to the onset of symptoms, most will go on to have age-appropriate cognitive and motor function, along with 100% overall survival. Those who underwent UCB transplantation after the onset of symptoms showed little improvement in neurologic function and had an overall survival of only 43%. The study demonstrates the importance of early recognition of inborn errors along with early intervention with stem cell transplantation before irreversible damage occurs.

Hurler’s syndrome

Hurler’s syndrome is an autosomal recessive mucopolysaccharidosis caused by deficiency of alpha-L-iduronidase. Multiple organs, including the central nervous system, heart, bone, eyes, and liver are affected.  Although enzyme replacement therapy has been available since 2003, due to poor CNS penetration, it does not completely prevent neurologic deterioration. Therefore, allogeneic stem cell transplantation remains the treatment of choice. Both European and North American registry data suggest that over 500 patients with Hurler’s syndrome have been treated with allogeneic stem cell transplantation. Staba and colleagues reported the Duke University experience with UCB transplantation for 20 children with Hurler’s syndrome [41]. The patients were prepared with high dose conditioning and received UCB units from mismatched unrelated donors. The median cell dose was 8.8x107 nucleated cells/kg. Only one patient failed to engraft with donor cells. Long-term survival was achieved in 17 of 20 patients with all surviving patients having normal alpha-L-iduronidase activity. Many of the surviving children continue to have neurocognitive impairment. Despite this, 81% of the surviving school-age children attend school in age-appropriate classrooms [36]. However, many Hurler’s patients continue to have problems with skeletal deformities that require corrective surgery.

Boelens and colleagues reviewed data from the European Blood and Marrow Transplant Registry regarding outcome of patients with Hurler’s syndrome undergoing allogeneic transplantation [6]. While overall survival was not affected by cell source selection, the data suggested that UCB grafts significantly improved the chance for achieving full donor chimerism and, as a result, normal circulating enzyme levels compared to patients receiving peripheral blood or bone marrow grafts.

X-linked Adrenoleukodystrophy (X-ALD)

X-ALD is a peroxisomal disorder stemming from a defective ABCD1 gene. This results in accumulation of long chain fatty acids, which has devastating neurologic consequences. The therapeutic potential of UCB transplantation was best described by Beam and colleagues who report the outcomes of 12 boys, 3 of whom were transplanted early in life, before symptoms of the disease developed [3]. All patients received high dose conditioning with busulfan, cyclophosphamide, and anti-thymocyte globulin followed by partially matched unrelated UCB transplantation. Extensive baseline neurophysiologic, neuroimaging and neurodevelopmental testing was performed prior to transplantation and followed serially after the transplantation. One patient died early from toxicity and another experienced primary graft failure, but was rescued with a second transplant. Overall survival at 6 months was 67%. The authors found that the degree of pre-transplant ALD-associated brain involvement (Loes score) was a strong predictor of post-transplantation cognitive and motor outcome. Many of the patients with severe neurocognitive impairment at the time of transplantation experienced disease progression despite transplantation. In contrast, the 3 boys who were asymptomatic at the time of transplant had excellent outcomes.

Composite reports of UCB transplantation for rare inborn errors

Disease-specific reports of allogeneic transplantation for rare inborn errors of metabolism lack the detail or sample size to draw definitive conclusions about outcomes [30, 36, 44]. Table 1 lists the disorders that have been treated with UCB transplantation. Questions remain as to the appropriate timing for the transplant as well as the therapeutic benefit. It is for this reason that use of allogeneic SCT for treatment of many of these disorders remains investigational. 

Table 1. Inborn metabolism errors treated with umbilical cord blood transplantation

Hurler syndrome

Krabbe's disease

Sanfilippo syndrome

Metachromatic leukodystrophy

Adrenoleukodystrophy

Tay Sachs disease

Hunter syndrome

Lesch-Nyhan disease

Sandhoff disease

Hurler Scheie

Neimann-Pick

Alpha mannosidosis

GM1 gangliosidosis

I-cell disease

Maroteaux-Lamy syndrome

Pelizaeus-Merzbacher disease

Fucosidosis

Wolman disease (Acid Lipase Deficiency)

 
The common theme among all the reports is that the earlier the transplant is done, the better the outcome. In the largest of these composite reports from the Duke University group, 159 children representing 16 different inborn errors of metabolism were transplanted following high dose conditioning (busulfan, cyclophosphamide, and equine anti-thymocyte globulin) over a 12-year period, ending in 2007. The probability of engraftment, acute and chronic GvHD, overall survival and factors influencing survival has been shown [36, Fig. 1]. Of note, the 1 and 5 year overall survivals for the most common disorders treated on the study (Hurler, Hunter, and Sanfilippo syndrome, metachromatic leukodystrophy, and adrenoleukodystrophy) were all similar. This suggests that timing of the transplant, not the underlying disease, is most important in predicting outcome.

Umbilical cord blood transplantation for hemoglobinopathies

Related UCB transplantation for β-thalassemia and sickle cell disease

Unlike the situation with inborn errors of metabolism, there is an established role for allogeneic stem cell transplantation for the treatment of β-thalassemia and sickle cell disease [27, 28, 49]. The published experience of UCB transplantation for β-thalassemia remains quite limited [12, 26]. The largest report comes from the Eurocord registry data describing the outcome of 33 β-thalassemia patients transplanted with matched related UCB grafts [26]. All patients had a low disease severity (Pesaro 1 in 20 pts, Pesaro 2 in 13 pts). All patients received high dose e conditioning and GvHD prophylaxis with cyclosporine alone or combined with methotrexate. Seven of 33 patients experienced graft failure, but were rescued with either autologous stem cells or bone marrow from the original matched sibling cord blood donor at a later date.  With a median follow-up of 24 months, all 33 patients were alive and well, but 4 retained the β-thalassemia phenotype.

The Locatelli report also included outcomes of 11 patients with sickle cell disease transplanted with UCB from related donors matched 6/6 (9 pts) or 5/6 (2 pts) [26]. The conditioning and GvHD prophylaxis regimens were similar to those used for the β-thalassemia patients. Primary engraftment was achieved in 10 of 11 patients, and all 11 patients are alive and well (1 with sickle cell disease) with a median follow-up of 24 months.

Unrelated UCB transplantation for β-thalassemia and sickle cell disease

There has yet to be enough published experience with unrelated UCB transplantation for β-thalassemia or sickle cell disease to fully assess the risk versus benefit considerations. The relative dearth of reports in the literature likely portrays unresolved challenges that remain with this mode of therapy. The few available reports suggest feasibility of unrelated UCB transplantation for hemoglobinopathies [1, 18, 19, 46]. However, it appears that establishment of stable donor engraftment is more challenging in this population of patients [1]. This may be related to the chemotherapy naïve status of the patients combined with a highly proliferative, cellular bone marrow milieu.

Umbilical cord blood transplantation for bone marrow failure disorders

The published experience with UCB for treatment of acquired bone marrow failure disorders is outlined in Table 2. Most investigators have relegated UCB transplantation to a treatment of last resort. Thus, those transplanted with UCB represent an extremely high-risk subset of patients who have failed prior therapy. Interpretation of the data is further compromised by the heterogeneous transplantation techniques. The data suggests that UCB transplantation for severe aplastic anemia is feasible. Larger studies will be needed to garner a better understanding of the relative risk of graft failure compared to patients with other non-malignant or malignant disorders.

Table 2. Umbilical cord blood transplantation for treatment of severe aplastic anemia and paroxysmal nocturnal hemoglobinurea

Reference

Disorder-
number
of patients

Median
Age
(yrs)

Preparative
Regimen

Median
Cryopreserved
Cell Dose
(x 107/kg)

Percent
donor
engraftment
(%)

Outcome
(%)

(Mao,
et al 2005)

AA-9

25

Cy/ATG

2.19 (1.6-10.7)*

78

EFS-78

OS-78

(Ohga,
et al 2006)

AA-1

11

TBI-5Gy
Melphalan 120mg/m2
Fludarabine 120mg/m2

3.9

100

EFS-100

OS-100

(Chan,
et al 2008)

AA-9

9

Cy/ATG-2
Cy/Flu/ATG-7

5.4 (3.5-20)

67

EFS-67

OS-78

 

(Yoshimi,
et al 2008)

AA-31

28

TBI (4-5Gy)/Flu/Mel-12
TBI (4-5Gy)/Flu/Cy-5
TBI (10-12Gy)/Cy/ATG-3
Other-11

NA

55

OS (2yrs)-41

(Ruggeri,
et al 2008)

SAA-4

PNH-1

19

Bu/Cy/Flu-3
Flu/Cy-1
Flu/Cy/TBI(2Gy)

4.7 (2.9-9.7)

(Dual Cord Blood Graft)

80

EFS-60

OS-80

*Post-thaw cell dose (cryopreserved cell dose not reported)

References

1. Adamkiewicz, T.V., Mehta, P.S., Boyer, M.W., Kedar, A., Olson, T.A., Olson, E., Chiang, K.Y., Maurer, D., Mogul, M.J., Wingard, J.R. & Yeager, A.M. (2004) Transplantation of unrelated placental blood cells in children with high-risk sickle cell disease. Bone Marrow Transplant, 34, 405-411.

2. Barker, J.N., Krepski, T.P., DeFor, T.E., Davies, S.M., Wagner, J.E. & Weisdorf, D.J. (2002) Searching for unrelated donor hematopoietic stem cells: availability and speed of umbilical cord blood versus bone marrow. Biol Blood Marrow Transplant, 8, 257-260.

3. Beam, D., Poe, M.D., Provenzale, J.M., Szabolcs, P., Martin, P.L., Prasad, V., Parikh, S., Driscoll, T., Mukundan, S., Kurtzberg, J. & Escolar, M.L. (2007) Outcomes of unrelated umbilical cord blood transplantation for X-linked adrenoleukodystrophy. Biol Blood Marrow Transplant, 13, 665-674.

4. Bhattacharya, A., Slatter, M., Curtis, A., Chapman, C.E., Barge, D., Jackson, A., Flood, T.J., Abinun, M., Cant, A.J. & Gennery, A.R. (2003) Successful umbilical cord blood stem cell transplantation for chronic granulomatous disease. Bone Marrow Transplant, 31, 403-405.

5. Bhattacharya, A., Slatter, M.A., Chapman, C.E., Barge, D., Jackson, A., Flood, T.J., Abinun, M., Cant, A.J. & Gennery, A.R. (2005) Single centre experience of umbilical cord stem cell transplantation for primary immunodeficiency. Bone Marrow Transplant, 36, 295-299.

6. Boelens, J.J., Wynn, R.F., O'Meara, A., Veys, P., Bertrand, Y., Souillet, G., Wraith, J.E., Fischer, A., Cavazzana-Calvo, M., Sykora, K.W., Sedlacek, P., Rovelli, A., Uiterwaal, C.S. & Wulffraat, N. (2007) Outcomes of hematopoietic stem cell transplantation for Hurler's syndrome in Europe: a risk factor analysis for graft failure. Bone Marrow Transplant, 40, 225-233.

7. Chan, K.W., McDonald, L., Lim, D., Grimley, M.S., Grayson, G. & Wall, D.A. (2008) Unrelated cord blood transplantation in children with idiopathic severe aplastic anemia. Bone Marrow Transplant, 42, 589-595.

8. Cooper, N., Rao, K., Goulden, N., Webb, D., Amrolia, P. & Veys, P. (2008) The use of reduced-intensity stem cell transplantation in haemophagocytic lymphohistiocytosis and Langerhans cell histiocytosis. Bone Marrow Transplant, 42 Suppl 2, S47-50.

9. Di Ferrante, N., Nichols, B.L., Donnelly, P.V., Neri, G., Hrgovcic, R. & Berglund, R.K. (1971) Induced degradation of glycosaminoglycans in Hurler's and Hunter's syndromes by plasma infusion. Proc Natl Acad Sci U S A, 68, 303-307.

10. Diaz de Heredia, C., Ortega, J.J., Diaz, M.A., Olive, T., Badell, I., Gonzalez-Vicent, M. & Sanchez de Toledo, J. (2008) Unrelated cord blood transplantation for severe combined immunodeficiency and other primary immunodeficiencies. Bone Marrow Transplant, 41, 627-633.

11. Escolar, M.L., Poe, M.D., Provenzale, J.M., Richards, K.C., Allison, J., Wood, S., Wenger, D.A., Pietryga, D., Wall, D., Champagne, M., Morse, R., Krivit, W. & Kurtzberg, J. (2005) Transplantation of umbilical-cord blood in babies with infantile Krabbe's disease. N Engl J Med, 352, 2069-2081.

12. Fang, J., Huang, S., Chen, C., Zhou, D., Li, C.K., Li, Y. & Huang, K. (2004) Umbilical cord blood transplantation in Chinese children with beta-thalassemia. J Pediatr Hematol Oncol, 26, 185-189.

13. Filipovich, A.H., Stone, J.V., Tomany, S.C., Ireland, M., Kollman, C., Pelz, C.J., Casper, J.T., Cowan, M.J., Edwards, J.R., Fasth, A., Gale, R.P., Junker, A., Kamani, N.R., Loechelt, B.J., Pietryga, D.W., Ringden, O., Vowels, M., Hegland, J., Williams, A.V., Klein, J.P., Sobocinski, K.A., Rowlings, P.A. & Horowitz, M.M. (2001) Impact of donor type on outcome of bone marrow transplantation for Wiskott-Aldrich syndrome: collaborative study of the International Bone Marrow Transplant Registry and the National Marrow Donor Program. Blood, 97, 1598-1603.

15. Gluckman, E., Broxmeyer, H.A., Auerbach, A.D., Friedman, H.S., Douglas, G.W., Devergie, A., Esperou, H., Thierry, D., Socie, G., Lehn, P. & et al. (1989, now open access in this issue of CTT) Hematopoietic reconstitution in a patient with Fanconi's anemia by means of umbilical-cord blood from an HLA-identical sibling. N Engl J Med, 321, 1174-1178.

16. Gluckman, E.G., Roch, V.V. & Chastang, C. (1997) Use of Cord Blood Cells for Banking and Transplant. Oncologist, 2, 340-343.

17. Horwitz ME, B.A., Brown BS, Carter CS, Childs R, Gallin J, Holland S, Linton GF, Miller JA, Leitman SF, Read EJ, Malech HL (2001) Treatment of Chronic Granulomatous Disease with Nonmyeloablative Conditioning and a T-cell Depleted Hematopoietic Allograft. N Engl J Med, 344, 881.

18. Jaing, T.H., Hung, I.J., Yang, C.P., Chen, S.H., Sun, C.F. & Chow, R. (2005) Rapid and complete donor chimerism after unrelated mismatched cord blood transplantation in 5 children with beta-thalassemia major. Biol Blood Marrow Transplant, 11, 349-353.

19. Jaing, T.H., Yang, C.P., Hung, I.J., Chen, S.H., Sun, C.F. & Chow, R. (2007) Transplantation of unrelated donor umbilical cord blood utilizing double-unit grafts for five teenagers with transfusion-dependent thalassemia. Bone Marrow Transplant, 40, 307-311.

20. Knudson, A.G., Jr., Di Ferrante, N. & Curtis, J.E. (1971) Effect of leukocyte transfusion in a child with type II mucopolysaccharidosis. Proc Natl Acad Sci U S A, 68, 1738-1741.

21. Knutsen, A.P., Steffen, M., Wassmer, K. & Wall, D.A. (2003) Umbilical cord blood transplantation in Wiskott Aldrich syndrome. J Pediatr, 142, 519-523.

22. Knutsen, A.P. & Wall, D.A. (2000) Umbilical cord blood transplantation in severe T-cell immunodeficiency disorders: two-year experience. J Clin Immunol, 20, 466-476.

23. Kurtzberg, J. (2009) Update on umbilical cord blood transplantation. Curr Opin Pediatr, 21, 22-29.

24. Kurtzberg, J., Graham, M., Casey, J., Olson, J., Stevens, C.E. & Rubinstein, P. (1994) The use of umbilical cord blood in mismatched related and unrelated hemopoietic stem cell transplantation. Blood Cells, 20, 275-283; discussion 284.

25. Kurtzberg, J., Prasad, V.K., Carter, S.L., Wagner, J.E., Baxter-Lowe, L.A., Wall, D., Kapoor, N., Guinan, E.C., Feig, S.A., Wagner, E.L. & Kernan, N.A. (2008) Results of the Cord Blood Transplantation Study (COBLT): clinical outcomes of unrelated donor umbilical cord blood transplantation in pediatric patients with hematologic malignancies. Blood, 112, 4318-4327.

26. Locatelli, F., Rocha, V., Reed, W., Bernaudin, F., Ertem, M., Grafakos, S., Brichard, B., Li, X., Nagler, A., Giorgiani, G., Haut, P.R., Brochstein, J.A., Nugent, D.J., Blatt, J., Woodard, P., Kurtzberg, J., Rubin, C.M., Miniero, R., Lutz, P., Raja, T., Roberts, I., Will, A.M., Yaniv, I., Vermylen, C., Tannoia, N., Garnier, F., Ionescu, I., Walters, M.C., Lubin, B.H. & Gluckman, E. (2003) Related umbilical cord blood transplantation in patients with thalassemia and sickle cell disease. Blood, 101, 2137-2143.

27. Lucarelli, G., Clift, R.A., Galimberti, M., Polchi, P., Angelucci, E., Baronciani, D., Giardini, C., Andreani, M., Manna, M., Nesci, S., Agostinelli, F., Rapa, S., Ripalti, M. & Albertini, F. (1996) Marrow transplantation for patients with thalassemia: results in class 3 patients. Blood, 87, 2082-2088.

28. Lucarelli, G., Galimberti, M., Polchi, P., Angelucci, E., Baronciani, D., Giardini, C., Politi, P., Durazzi, S.M., Muretto, P. & Albertini, F. (1990) Bone marrow transplantation in patients with thalassemia. N Engl J Med, 322, 417-421.

29. Mao, P., Zhu, Z., Wang, H., Wang, S., Mo, W., Ying, Y., Li, Q. & Xu, Y. (2005) Sustained and stable hematopoietic donor-recipient mixed chimerism after unrelated cord blood transplantation for adult patients with severe aplastic anemia. Eur J Haematol, 75, 430-435.

30. Martin, P.L., Carter, S.L., Kernan, N.A., Sahdev, I., Wall, D., Pietryga, D., Wagner, J.E. & Kurtzberg, J. (2006) Results of the cord blood transplantation study (COBLT): outcomes of unrelated donor umbilical cord blood transplantation in pediatric patients with lysosomal and peroxisomal storage diseases. Biol Blood Marrow Transplant, 12, 184-194.

31. Mochizuki, K., Kikuta, A., Ito, M., Akaihata, M., Sano, H., Ohto, H. & Hosoya, M. (2009) Successful unrelated cord blood transplantation for chronic granulomatous disease: a case report and review of the literature. Pediatr Transplant, 13, 384-389.

32. Nakano, T., Boku, E., Yoshioka, A. & Fujimura, Y. (1999) A Case of McLeod Phenotype Chronic Granulomatous Disease who Received Unrelated Cord Blood Transplantation. Journal of Pediatric Hematology, 12, 264.

33. Ohga, S., Ichino, K., Goto, K., Hattori, S., Nomura, A., Takada, H., Nakamura, K. & Hara, T. (2006) Unrelated donor cord blood transplantation for childhood severe aplastic anemia after a modified conditioning. Pediatr Transplant, 10, 497-500.

34. Ohga, S., Kudo, K., Ishii, E., Honjo, S., Morimoto, A., Osugi, Y., Sawada, A., Inoue, M., Tabuchi, K., Suzuki, N., Ishida, Y., Imashuku, S., Kato, S. & Hara, T. (2009) Hematopoietic stem cell transplantation for familial hemophagocytic lymphohistiocytosis and Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis in Japan. Pediatr Blood Cancer, 54, 299-306.

35. Parikh, S.H., Szabolcs, P., Prasad, V.K., Lakshminarayanan, S., Martin, P.L., Driscoll, T.A. & Kurtzberg, J. (2007) Correction of chronic granulomatous disease after second unrelated-donor umbilical cord blood transplantation. Pediatr Blood Cancer, 49, 982-984.

36. Prasad, V.K., Mendizabal, A., Parikh, S.H., Szabolcs, P., Driscoll, T.A., Page, K., Lakshminarayanan, S., Allison, J., Wood, S., Semmel, D., Escolar, M.L., Martin, P.L., Carter, S. & Kurtzberg, J. (2008) Unrelated donor umbilical cord blood transplantation for inherited metabolic disorders in 159 pediatric patients from a single center: influence of cellular composition of the graft on transplantation outcomes. Blood, 112, 2979-2989. Figure 3. Figure 1.

37. Rocha, V., Wagner, J.E., Jr., Sobocinski, K.A., Klein, J.P., Zhang, M.J., Horowitz, M.M. & Gluckman, E. (2000) Graft-versus-host disease in children who have received a cord-blood or bone marrow transplant from an HLA-identical sibling. Eurocord and International Bone Marrow Transplant Registry Working Committee on Alternative Donor and Stem Cell Sources. N Engl J Med, 342, 1846-1854.

38. Rogers, I., Yamanaka, N., Bielecki, R., Wong, C.J., Chua, S., Yuen, S. & Casper, R.F. (2007) Identification and analysis of in vitro cultured CD45-positive cells capable of multi-lineage differentiation. Exp Cell Res, 313, 1839-1852.

39. Ruggeri, A., de Latour, R.P., Rocha, V., Larghero, J., Robin, M., Rodrigues, C.A., Traineau, R., Ribaud, P., Ferry, C., Devergie, A., Gluckman, E. & Socie, G. (2008) Double cord blood transplantation in patients with high risk bone marrow failure syndromes. Br J Haematol, 143, 404-408.

40. Seger, R.A., Gungor, T., Belohradsky, B.H., Blanche, S., Bordigoni, P., Di Bartolomeo, P., Flood, T., Landais, P., Muller, S., Ozsahin, H., Passwell, J.H., Porta, F., Slavin, S., Wulffraat, N., Zintl, F., Nagler, A., Cant, A. & Fischer, A. (2002) Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft: a survey of the European experience, 1985-2000. Blood, 100, 4344-4350.

41. Staba, S.L., Escolar, M.L., Poe, M., Kim, Y., Martin, P.L., Szabolcs, P., Allison-Thacker, J., Wood, S., Wenger, D.A., Rubinstein, P., Hopwood, J.J., Krivit, W. & Kurtzberg, J. (2004) Cord-blood transplants from unrelated donors in patients with Hurler's syndrome. N Engl J Med, 350, 1960-1969.

42. Sun, J.M., Driscoll, T., Prasad, V.K., Parikh, S.H., Szabolcs, P., Kurtzberg, J. & Martin, P. (2009) Unrelated Umbilical Cord Blood Transplantation is an Effective Therapy for Wiskott-Aldrich Syndrome. Biol Blood Marrow Transplant, 15, 76.

43. Suzuki, N., Hatakeyama, N., Yamamoto, M., Mizue, N., Kuroiwa, Y., Yoda, M., Takahashi, J., Tani, Y. & Tsutsumi, H. (2007) Treatment of McLeod phenotype chronic granulomatous disease with reduced-intensity conditioning and unrelated-donor umbilical cord blood transplantation. Int J Hematol, 85, 70-72.

44. Tokimasa, S., Ohta, H., Takizawa, S., Kusuki, S., Hashii, Y., Sakai, N., Taniike, M., Ozono, K. & Hara, J. (2008) Umbilical cord-blood transplantations from unrelated donors in patients with inherited metabolic diseases: Single-institute experience. Pediatr Transplant, 12, 672-676.

45. Tsuji, Y., Imai, K., Kajiwara, M., Aoki, Y., Isoda, T., Tomizawa, D., Imai, M., Ito, S., Maeda, H., Minegishi, Y., Ohkawa, H., Yata, J., Sasaki, N., Kogawa, K., Nagasawa, M., Morio, T., Nonoyama, S. & Mizutani, S. (2006) Hematopoietic stem cell transplantation for 30 patients with primary immunodeficiency diseases: 20 years experience of a single team. Bone Marrow Transplant, 37, 469-477.

46. Vanichsetakul, P., Wacharaprechanont, T., R, O.C., Seksarn, P. & Kupatawintu, P. (2004) Umbilical cord blood transplantation in children with beta-thalassemia diseases. J Med Assoc Thai, 87 Suppl 2, S62-67.

47. Wagner, J.E., Kernan, N.A., Steinbuch, M., Broxmeyer, H.E. & Gluckman, E. (1995) Allogeneic sibling umbilical-cord-blood transplantation in children with malignant and non-malignant disease.[see comment]. Lancet, 346, 214-219.

48. Wagner, J.E., Rosenthal, J., Sweetman, R., Shu, X.O., Davies, S.M., Ramsay, N.K., McGlave, P.B., Sender, L. & Cairo, M.S. (1996) Successful transplantation of HLA-matched and HLA-mismatched umbilical cord blood from unrelated donors: analysis of engraftment and acute graft-versus-host disease. Blood, 88, 795-802.

49. Walters, M.C., Storb, R., Patience, M., Leisenring, W., Taylor, T., Sanders, J.E., Buchanan, G.E., Rogers, Z.R., Dinndorf, P., Davies, S.C., Roberts, I.A., Dickerhoff, R., Yeager, A.M., Hsu, L., Kurtzberg, J., Ohene-Frempong, K., Bunin, N., Bernaudin, F., Wong, W.Y., Scott, J.P., Margolis, D., Vichinsky, E., Wall, D.A., Wayne, A.S., Pegelow, C., Redding-Lallinger, R., Wiley, J., Klemperer, M., Mentzer, W.C., Smith, F.O. & Sullivan, K.M. (2000) Impact of bone marrow transplantation for symptomatic sickle cell disease: an interim report. Multicenter investigation of bone marrow transplantation for sickle cell disease. Blood, 95, 1918-1924.

50. Wang, K., Lin, E., Moore, T. & Roberts, R. (2009) Cord Blood Transplantation for Treatment of Chediak-Higashi Syndrome. Clinical Immunology, 131, S77-S78.

51. Yoshimi, A., Kojima, S., Taniguchi, S., Hara, J., Matsui, T., Takahashi, Y., Azuma, H., Kato, K., Nagamura-Inoue, T., Kai, S. & Kato, S. (2008) Unrelated cord blood transplantation for severe apastic anemia. Biol Blood Marrow Transplant, 14, 1057-1063.

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Since the first related donor umbilical cord blood (UCB) transplant in 1988 for a patient with Fanconi anemia, and the first successful unrelated donor UCB transplant in 1993, an estimated 15,000 UCB transplantations have been performed [23]. Today, this approach is being applied to patients of all ages with a variety of diseases, including nonmalignant hematologic disorders and congenital metabolic disorders, as well as hematologic malignancies [2, 15, 16]. Between 2004 and 2007, the Center for International Blood and Marrow Transplant Research (CIBMTR) reported that for patients under age 20 years, 40% of unrelated donor stem cell grafts were collected from the bone marrow, 40% from umbilical cord blood, and 20% from peripheral blood. In contrast, for patients over age 20 years, only 7% of unrelated stem cell grafts were derived from UCB during the same time period. There are a number of factors contributing to increased usage of UCB stem cells. The most important factor is that results with UCB have improved progressively. 

Furthermore, the cord blood banking infrastructure has improved, allowing for increased availability of high quality unrelated UCB. Compared to stem cell grafts obtained from unrelated adult donors, UCB stem cells can be procured more quickly, without risk or inconvenience to the donor. Finally, there is the possibility that contained within the UCB are totipotential stem cells with regenerative potential for non-hematopoietic tissues [23, 38]. This is particularly relevant when treating inborn errors of metabolism, which can result in damage to neuronal tissue.

This review will focus on the use of UCB transplantation to treat inherited or acquired hematopoietic disorders. Included are inborn errors of metabolism, in which promising outcomes have been demonstrated with allogeneic stem cell transplantation. As a group, bone marrow failure and congenital immunodeficiency disorders, as well as inborn errors of metabolism are rare. As a result, the worldwide experience with UCB transplantation is limited. Despite this, it is clear that UCB has proven to be a viable and effective stem cell source that will continue to play a major role in allogeneic stem cell therapy.

Use of UCB stem cell grafts for allogeneic transplantation; historical perspective

The 1988 report of successful engraftment and outcome of a patient with Fanconi anemia who was transplanted with cord blood from a new-born HLA-identical sibling, generated considerable interest in further development of this novel transplant approach [15]. From 1988 until 1993, UCB transplants were limited to grafts collected from HLA-identical related donors. This early experience was important in that it confirmed the pre-clinical observation that contained within the UCB graft were true pluripotent long-term repopulating cells. What also became apparent from the early experience was that the graft vs host disease (GvHD)-inducing potential of HLA-matched related cord blood T-cells was less than been observed with similarly matched bone marrow grafts [37,47]. The encouraging results in matched related donor cord blood transplantation prompted Kurtzberg and colleagues to perform the first mismatched cord blood transplantation [24]. This series of three patients and the larger series later reported by Wagner and colleagues were notable for the engraftment potential and low GvHD potential of these unrelated, cryopreserved cells [24, 48]. Due to the limited number of stem cells contained within the cord blood graft, early experience was restricted primarily to children where the UCB cell dose relative to body weight was more favorable.  However, as promising outcome data began to emerge from large UCB bank and international registry studies, the experience in adult patients began to grow.
 
In recent years, great strides have been made in identifying factors predictive of successful outcome.  The two most important characteristics of an UCB graft are the cellular content and donor-recipient HLA-matching. It is generally accepted that a total nucleated cell dose under 2 x 107/kg recipient body weight results in an unacceptably high rate of graft failure. CD34+ cell content and colony forming unit potential of the donor graft have also proven to be predictive of donor cell engraftment [25]. However, practical issues surrounding accurate characterization of prospective units for their progenitor cell content remain to be worked out. For example, while CD34+ cell content is often enumerated by individual cord blood banks prior to cryopreservation, there remains considerable concern that inter-bank comparison of these values is not valid due to subtle differences in CD34+ quantification techniques. Therefore, choosing cord blood units based on CD34+ cell content as measured by different banks is not yet realistic.

As the outcome data are presented in this review, it is important to remember that earlier results were significantly compromised by lack of a clear understanding of the many factors that contribute to successful UCB transplantation. While advances in supportive care, patient selection, and transplantation techniques have improved outcomes of allogeneic stem cell transplantation as a whole, the advances are more pronounced with UCB transplantation.

Umbilical cord blood transplantation for inherited immunodeficiency disorders

Lymphoid immunodeficiency disorders

Severe Combined Immunodeficiency Disorders (SCID)

Included in this discussion of UCB transplantation for SCID will be the classical form of SCID characterized by an X-linked mutation of the common gamma-chain, adenosine deaminase deficient SCID, autosomal recessive SCID, and Omenn syndrome. Data on cord blood transplantation for treatment of these disorders remain scant. The largest single center series comes from Diaz de Heredia and colleagues who report the outcomes of 12 SCID patients (median age 11.6 months) transplanted with UCB at three Spanish hospitals between 1996 and 2002 [10]. All but 2 patients received a high dose busulfan/cyclophosphamide preparative regimen. Two patients received a reduced intensity melphalan/fludarabine preparative regimen. All patients achieved donor stem cell engraftment. The 5-year overall survival (which includes 3 additional patients with non-SCID immunodeficiency disorders) was 73%, with 3 patients dying from graft versus host disease, and one from progressive interstitial lung disease. Importantly, all surviving children had normal age-adjusted levels of T-cells, B-cells and NK cells by 24 months following transplantation.  In contrast to what has been observed following stem cell transplantation without conditioning, quantitative and qualitative T-cell and B-cell functions are durable following UCB transplantation using high intensity transplant conditioning. 

The outcomes of 16 children transplanted with UCB for treatment of SCID are reported in three separate retrospective reports [5, 22, 45]. One of 16 failed to engraft, and 13 of 16 are long-term survivors with normalization of immune function.

Wiscott-Aldrich Syndrome

Wiscott-Aldrich Syndrome (WAS) is due to an X-linked mutation in the WASP gene, with an incidence of 4 per million live male births. The role of stem cell transplantation for treatment of this disorder has been firmly established. The initial reports demonstrated cure rates as high as 89% when matched unrelated donor transplantation is performed before the age of 5 years [13]. The published experience of UCB transplantation for WAS has grown significantly in the past few years. In 2003, Knutsen and colleagues were among the first to demonstrate feasibility of UCB transplantation for WAS with successful treatment of 3 children age 2–8 yrs [21]. More recently, the Duke University group reported the outcome of 15 patients transplanted with UCB between 1998 and 2007 [42]. All patients achieved donor cell engraftment following a conditioning regimen consisting of busulfan, cyclophosphamide, +/- ATG. Six of 15 patients died from transplant-related complications, resulting in an overall survival of 60%. Chronic GvHD was observed in 11 of 12 surviving patients (limited in 10, extensive in 1). The authors found this incidence of chronic GvHD to be in excess of what has been observed in other patients with congenital immunodeficiency disorders transplanted with UCB. They postulate a potential link to pre-existing eczema, which is commonly seen in patients with WAS. 

A recent review of registry data collected by the CIBMTR (unpublished) compared 113 WAS recipients of unrelated bone marrow with 65 WAS recipients of unrelated cord blood transplants carried out between 1995 and 2005. This analysis showed equivalent 3-year survival for recipients age <5 years at the time of transplantation (73% vs 75%). Taken together, these data support the use of UCB for stem cell transplantation of WAS.

The CIBMTR has received registration reports of UCB transplantation for other rare lymphoid immunodeficiency disorders. These include Cartilage Hair Hypoplasia, X-linked Lymphoproliferative syndrome, Common Variable Immunodeficiency, Reticular dysgenesis and Bare Lymphocyte syndrome. Unfortunately, the outcomes of these transplants are not available for review.

Myeloid immunodeficiency disorders

Chronic Granulomatous Disease (CGD)

CGD is a congenital neutrophil disorder that is a consequence of an X-linked or autosomal recessive mutation in the NADPH-oxidase complex. The curative potential of stem cell transplantation has been clearly demonstrated [17, 40]. There are 8 reported cases of UCB transplantation for CGD [4, 31, 32, 35, 43]. Reduced intensity conditioning was successfully used in the oldest patient of this compilation of reports (age 20 yrs). The others were conditioned with high intensity regimen; 2 experienced primary graft failure. Six of 8 patients are long-term survivors.

Leukocyte adhesion deficiency is another life-threatening myeloid immune disorder. To date, there are no published reports of UCB transplantation for treatment of this disorder.

Immune/Inflammatory disorders

Hemophagocytic Lymphohistiocytosis (HLH)

The familial or inherited form of HLH as well as the EBV-associated HLH will be considered together in this review. In general, the outcomes of allogeneic stem cell transplantation following high dose conditioning, regardless of the stem cell source, are not as favorable as that observed for other inherited immunodeficiencies. This has prompted a movement toward the use of reduced intensity preparative regimens for this disorder [8]. Ohga and colleagues recently reviewed data from the Japanese Society of Pediatric Hematology [34]. Outcomes of 57 patients (familial HLA-43, EBV-associated HLH-14), 21 of whom received UCB grafts, are reported. The overall survival by log-rank analysis of the UCB transplant recipients was 66%, which did not differ from recipients of related or unrelated bone marrow or peripheral blood stem cell transplantation.

Chediak-Higashi

The team from the University of California at Los Angeles has reported in abstract form successful UCB transplantation of 3 patients with Chediak-Higashi. Limited information is available on long-term outcome [50].

Umbilical cord blood transplantation for inborn errors of metabolism

Current data supports the use of allogeneic stem cell transplantation for the treatment of lysosomal and peroxisomal storage disorders. Enzyme replacement therapies are currently available, but questions remain as to the long-term efficacy of these therapies and their ability to positively impact the natural history of the disorder. Stem cell transplantation provides the opportunity for enzyme replacement via “cross correction” of enzyme-deficient cells by neighboring donor derived, enzyme-replete cells [9, 20]. Furthermore, stem cell transplantation (and UCB transplantation in particular) provides the potential for repair of damaged non-hematopoietic tissue such as microglial cells in the brain and Kupffer cells in the liver via differentiation of tissue-specific progenitor cells or transdifferentiation.

Lysosomal and peroxisomal storage diseases affect multiple organ systems, with the central and peripheral nervous system particularly impacted. Depending on the extent of damage at the time of stem cell transplantation, the impact of allogeneic SCT may require extensive and sophisticated neurocognitive testing to objectively measure response. It is clear that many of the neurocognitive deficits incurred by the patients will not be corrected by stem cell transplantation. However, a plateau in survival appears to be evident from a large, single center series of UCB transplants for inherited metabolic disorders [36, Fig. 3]. Longer follow-up and more experience will be required to optimize the timing and impact of this treatment modality.

Krabbe’s disease

The potential for UCB transplantation to favorably impact on the natural history of inborn errors of metabolism was elegantly demonstrated by Escolar and colleagues in patients with Krabbe’s disease [11]. Children born with Krabbe’s disease are deficient of the lysosomal enzyme galactocerebrosidase. As a result, the children experience rapidly progressive neurologic deterioration and death at an early age. Escolar et al found that when children undergo UCB transplantation prior to the onset of symptoms, most will go on to have age-appropriate cognitive and motor function, along with 100% overall survival. Those who underwent UCB transplantation after the onset of symptoms showed little improvement in neurologic function and had an overall survival of only 43%. The study demonstrates the importance of early recognition of inborn errors along with early intervention with stem cell transplantation before irreversible damage occurs.

Hurler’s syndrome

Hurler’s syndrome is an autosomal recessive mucopolysaccharidosis caused by deficiency of alpha-L-iduronidase. Multiple organs, including the central nervous system, heart, bone, eyes, and liver are affected.  Although enzyme replacement therapy has been available since 2003, due to poor CNS penetration, it does not completely prevent neurologic deterioration. Therefore, allogeneic stem cell transplantation remains the treatment of choice. Both European and North American registry data suggest that over 500 patients with Hurler’s syndrome have been treated with allogeneic stem cell transplantation. Staba and colleagues reported the Duke University experience with UCB transplantation for 20 children with Hurler’s syndrome [41]. The patients were prepared with high dose conditioning and received UCB units from mismatched unrelated donors. The median cell dose was 8.8x107 nucleated cells/kg. Only one patient failed to engraft with donor cells. Long-term survival was achieved in 17 of 20 patients with all surviving patients having normal alpha-L-iduronidase activity. Many of the surviving children continue to have neurocognitive impairment. Despite this, 81% of the surviving school-age children attend school in age-appropriate classrooms [36]. However, many Hurler’s patients continue to have problems with skeletal deformities that require corrective surgery.

Boelens and colleagues reviewed data from the European Blood and Marrow Transplant Registry regarding outcome of patients with Hurler’s syndrome undergoing allogeneic transplantation [6]. While overall survival was not affected by cell source selection, the data suggested that UCB grafts significantly improved the chance for achieving full donor chimerism and, as a result, normal circulating enzyme levels compared to patients receiving peripheral blood or bone marrow grafts.

X-linked Adrenoleukodystrophy (X-ALD)

X-ALD is a peroxisomal disorder stemming from a defective ABCD1 gene. This results in accumulation of long chain fatty acids, which has devastating neurologic consequences. The therapeutic potential of UCB transplantation was best described by Beam and colleagues who report the outcomes of 12 boys, 3 of whom were transplanted early in life, before symptoms of the disease developed [3]. All patients received high dose conditioning with busulfan, cyclophosphamide, and anti-thymocyte globulin followed by partially matched unrelated UCB transplantation. Extensive baseline neurophysiologic, neuroimaging and neurodevelopmental testing was performed prior to transplantation and followed serially after the transplantation. One patient died early from toxicity and another experienced primary graft failure, but was rescued with a second transplant. Overall survival at 6 months was 67%. The authors found that the degree of pre-transplant ALD-associated brain involvement (Loes score) was a strong predictor of post-transplantation cognitive and motor outcome. Many of the patients with severe neurocognitive impairment at the time of transplantation experienced disease progression despite transplantation. In contrast, the 3 boys who were asymptomatic at the time of transplant had excellent outcomes.

Composite reports of UCB transplantation for rare inborn errors

Disease-specific reports of allogeneic transplantation for rare inborn errors of metabolism lack the detail or sample size to draw definitive conclusions about outcomes [30, 36, 44]. Table 1 lists the disorders that have been treated with UCB transplantation. Questions remain as to the appropriate timing for the transplant as well as the therapeutic benefit. It is for this reason that use of allogeneic SCT for treatment of many of these disorders remains investigational. 

Table 1. Inborn metabolism errors treated with umbilical cord blood transplantation

Hurler syndrome

Krabbe's disease

Sanfilippo syndrome

Metachromatic leukodystrophy

Adrenoleukodystrophy

Tay Sachs disease

Hunter syndrome

Lesch-Nyhan disease

Sandhoff disease

Hurler Scheie

Neimann-Pick

Alpha mannosidosis

GM1 gangliosidosis

I-cell disease

Maroteaux-Lamy syndrome

Pelizaeus-Merzbacher disease

Fucosidosis

Wolman disease (Acid Lipase Deficiency)

 
The common theme among all the reports is that the earlier the transplant is done, the better the outcome. In the largest of these composite reports from the Duke University group, 159 children representing 16 different inborn errors of metabolism were transplanted following high dose conditioning (busulfan, cyclophosphamide, and equine anti-thymocyte globulin) over a 12-year period, ending in 2007. The probability of engraftment, acute and chronic GvHD, overall survival and factors influencing survival has been shown [36, Fig. 1]. Of note, the 1 and 5 year overall survivals for the most common disorders treated on the study (Hurler, Hunter, and Sanfilippo syndrome, metachromatic leukodystrophy, and adrenoleukodystrophy) were all similar. This suggests that timing of the transplant, not the underlying disease, is most important in predicting outcome.

Umbilical cord blood transplantation for hemoglobinopathies

Related UCB transplantation for β-thalassemia and sickle cell disease

Unlike the situation with inborn errors of metabolism, there is an established role for allogeneic stem cell transplantation for the treatment of β-thalassemia and sickle cell disease [27, 28, 49]. The published experience of UCB transplantation for β-thalassemia remains quite limited [12, 26]. The largest report comes from the Eurocord registry data describing the outcome of 33 β-thalassemia patients transplanted with matched related UCB grafts [26]. All patients had a low disease severity (Pesaro 1 in 20 pts, Pesaro 2 in 13 pts). All patients received high dose e conditioning and GvHD prophylaxis with cyclosporine alone or combined with methotrexate. Seven of 33 patients experienced graft failure, but were rescued with either autologous stem cells or bone marrow from the original matched sibling cord blood donor at a later date.  With a median follow-up of 24 months, all 33 patients were alive and well, but 4 retained the β-thalassemia phenotype.

The Locatelli report also included outcomes of 11 patients with sickle cell disease transplanted with UCB from related donors matched 6/6 (9 pts) or 5/6 (2 pts) [26]. The conditioning and GvHD prophylaxis regimens were similar to those used for the β-thalassemia patients. Primary engraftment was achieved in 10 of 11 patients, and all 11 patients are alive and well (1 with sickle cell disease) with a median follow-up of 24 months.

Unrelated UCB transplantation for β-thalassemia and sickle cell disease

There has yet to be enough published experience with unrelated UCB transplantation for β-thalassemia or sickle cell disease to fully assess the risk versus benefit considerations. The relative dearth of reports in the literature likely portrays unresolved challenges that remain with this mode of therapy. The few available reports suggest feasibility of unrelated UCB transplantation for hemoglobinopathies [1, 18, 19, 46]. However, it appears that establishment of stable donor engraftment is more challenging in this population of patients [1]. This may be related to the chemotherapy naïve status of the patients combined with a highly proliferative, cellular bone marrow milieu.

Umbilical cord blood transplantation for bone marrow failure disorders

The published experience with UCB for treatment of acquired bone marrow failure disorders is outlined in Table 2. Most investigators have relegated UCB transplantation to a treatment of last resort. Thus, those transplanted with UCB represent an extremely high-risk subset of patients who have failed prior therapy. Interpretation of the data is further compromised by the heterogeneous transplantation techniques. The data suggests that UCB transplantation for severe aplastic anemia is feasible. Larger studies will be needed to garner a better understanding of the relative risk of graft failure compared to patients with other non-malignant or malignant disorders.

Table 2. Umbilical cord blood transplantation for treatment of severe aplastic anemia and paroxysmal nocturnal hemoglobinurea

Reference

Disorder-
number
of patients

Median
Age
(yrs)

Preparative
Regimen

Median
Cryopreserved
Cell Dose
(x 107/kg)

Percent
donor
engraftment
(%)

Outcome
(%)

(Mao,
et al 2005)

AA-9

25

Cy/ATG

2.19 (1.6-10.7)*

78

EFS-78

OS-78

(Ohga,
et al 2006)

AA-1

11

TBI-5Gy
Melphalan 120mg/m2
Fludarabine 120mg/m2

3.9

100

EFS-100

OS-100

(Chan,
et al 2008)

AA-9

9

Cy/ATG-2
Cy/Flu/ATG-7

5.4 (3.5-20)

67

EFS-67

OS-78

 

(Yoshimi,
et al 2008)

AA-31

28

TBI (4-5Gy)/Flu/Mel-12
TBI (4-5Gy)/Flu/Cy-5
TBI (10-12Gy)/Cy/ATG-3
Other-11

NA

55

OS (2yrs)-41

(Ruggeri,
et al 2008)

SAA-4

PNH-1

19

Bu/Cy/Flu-3
Flu/Cy-1
Flu/Cy/TBI(2Gy)

4.7 (2.9-9.7)

(Dual Cord Blood Graft)

80

EFS-60

OS-80

*Post-thaw cell dose (cryopreserved cell dose not reported)

References

1. Adamkiewicz, T.V., Mehta, P.S., Boyer, M.W., Kedar, A., Olson, T.A., Olson, E., Chiang, K.Y., Maurer, D., Mogul, M.J., Wingard, J.R. & Yeager, A.M. (2004) Transplantation of unrelated placental blood cells in children with high-risk sickle cell disease. Bone Marrow Transplant, 34, 405-411.

2. Barker, J.N., Krepski, T.P., DeFor, T.E., Davies, S.M., Wagner, J.E. & Weisdorf, D.J. (2002) Searching for unrelated donor hematopoietic stem cells: availability and speed of umbilical cord blood versus bone marrow. Biol Blood Marrow Transplant, 8, 257-260.

3. Beam, D., Poe, M.D., Provenzale, J.M., Szabolcs, P., Martin, P.L., Prasad, V., Parikh, S., Driscoll, T., Mukundan, S., Kurtzberg, J. & Escolar, M.L. (2007) Outcomes of unrelated umbilical cord blood transplantation for X-linked adrenoleukodystrophy. Biol Blood Marrow Transplant, 13, 665-674.

4. Bhattacharya, A., Slatter, M., Curtis, A., Chapman, C.E., Barge, D., Jackson, A., Flood, T.J., Abinun, M., Cant, A.J. & Gennery, A.R. (2003) Successful umbilical cord blood stem cell transplantation for chronic granulomatous disease. Bone Marrow Transplant, 31, 403-405.

5. Bhattacharya, A., Slatter, M.A., Chapman, C.E., Barge, D., Jackson, A., Flood, T.J., Abinun, M., Cant, A.J. & Gennery, A.R. (2005) Single centre experience of umbilical cord stem cell transplantation for primary immunodeficiency. Bone Marrow Transplant, 36, 295-299.

6. Boelens, J.J., Wynn, R.F., O'Meara, A., Veys, P., Bertrand, Y., Souillet, G., Wraith, J.E., Fischer, A., Cavazzana-Calvo, M., Sykora, K.W., Sedlacek, P., Rovelli, A., Uiterwaal, C.S. & Wulffraat, N. (2007) Outcomes of hematopoietic stem cell transplantation for Hurler's syndrome in Europe: a risk factor analysis for graft failure. Bone Marrow Transplant, 40, 225-233.

7. Chan, K.W., McDonald, L., Lim, D., Grimley, M.S., Grayson, G. & Wall, D.A. (2008) Unrelated cord blood transplantation in children with idiopathic severe aplastic anemia. Bone Marrow Transplant, 42, 589-595.

8. Cooper, N., Rao, K., Goulden, N., Webb, D., Amrolia, P. & Veys, P. (2008) The use of reduced-intensity stem cell transplantation in haemophagocytic lymphohistiocytosis and Langerhans cell histiocytosis. Bone Marrow Transplant, 42 Suppl 2, S47-50.

9. Di Ferrante, N., Nichols, B.L., Donnelly, P.V., Neri, G., Hrgovcic, R. & Berglund, R.K. (1971) Induced degradation of glycosaminoglycans in Hurler's and Hunter's syndromes by plasma infusion. Proc Natl Acad Sci U S A, 68, 303-307.

10. Diaz de Heredia, C., Ortega, J.J., Diaz, M.A., Olive, T., Badell, I., Gonzalez-Vicent, M. & Sanchez de Toledo, J. (2008) Unrelated cord blood transplantation for severe combined immunodeficiency and other primary immunodeficiencies. Bone Marrow Transplant, 41, 627-633.

11. Escolar, M.L., Poe, M.D., Provenzale, J.M., Richards, K.C., Allison, J., Wood, S., Wenger, D.A., Pietryga, D., Wall, D., Champagne, M., Morse, R., Krivit, W. & Kurtzberg, J. (2005) Transplantation of umbilical-cord blood in babies with infantile Krabbe's disease. N Engl J Med, 352, 2069-2081.

12. Fang, J., Huang, S., Chen, C., Zhou, D., Li, C.K., Li, Y. & Huang, K. (2004) Umbilical cord blood transplantation in Chinese children with beta-thalassemia. J Pediatr Hematol Oncol, 26, 185-189.

13. Filipovich, A.H., Stone, J.V., Tomany, S.C., Ireland, M., Kollman, C., Pelz, C.J., Casper, J.T., Cowan, M.J., Edwards, J.R., Fasth, A., Gale, R.P., Junker, A., Kamani, N.R., Loechelt, B.J., Pietryga, D.W., Ringden, O., Vowels, M., Hegland, J., Williams, A.V., Klein, J.P., Sobocinski, K.A., Rowlings, P.A. & Horowitz, M.M. (2001) Impact of donor type on outcome of bone marrow transplantation for Wiskott-Aldrich syndrome: collaborative study of the International Bone Marrow Transplant Registry and the National Marrow Donor Program. Blood, 97, 1598-1603.

15. Gluckman, E., Broxmeyer, H.A., Auerbach, A.D., Friedman, H.S., Douglas, G.W., Devergie, A., Esperou, H., Thierry, D., Socie, G., Lehn, P. & et al. (1989, now open access in this issue of CTT) Hematopoietic reconstitution in a patient with Fanconi's anemia by means of umbilical-cord blood from an HLA-identical sibling. N Engl J Med, 321, 1174-1178.

16. Gluckman, E.G., Roch, V.V. & Chastang, C. (1997) Use of Cord Blood Cells for Banking and Transplant. Oncologist, 2, 340-343.

17. Horwitz ME, B.A., Brown BS, Carter CS, Childs R, Gallin J, Holland S, Linton GF, Miller JA, Leitman SF, Read EJ, Malech HL (2001) Treatment of Chronic Granulomatous Disease with Nonmyeloablative Conditioning and a T-cell Depleted Hematopoietic Allograft. N Engl J Med, 344, 881.

18. Jaing, T.H., Hung, I.J., Yang, C.P., Chen, S.H., Sun, C.F. & Chow, R. (2005) Rapid and complete donor chimerism after unrelated mismatched cord blood transplantation in 5 children with beta-thalassemia major. Biol Blood Marrow Transplant, 11, 349-353.

19. Jaing, T.H., Yang, C.P., Hung, I.J., Chen, S.H., Sun, C.F. & Chow, R. (2007) Transplantation of unrelated donor umbilical cord blood utilizing double-unit grafts for five teenagers with transfusion-dependent thalassemia. Bone Marrow Transplant, 40, 307-311.

20. Knudson, A.G., Jr., Di Ferrante, N. & Curtis, J.E. (1971) Effect of leukocyte transfusion in a child with type II mucopolysaccharidosis. Proc Natl Acad Sci U S A, 68, 1738-1741.

21. Knutsen, A.P., Steffen, M., Wassmer, K. & Wall, D.A. (2003) Umbilical cord blood transplantation in Wiskott Aldrich syndrome. J Pediatr, 142, 519-523.

22. Knutsen, A.P. & Wall, D.A. (2000) Umbilical cord blood transplantation in severe T-cell immunodeficiency disorders: two-year experience. J Clin Immunol, 20, 466-476.

23. Kurtzberg, J. (2009) Update on umbilical cord blood transplantation. Curr Opin Pediatr, 21, 22-29.

24. Kurtzberg, J., Graham, M., Casey, J., Olson, J., Stevens, C.E. & Rubinstein, P. (1994) The use of umbilical cord blood in mismatched related and unrelated hemopoietic stem cell transplantation. Blood Cells, 20, 275-283; discussion 284.

25. Kurtzberg, J., Prasad, V.K., Carter, S.L., Wagner, J.E., Baxter-Lowe, L.A., Wall, D., Kapoor, N., Guinan, E.C., Feig, S.A., Wagner, E.L. & Kernan, N.A. (2008) Results of the Cord Blood Transplantation Study (COBLT): clinical outcomes of unrelated donor umbilical cord blood transplantation in pediatric patients with hematologic malignancies. Blood, 112, 4318-4327.

26. Locatelli, F., Rocha, V., Reed, W., Bernaudin, F., Ertem, M., Grafakos, S., Brichard, B., Li, X., Nagler, A., Giorgiani, G., Haut, P.R., Brochstein, J.A., Nugent, D.J., Blatt, J., Woodard, P., Kurtzberg, J., Rubin, C.M., Miniero, R., Lutz, P., Raja, T., Roberts, I., Will, A.M., Yaniv, I., Vermylen, C., Tannoia, N., Garnier, F., Ionescu, I., Walters, M.C., Lubin, B.H. & Gluckman, E. (2003) Related umbilical cord blood transplantation in patients with thalassemia and sickle cell disease. Blood, 101, 2137-2143.

27. Lucarelli, G., Clift, R.A., Galimberti, M., Polchi, P., Angelucci, E., Baronciani, D., Giardini, C., Andreani, M., Manna, M., Nesci, S., Agostinelli, F., Rapa, S., Ripalti, M. & Albertini, F. (1996) Marrow transplantation for patients with thalassemia: results in class 3 patients. Blood, 87, 2082-2088.

28. Lucarelli, G., Galimberti, M., Polchi, P., Angelucci, E., Baronciani, D., Giardini, C., Politi, P., Durazzi, S.M., Muretto, P. & Albertini, F. (1990) Bone marrow transplantation in patients with thalassemia. N Engl J Med, 322, 417-421.

29. Mao, P., Zhu, Z., Wang, H., Wang, S., Mo, W., Ying, Y., Li, Q. & Xu, Y. (2005) Sustained and stable hematopoietic donor-recipient mixed chimerism after unrelated cord blood transplantation for adult patients with severe aplastic anemia. Eur J Haematol, 75, 430-435.

30. Martin, P.L., Carter, S.L., Kernan, N.A., Sahdev, I., Wall, D., Pietryga, D., Wagner, J.E. & Kurtzberg, J. (2006) Results of the cord blood transplantation study (COBLT): outcomes of unrelated donor umbilical cord blood transplantation in pediatric patients with lysosomal and peroxisomal storage diseases. Biol Blood Marrow Transplant, 12, 184-194.

31. Mochizuki, K., Kikuta, A., Ito, M., Akaihata, M., Sano, H., Ohto, H. & Hosoya, M. (2009) Successful unrelated cord blood transplantation for chronic granulomatous disease: a case report and review of the literature. Pediatr Transplant, 13, 384-389.

32. Nakano, T., Boku, E., Yoshioka, A. & Fujimura, Y. (1999) A Case of McLeod Phenotype Chronic Granulomatous Disease who Received Unrelated Cord Blood Transplantation. Journal of Pediatric Hematology, 12, 264.

33. Ohga, S., Ichino, K., Goto, K., Hattori, S., Nomura, A., Takada, H., Nakamura, K. & Hara, T. (2006) Unrelated donor cord blood transplantation for childhood severe aplastic anemia after a modified conditioning. Pediatr Transplant, 10, 497-500.

34. Ohga, S., Kudo, K., Ishii, E., Honjo, S., Morimoto, A., Osugi, Y., Sawada, A., Inoue, M., Tabuchi, K., Suzuki, N., Ishida, Y., Imashuku, S., Kato, S. & Hara, T. (2009) Hematopoietic stem cell transplantation for familial hemophagocytic lymphohistiocytosis and Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis in Japan. Pediatr Blood Cancer, 54, 299-306.

35. Parikh, S.H., Szabolcs, P., Prasad, V.K., Lakshminarayanan, S., Martin, P.L., Driscoll, T.A. & Kurtzberg, J. (2007) Correction of chronic granulomatous disease after second unrelated-donor umbilical cord blood transplantation. Pediatr Blood Cancer, 49, 982-984.

36. Prasad, V.K., Mendizabal, A., Parikh, S.H., Szabolcs, P., Driscoll, T.A., Page, K., Lakshminarayanan, S., Allison, J., Wood, S., Semmel, D., Escolar, M.L., Martin, P.L., Carter, S. & Kurtzberg, J. (2008) Unrelated donor umbilical cord blood transplantation for inherited metabolic disorders in 159 pediatric patients from a single center: influence of cellular composition of the graft on transplantation outcomes. Blood, 112, 2979-2989. Figure 3. Figure 1.

37. Rocha, V., Wagner, J.E., Jr., Sobocinski, K.A., Klein, J.P., Zhang, M.J., Horowitz, M.M. & Gluckman, E. (2000) Graft-versus-host disease in children who have received a cord-blood or bone marrow transplant from an HLA-identical sibling. Eurocord and International Bone Marrow Transplant Registry Working Committee on Alternative Donor and Stem Cell Sources. N Engl J Med, 342, 1846-1854.

38. Rogers, I., Yamanaka, N., Bielecki, R., Wong, C.J., Chua, S., Yuen, S. & Casper, R.F. (2007) Identification and analysis of in vitro cultured CD45-positive cells capable of multi-lineage differentiation. Exp Cell Res, 313, 1839-1852.

39. Ruggeri, A., de Latour, R.P., Rocha, V., Larghero, J., Robin, M., Rodrigues, C.A., Traineau, R., Ribaud, P., Ferry, C., Devergie, A., Gluckman, E. & Socie, G. (2008) Double cord blood transplantation in patients with high risk bone marrow failure syndromes. Br J Haematol, 143, 404-408.

40. Seger, R.A., Gungor, T., Belohradsky, B.H., Blanche, S., Bordigoni, P., Di Bartolomeo, P., Flood, T., Landais, P., Muller, S., Ozsahin, H., Passwell, J.H., Porta, F., Slavin, S., Wulffraat, N., Zintl, F., Nagler, A., Cant, A. & Fischer, A. (2002) Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft: a survey of the European experience, 1985-2000. Blood, 100, 4344-4350.

41. Staba, S.L., Escolar, M.L., Poe, M., Kim, Y., Martin, P.L., Szabolcs, P., Allison-Thacker, J., Wood, S., Wenger, D.A., Rubinstein, P., Hopwood, J.J., Krivit, W. & Kurtzberg, J. (2004) Cord-blood transplants from unrelated donors in patients with Hurler's syndrome. N Engl J Med, 350, 1960-1969.

42. Sun, J.M., Driscoll, T., Prasad, V.K., Parikh, S.H., Szabolcs, P., Kurtzberg, J. & Martin, P. (2009) Unrelated Umbilical Cord Blood Transplantation is an Effective Therapy for Wiskott-Aldrich Syndrome. Biol Blood Marrow Transplant, 15, 76.

43. Suzuki, N., Hatakeyama, N., Yamamoto, M., Mizue, N., Kuroiwa, Y., Yoda, M., Takahashi, J., Tani, Y. & Tsutsumi, H. (2007) Treatment of McLeod phenotype chronic granulomatous disease with reduced-intensity conditioning and unrelated-donor umbilical cord blood transplantation. Int J Hematol, 85, 70-72.

44. Tokimasa, S., Ohta, H., Takizawa, S., Kusuki, S., Hashii, Y., Sakai, N., Taniike, M., Ozono, K. & Hara, J. (2008) Umbilical cord-blood transplantations from unrelated donors in patients with inherited metabolic diseases: Single-institute experience. Pediatr Transplant, 12, 672-676.

45. Tsuji, Y., Imai, K., Kajiwara, M., Aoki, Y., Isoda, T., Tomizawa, D., Imai, M., Ito, S., Maeda, H., Minegishi, Y., Ohkawa, H., Yata, J., Sasaki, N., Kogawa, K., Nagasawa, M., Morio, T., Nonoyama, S. & Mizutani, S. (2006) Hematopoietic stem cell transplantation for 30 patients with primary immunodeficiency diseases: 20 years experience of a single team. Bone Marrow Transplant, 37, 469-477.

46. Vanichsetakul, P., Wacharaprechanont, T., R, O.C., Seksarn, P. & Kupatawintu, P. (2004) Umbilical cord blood transplantation in children with beta-thalassemia diseases. J Med Assoc Thai, 87 Suppl 2, S62-67.

47. Wagner, J.E., Kernan, N.A., Steinbuch, M., Broxmeyer, H.E. & Gluckman, E. (1995) Allogeneic sibling umbilical-cord-blood transplantation in children with malignant and non-malignant disease.[see comment]. Lancet, 346, 214-219.

48. Wagner, J.E., Rosenthal, J., Sweetman, R., Shu, X.O., Davies, S.M., Ramsay, N.K., McGlave, P.B., Sender, L. & Cairo, M.S. (1996) Successful transplantation of HLA-matched and HLA-mismatched umbilical cord blood from unrelated donors: analysis of engraftment and acute graft-versus-host disease. Blood, 88, 795-802.

49. Walters, M.C., Storb, R., Patience, M., Leisenring, W., Taylor, T., Sanders, J.E., Buchanan, G.E., Rogers, Z.R., Dinndorf, P., Davies, S.C., Roberts, I.A., Dickerhoff, R., Yeager, A.M., Hsu, L., Kurtzberg, J., Ohene-Frempong, K., Bunin, N., Bernaudin, F., Wong, W.Y., Scott, J.P., Margolis, D., Vichinsky, E., Wall, D.A., Wayne, A.S., Pegelow, C., Redding-Lallinger, R., Wiley, J., Klemperer, M., Mentzer, W.C., Smith, F.O. & Sullivan, K.M. (2000) Impact of bone marrow transplantation for symptomatic sickle cell disease: an interim report. Multicenter investigation of bone marrow transplantation for sickle cell disease. Blood, 95, 1918-1924.

50. Wang, K., Lin, E., Moore, T. & Roberts, R. (2009) Cord Blood Transplantation for Treatment of Chediak-Higashi Syndrome. Clinical Immunology, 131, S77-S78.

51. Yoshimi, A., Kojima, S., Taniguchi, S., Hara, J., Matsui, T., Takahashi, Y., Azuma, H., Kato, K., Nagamura-Inoue, T., Kai, S. & Kato, S. (2008) Unrelated cord blood transplantation for severe apastic anemia. Biol Blood Marrow Transplant, 14, 1057-1063.

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Хорвитц, Нельсон Чао</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(63) "

Митчелл Э. Хорвитц, Нельсон Чао

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По мере улучшения результатов трансплантации клеток пуповинной крови (ТКПК), подлежат пересмотру также и расчеты соотношений риска и выгоды при лечении неопухолевых заболеваний. Недавно полученные результаты дают основания считать, что исход ТКПК сравним с таковым при пересадке от совместимого неродственного донора. Следовательно, в отношении больных, не подлежащих такой потенциально излечивающей терапии из-за отсутствия подходящего совместимого донора, могут рассматриваться возможности совместимой или несовместимой трансплантации неродственных клеток пуповинной крови. В данном обзорe будут обсуждаться наиболее современные данные, касающиеся ТКПК в целях лечения врожденных иммунодефицитных заболеваний, врожденных болезней обмена веществ, синдромов дефицита функций костного мозга и гемоглобинопатий.

Ключевые слова

трансплантация стволовых клеток, пуповинная кровь, исходы, клинические результаты, иммунодефицит, неопухолевые заболевания, дефицит функций костного мозга, обзор

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Mitchell E. Horwitz (MD), Nelson Chao (MD, MBA)

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Division of Cellular Therapy, Duke University Medical Center, Durham, North Carolina, USA

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Organization" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_EN"]=> array(36) { ["ID"]=> string(2) "39" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Description / Summary" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "39" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "18932" ["VALUE"]=> array(2) { ["TEXT"]=> string(1059) "<p class="bodytext">As the outcomes of umbilical cord blood transplantation improve, the risk versus benefit considerations with respect to treatment of non-malignant disorders must be reassessed. Recent data would suggest that the outcome of umbilical cord blood transplantation is comparable to that of matched unrelated donor transplantation. Thus, patients felt not to be candidates for this potentially curative treatment modality due to lack of an available matched donor should be considered for matched or mismatched unrelated umbilical cord blood transplantation. This review will cover the most recent data pertaining to umbilical cord blood transplantation for the treatment of congenital immunodeficiency disorders, inborn errors of metabolism, bone marrow failure disorders, and hemoglobinopathies.   </p> <h3>Keywords</h3> <p> stem cell transplantation, umbilical cord blood, outcomes, clinical results, immunodeficiency, non-malignant disorders, bone marrow failure, review </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(1013) "

As the outcomes of umbilical cord blood transplantation improve, the risk versus benefit considerations with respect to treatment of non-malignant disorders must be reassessed. Recent data would suggest that the outcome of umbilical cord blood transplantation is comparable to that of matched unrelated donor transplantation. Thus, patients felt not to be candidates for this potentially curative treatment modality due to lack of an available matched donor should be considered for matched or mismatched unrelated umbilical cord blood transplantation. This review will cover the most recent data pertaining to umbilical cord blood transplantation for the treatment of congenital immunodeficiency disorders, inborn errors of metabolism, bone marrow failure disorders, and hemoglobinopathies.  

Keywords

stem cell transplantation, umbilical cord blood, outcomes, clinical results, immunodeficiency, non-malignant disorders, bone marrow failure, review

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Mitchell E. Horwitz (MD), Nelson Chao (MD, MBA)

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Mitchell E. Horwitz (MD), Nelson Chao (MD, MBA)

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As the outcomes of umbilical cord blood transplantation improve, the risk versus benefit considerations with respect to treatment of non-malignant disorders must be reassessed. Recent data would suggest that the outcome of umbilical cord blood transplantation is comparable to that of matched unrelated donor transplantation. Thus, patients felt not to be candidates for this potentially curative treatment modality due to lack of an available matched donor should be considered for matched or mismatched unrelated umbilical cord blood transplantation. This review will cover the most recent data pertaining to umbilical cord blood transplantation for the treatment of congenital immunodeficiency disorders, inborn errors of metabolism, bone marrow failure disorders, and hemoglobinopathies.  

Keywords

stem cell transplantation, umbilical cord blood, outcomes, clinical results, immunodeficiency, non-malignant disorders, bone marrow failure, review

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As the outcomes of umbilical cord blood transplantation improve, the risk versus benefit considerations with respect to treatment of non-malignant disorders must be reassessed. Recent data would suggest that the outcome of umbilical cord blood transplantation is comparable to that of matched unrelated donor transplantation. Thus, patients felt not to be candidates for this potentially curative treatment modality due to lack of an available matched donor should be considered for matched or mismatched unrelated umbilical cord blood transplantation. This review will cover the most recent data pertaining to umbilical cord blood transplantation for the treatment of congenital immunodeficiency disorders, inborn errors of metabolism, bone marrow failure disorders, and hemoglobinopathies.  

Keywords

stem cell transplantation, umbilical cord blood, outcomes, clinical results, immunodeficiency, non-malignant disorders, bone marrow failure, review

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Division of Cellular Therapy, Duke University Medical Center, Durham, North Carolina, USA

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Division of Cellular Therapy, Duke University Medical Center, Durham, North Carolina, USA

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Митчелл Э. Хорвитц, Нельсон Чао

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Митчелл Э. Хорвитц, Нельсон Чао

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Недавно полученные результаты дают основания считать, что исход ТКПК сравним с таковым при пересадке от совместимого неродственного донора. Следовательно, в отношении больных, не подлежащих такой потенциально излечивающей терапии из-за отсутствия подходящего совместимого донора, могут рассматриваться возможности совместимой или несовместимой трансплантации неродственных клеток пуповинной крови. В данном обзорe будут обсуждаться наиболее современные данные, касающиеся ТКПК в целях лечения врожденных иммунодефицитных заболеваний, врожденных болезней обмена веществ, синдромов дефицита функций костного мозга и гемоглобинопатий. </p> <h3>Ключевые слова</h3> <p> трансплантация стволовых клеток, пуповинная кровь, исходы, клинические результаты, иммунодефицит, неопухолевые заболевания, дефицит функций костного мозга, обзор</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(1884) "

По мере улучшения результатов трансплантации клеток пуповинной крови (ТКПК), подлежат пересмотру также и расчеты соотношений риска и выгоды при лечении неопухолевых заболеваний. Недавно полученные результаты дают основания считать, что исход ТКПК сравним с таковым при пересадке от совместимого неродственного донора. Следовательно, в отношении больных, не подлежащих такой потенциально излечивающей терапии из-за отсутствия подходящего совместимого донора, могут рассматриваться возможности совместимой или несовместимой трансплантации неродственных клеток пуповинной крови. В данном обзорe будут обсуждаться наиболее современные данные, касающиеся ТКПК в целях лечения врожденных иммунодефицитных заболеваний, врожденных болезней обмена веществ, синдромов дефицита функций костного мозга и гемоглобинопатий.

Ключевые слова

трансплантация стволовых клеток, пуповинная кровь, исходы, клинические результаты, иммунодефицит, неопухолевые заболевания, дефицит функций костного мозга, обзор

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По мере улучшения результатов трансплантации клеток пуповинной крови (ТКПК), подлежат пересмотру также и расчеты соотношений риска и выгоды при лечении неопухолевых заболеваний. Недавно полученные результаты дают основания считать, что исход ТКПК сравним с таковым при пересадке от совместимого неродственного донора. Следовательно, в отношении больных, не подлежащих такой потенциально излечивающей терапии из-за отсутствия подходящего совместимого донора, могут рассматриваться возможности совместимой или несовместимой трансплантации неродственных клеток пуповинной крови. В данном обзорe будут обсуждаться наиболее современные данные, касающиеся ТКПК в целях лечения врожденных иммунодефицитных заболеваний, врожденных болезней обмена веществ, синдромов дефицита функций костного мозга и гемоглобинопатий.

Ключевые слова

трансплантация стволовых клеток, пуповинная кровь, исходы, клинические результаты, иммунодефицит, неопухолевые заболевания, дефицит функций костного мозга, обзор

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1. Introduction

Hematopoietic cell transplantation (HCT) is a prototypic stem cell therapy, and has been a life-saving measure for tens of thousands of patients. Over its relatively short history, the study of transplantation has shown that the transfer of relatively few cells can lead to the development of a fully functional lympho-hematopoietic system in the recipient, that bidirectional immunologic tolerance between post-natal tissues is possible, and that cancer can be eradicated by immunologic means.

After the seminal insight that cells with two different enzyme deficiencies can complement each other [1], a paradigm shift occurred, according to which stem cell transfer is applicable to equally fatal but non-malignant disorders [2]. This has translated into the establishment of transplantation as the standard of care for some of these enzyme disorders; monitoring of hundreds of patients with congenital metabolic disorders after transplantation has shown that long-lasting cross correction can be achieved. Conceptually, these benefits have been limited to congenital defects of enzymes, but there is no intellectual barrier to applying this strategy to other diseases where structural proteins are deficient, such as in extracellular matrix disorders.

In this review, we intend to present experiences with hematopoietic cell transplantation that have established its functionality and benefits for children with congenital metabolic storage diseases, and to describe some limitations and open questions regarding HCT for these conditions. 

2. Conditioning regimens and graft sources

HCT for malignant as well as non-malignant diseases has traditionally been preceded by myeloablative doses of total body irradiation (TBI) and chemotherapy, or more commonly in the non-malignant setting, with myeloablative doses of busulfan combined with cyclophosphamide [3-6]. These regimens were also originally designed to be effective in treating the underlying malignancy, particularly leukemia, as well as providing intensive immunosuppression to prevent graft rejection. Although effective at achieving durable engraftment in most patients, intensive chemotherapy leads to a significant risk of short-term morbidity and a 10–30% risk of transplant-related mortality in patients with inborn errors of metabolism (IEM) [7]. Additionally, exposure to high doses of these agents can lead to a risk of significant late effects (cataracts, endocrinopathies, pulmonary and cardiac abnormalities, and new malignancies) as discussed later in this chapter. For these reasons, many parents and non-transplant physicians have been unwilling to accept the risks of HCT for children with IEM. 

The demonstration that stable mixed chimerism could be achieved with sub-lethal doses of TBI (approximately one-sixth of the dose administered with standard TBI) and immunosuppression with cyclosporine and mycophenolate mofetil led to the widespread development of so-called non-myeloablative or reduced intensity conditioning regimens [8]. While these regimens were initially intended for patients who were ineligible for standard high dose conditioning, the fact that these regimens avoid many of the major short and long term toxicities associated with HCT has made this approach very attractive for use in children with non-malignant disorders. Fludarabine, a relatively new chemotherapeutic agent that has been widely used for conditioning, is highly immunosuppressive and has limited non-hematologic toxicity [9]. It has been used with low-dose TBI or without TBI in combination with busulfan, melphalan, or other agents. The use of these regimens in patients who are “chemotherapy naive” and who have normal immune systems, such as patients with IEM, has been very limited and associated with high rates of graft rejection. Additionally, measures commonly employed with reduced intensity conditioning to improve or boost engraftment, such as donor lymphocyte infusions, are associated with a high risk of acute and chronic graft vs. host disease (GVHD). Despite these issues, the use of reduced intensity conditioning in patients with IEM is a desirable goal, and research continues to refine these regimens with the objective of optimizing engraftment and minimizing toxicity. 

The other consideration regarding HCT for patients with IEM is graft source. Obviously the preference is for HLA-matched sibling donors, but this is an option for only a minority of patients. The availability may be even lower for this patient group because siblings can also be affected with the disease. Certainly many of the potential matched sibling donors may be carriers of the disease in question. The question as to whether an alternative donor should be used preferentially over a sibling shown to be a carrier remains unanswered. Alternative unrelated donor sources (bone marrow, peripheral blood stem cells, cord blood) have been routinely utilized with good results. Acute and chronic GVHD is the major limitation to the use of alternative donors, and in these patients with non-malignant disorders there is no benefit to be derived from GVHD. Methods employed to reduce the risk of GVHD include T cell depletion (TCD) and possibly the use of umbilical cord blood. Both of these methods appear to be effective in reducing the risk of GVHD, but each carries with it a higher risk of graft rejection as well as a higher risk of infectious complications (particularly from viruses).

3. Lysosomal storage diseases

3.1. Mucopolysaccharidoses

Mucopolysaccharidoses are autosomal recessive disorders characterized by deficiencies of enzymes needed for the stepwise catabolism of complex sugars termed glycosaminoglycans (GAG) [10-12]. Some of these conditions predominantly affect the viscera; the others are both neuronopathic and visceral. Many of them also exhibit a dynamic range from a less severe phenotype associated with hypomorphic mutations to severe ones generally associated with null mutations.

3.1.1. Mucopolysaccharidosis type I (Hurler Syndrome)

In mucopolysaccharidosis type I (MPS I), the deficiency of α-L-iduronidase (IDUA) results in lysosomal accumulation of the GAG heparan sulfate and dermatan sulfate. This in turn leads to progressive cellular and multi-organ dysfunction. While the clinical findings may be apparent at birth, the manifestations of the disease and onset of symptoms usually occur by six months of age. Multiple organ systems are affected, and many of these patients present with or develop hepatosplenomegaly, cardiac disease, umbilical or inguinal hernia, obstructive airway disease, chronic rhinitis and otitis, skeletal deformities, hydrocephalus, neurocognitive deterioration, and corneal clouding. If left untreated, death occurs between 5 and 10 years of age, primarily from cardiac causes.

Treatments focus on approaches to replace the missing IDUA. This can be achieved either by exogenous administration of IDUA or through the endogenous production of IDUA following stable engraftment of normal cells producing enzyme within the affected individual. The former is achieved by enzyme replacement therapy (ERT) available for MPS I since 2003 [13], and the latter by HCT, which was first shown to hold promise in 1980 [2]. The therapeutic basis for both treatment options is that IDUA can be taken up by recipient cells via the mannose-6-phosphate receptor and then be translocated to lysosomes where it mediates the hydrolysis of GAG.

HCT has been accepted as a standard of care for patients with severe forms of MPS I (Hurler Syndrome). Initially, unaffected HLA-genotypically-identical bone marrow donors were considered the optimal donors, but results with matched unrelated donors, and especially with cord blood, are encouraging. As a result of better availability of improved methods for HLA typing and supportive care, the early engraftment and survival rates have improved, and currently may be as high as 85% in institutions specializing in transplantation for metabolic storage diseases [5, 14-19].

Remarkably, donor-derived cells engraft even within the brain, thereby providing a source of enzyme to the central nervous system and halting the neurocognitive decline in most patients [20]. This is in addition to correction of most of the visceral signs of pathology, including cardiovascular function, organomegaly, and lung disease. In contrast, the heart valves and skeletal abnormalities are largely unaffected by this therapy.

ERT has been introduced for treatment of less severe visceral forms of MPS I, and is currently the standard of care in patients without neurologic disease, since IDUA does not cross the blood-brain barrier [21]. Recent data on a combination of ERT with HCT are encouraging, however, and appear to support the possibility that combination therapy is in fact the new standard of care for patients with Hurler Syndrome [22-24]. The rationale for this approach is based on identifying risks in the pre-transplant course that are associated with increased morbidity and mortality during and after HCT [7]. Most prominent among these risks are upper and lower lung disease. It follows that if the enzyme can be provided for a sufficient time before transplantation, GAG storage in viscera can be partially cleared, and may result in fewer complications during HCT. The possibility that pre-transplant enzyme replacement therapy will result in increased graft failure because of generation of antibodies against donor cells has not been borne out. Of note, some advocate the use of combination therapy primarily for patients with higher risk disease. We and others, however, offer combination therapy for all patients with MPS I who are considered for HCT, because of the low risks associated with enzyme therapy and the potential that it may decrease life-threatening complications after HCT. In addition, it is possible that decreases in GAG, after enzyme replacement therapy, but before the HCT, can create a more permissive environment in the bone marrow niche for donor engraftment when compared to the patients who did not receive ERT.

3.1.2. Other mucopolysaccharidoses

In contrast to Hurler Syndrome, HCT has not been shown to significantly alter the natural history of patients with severe mucopolysaccharidosis type II (Hunter Syndrome). The attenuated phenotypes may benefit from stem cell therapy, but for yet unknown reasons, children with severe MPS II phenotype do not appear to gain neurocognitive benefit from the transplant. Whether transplantation before the onset of symptoms, such as in the neonatal period, may improve outcomes is as  yet unclear. 

Similarly, early results with HCT using allogeneic grafts have not been very encouraging in patients with Sanfilippo Syndrome (MPS III). Only limited published data exist regarding transplant results, but available data suggest that, in contrast to MPS I, the neurologic deterioration of MPS III patients is not alleviated by transplantation.
Morquio Syndrome (MPS IV), is characterized by significant musculoskeletal disease with less prominent neurologic changes, and so far has not been shown to benefit from HCT.

In contrast, the visceral findings of Maroteaux-Lamy Syndrome (MPS VI) have been shown to improve with HCT. However, the availability of enzyme replacement therapy for MPS VI limits the need for HCT.

Finally, Sly Syndrome (MPS VII), which results in bone deformities, developmental delays, and organomegaly, has been treated with HCT with some positive response [25-27].

Thus, individual mucopolysaccharidoses differ substantially with regards to their responses to HCT and ERT. While HCT, especially in combination with ERT, is a standard of care for severe MPS I (Hurler Syndrome), the efficacy of standard methods of transplantation for MPS II and MPS III has not been established.

4. Sphingolipidoses

The glycosphingolipids are an important component of the cell membrane, consisting of polysaccharide bound to lipid, primarily ceramide, which is incorporated into the membrane [28]. The polysaccharide portion contributes to cell interactions, adhesion,  and signaling, in addition to other functions [29]. Degradation is accomplished through the action of lysosomal acid hydrolases, which serve to remove the carbohydrate moiety. Collectively the glycosphingolipid disorders are the most common cause of neurogenerative diseases (incidence approximately 1:18,000) in children [28]. With the exception of Fabry disease, these disorders are inherited in an autosomal recessive pattern. Based on the enzyme defect and substrate accumulation, these disorders are often divided into GM1 gangliosidosis, GM2 gangliosidoses (Tay-Sachs disease and Sandhoff disease), Fabry disease, multiple sulfatase deficiency, Gaucher disease, Niemann-Pick A and B, Farber disease, metachromatic leukodystrophy (MLD) and globoid cell leukodystrophy (GLD, also known as Krabbe disease). Most data regarding transplantation for these disorders relate to experience with MLD and GLD. These disorders will be discussed individually.

4.1. Metachromatic leukodystrophy

Metachromatic leukodystrophy (MLD) results from a decrease in arylsulfatase A (ARSA) activity, leading to the accumulation of the substrate cerebroside 3-sulfate, a component of myelin [30].  Decreased ARSA activity leads to demyelination of the white matter of the central nervous system (CNS) as well as the peripheral nerves [31].  Arylsulfatase A deficiency leading to MLD occurs with an overall incidence of approximately 1:40,000 births, while a higher frequency may be observed in specific populations [31-33]. There is significant phenotypic variation in MLD. In patients with the “late-infantile” form of the disease, neurological deterioration is initially observed within the first several years of life. Death generally ensues several years from diagnosis. Symptoms are associated with both central and peripheral demyelination, and motor-related difficulties are often apparent earlier than loss of cognition and language skills. The juvenile form of the disease has an onset from 4 years of age through adolescence [34-35]. Clinical manifestations of juvenile MLD are similar to the infantile form, although the rate of progression is slower. The adult form of the disease may become apparent as late as the seventh decade, and represents approximately 20% of cases of MLD [36]. Rather than presenting with motor-related difficulties, patients with late-onset disease may have emotional lability, progressive dementia, psychosis, and difficulties with substance abuse. There is a phenotype-genotype correlation in MLD, with more severe mutations resulting in more rapid accumulation of sulfatides and disease progression [37]. 

Krivit reported the results of the first transplant for MLD in 1990 [38]. Subsequently, reports of the success of transplantation for MLD generally have been limited to a small numbers of patients, and these data are difficult to assess due to variations in phenotype (late-infantile, juvenile, or adult forms) as well as the state of the disease at the time of transplantation [34]. Assessment of these outcomes is further limited by the lack of a universal standard for clinically assessing these patients both prior to and after transplantation. Obtaining such data will be critical to determining the utility of therapy, as asymptomatic patients or those early in their disease course are more likely to have better outcomes [16]. Similarly, those with less severe phenotypes may respond better to therapy. In regards to symptomatic late-infantile disease, while sulfatide levels decrease in urine and cerebrospinal fluid and the rate of progression may be less than observed in untreated siblings, the available data do not support the claim that transplantation has the capacity to stabilize disease [39]. The inability to deliver sufficient amounts of enzyme into the CNS is likely a primary limitation, as enzyme delivery is dependent on engraftment of cells such as the microglial population in the brain, which may take months following transplant [12, 27, 34]. In addition, despite engraftment of allogeneic cells, patients with infantile disease also appear to have progressive peripheral disease. Whether asymptomatic patients identified by neonatal screening or by family history who would be predicted to develop infantile disease can benefit from transplantation within the newborn period is debatable. Data available to address this question suggest that these patients continue to have progressive motor disabilities [34, 40-41]. In contrast, reports of the outcome of transplantation of later-onset disease (juvenile and adult forms) suggest that stabilization of the central nervous system may be achieved, even if patients are symptomatic at the time of transplantation [39,42-43]. As may be expected, the rate of decline prior to transplantation and the status of the disease at transplant are likely to affect outcomes [44]. 

4.2. Globoid cell leukodystrophy

The disorder known as globoid cell leukodystrophy (GLD) was initially described in 1916 by Krabbe, who reported infants developing spasticity and sclerosis of the brain [45]. Krabbe also described the characteristic “globoid cell” present in the white matter of affected patients. In 1970 the enzyme defect responsible for GLD was identified as the lysosomal enzyme galactocerebroside β-galactosidase (GALC) [46], also commonly referred to as galactocerebrosidase. In 1990 Zlotogora localized the gene to chromosome 14 [47], and the gene was cloned by Wenger’s laboratory in 1993 [48]. The primary substrate that accumulates in GLD is galactocerebroside, which is degraded by GALC to ceramide and galactose [49]. The metabolite psychosine accumulates as well in GLD, as it is a substrate for GALC [35]. Psychosine has been thought to contribute to cytotoxicity of cells in the CNS, including oligodendrocytes [50-52]. 

Globoid cell leukodystrophy has an incidence of 1:70,000–100,000, and presents with a varied phenotype, similar to MLD. Historically, 85–90% of patients with GLD develop symptoms as  infants [35]. Patients with infantile GLD characteristically become increasingly irritable, with increased sensitivity to stimuli, developmental arrest and subsequent regression [35]. Protein levels in the cerebro-spinal fluid are high.  Hypertonicity is apparent, with feeding difficulties and visual changes; increased deep tendon reflexes and seizures may be observed. Death generally results within a few years of the onset of symptoms. Other patients have less severe disease, and have been divided into late infantile (onset from 6 months to 3 years) and juvenile forms (ages 3–8 years), while some patients are not diagnosed until their second or third decades, and occasionally later [35]. As might be expected, these later onset patients have a less rapidly progressive disease course. 

The first description of the outcomes of GLD patients treated by allogeneic transplantation were provided by Krivit et al in 1998 [53]. Four of the 5 patients reported had late onset disease, while one had typical infantile GLD. For the older patients, the patients appeared to stabilize, or even improve, in regards to their disease. The patient with infantile disease was transplanted at 2 months of age. By now there is sufficient experience with transplantation of symptomatic patients with infantile disease to state that transplantation is not effective at arresting disease progression, although the clinical course may be attenuated [39]. In addressing this question, Escolar reported a staging system for clinically assessing patients with GLD in the pre-transplant period, and correlated this to outcomes [54]. There has recently been great interest in the outcomes of patients with presumed infantile GLD if these patients are transplanted in the neonatal period [55]. These very young and asymptomatic patients who would be predicted to have a severe phenotype, clearly have a different clinical course after transplantation than would be expected without transplantation  [56]. Based on this observation, there has been significant discussion regarding the use of newborn screening as a means of identifying these patients prior to the onset of symptoms [57, 58]. However, it remains unclear how patients who have severe genotypes and are transplanted in the first weeks of life will do as they age [55]. It is of interest that many of the difficulties these patients face are motor limitations, and this is likely at least in part due to peripheral nerve demyelination. Such a finding would be in keeping with observations in the twitcher mice, a model for GLD [59-61]. Thus far there has not been universal agreement to move towards neonatal screening for GLD with the intention of identifying and transplanting patients predicted to have severe disease soon after delivery, although screening is currently being done in New York, and is likely to be in place soon in several other US states. It should be noted that due to the severe time limitations in attempting to transplant asymptomatic neonates, a large proportion of these infants will require cord blood grafts. This has been suggested to be a preferred graft source, not only because of the expediency of moving to transplantation, but also because of the possibility of an increased ability of cord blood to transdifferentiate into a variety of non-hematopoietic stem cells or progenitor cells [16]. Additional clinical information will be required to determine if this will be the case. 

The efficacy of transplantation in patients with later onset GLD remains less well delineated than would be expected. It has previously been stated that patients with later onset disease are likely to benefit from transplantation [62]. In some cases, improvement has been reported [26]. However, data related to large series of patients focused on the function and neurocognitive outcomes are not available. It would be important to review the genotypic findings of an individual diagnosed by GALC activity to determine whether it is reasonable to pursue transplantation in an asymptomatic patient, as it is not necessarily clear what the anticipated course will be. However, if a patient with later-onset disease is early in the course of the disease, transplantation seems a reasonable option. It has been suggested that for a number of these diseases, multi-institutional trials with standard methods of analysis would prove very beneficial to the field [63], and despite the difficulties inherent in developing and funding these large trials that could require decades to complete, it is difficult to argue with this view. 

Other related lysosomal disorders have been treated with transplantation, although less data are available than for MLD and GLD. Niemann-Pick A and B result from a deficiency in sphingomyelinase. In Niemann-Pick A rapid neurologic progression is often observed. For these patients, who are severely affected and deteriorating rapidly, there are insufficient data to confirm that transplantation modifies the course of neurologic disease. In Niemann-Pick B, there is little published data, but our group and others have observed improvement in the marrow and lung pathology of these patients after transplant [64-65]. Niemann-Pick C has been shown to have 2 subtypes, both associated with accumulation of cholesterol. Niemann-Pick C1 is the most frequent form, but is not due to a lysosomal enzyme defect and therefore is less likely to respond to transplantation. In contrast, Niemann-Pick C2 disease is associated with a deficit in a lysosomal enzyme [66]. While it has been reported that there is an insufficient response of Niemann-Pick C to transplantation [67], the ability to separate the genotypes has only recently become available. Although it might be expected that type C2 may respond to transplantation, results have not been reported in individuals confirmed to have this genotype. As the C2 genotype is much less common than C1, genetic analysis prior to intervention will be of importance.

GM1 gangliosidosis is characterized by seizures and psychomotor deficits, and has infantile, juvenile, and adult onset forms [35, 68]. While little information is available regarding the utility of transplantation, a report describing a juvenile patient suggests there is little benefit from transplantation [69]. GM2 gangliosidosis disorders (Tay-Sachs and Sandhoff) are due to abnormalities within the hexosaminidase (HEX) gene [68]. In the case of Tay-Sachs, HEX A is deficient, while in Sandhoff HEX A and B are deficient. Unfortunately in most cases these disorders are rapidly progressive, and there is little information to suggest that symptomatic patients benefit from transplantation [40, 70]. However, it is as yet unclear as to whether those with late-onset disease or newborns predicted to have early-onset disease would benefit. Gaucher disease has been shown to benefit from transplantation [71-74], but as there is enzyme replacement therapy available for Gaucher, there is little enthusiasm for the morbidity and mortality associated with transplantation for this disorder. However, as the neuropathic form of Gaucher does not benefit from ERT [75], there may be interest in evaluating transplantation in patients with Gaucher who show evidence of neurologic deterioration [40]. Fabry disease is an X-linked disorder of the lysosomal enzyme α-galactosidase A, which results in accumulation of substrate in the kidneys, heart, eyes, and blood vessels, but does not have a significant neurological component. As enzyme replacement therapy is available for Fabry, there is currently no enthusiasm for transplantation [41]. 

4.3. Adrenoleukodystrophy

While GLD and MLD are autosomal recessive lysosomal enzyme deficiencies, adrenoleukodystrophy (ALD) is an X-linked disorder of the peroxisome that results in abnormal metabolism of very long chain fatty acids (VLCFA) due to decreased beta-oxidation. These VLCFA accumulate in the testes, adrenal gland, and white matter of the central nervous system [76]. For reasons that are not clear, approximately 40% of individuals with ALD under 20 years of age show a clinical course of rapid neurologic deterioration [77]. This condition, representing the cerebral form of ALD, is an inflammatory process present in the CNS, with a mixed cellular infiltrative process, although CD8+ T cells are prominent [78-79]. Eichler stated that the bulk of the inflammation occurs behind the area in which demyelination is seen, and he proposed that the infiltrative process occurs in response to demyelination rather than being its cause [80]. The beneficial effects of HCT are thought to be related at least in part to elimination of the active inflammation present in the CNS, although recent early findings of a gene therapy approach suggest that there is a corrective process provided by hematopoietically-derived cells [81]. Another important issue in regards to the early identification of ALD relates to adrenal insufficiency. Primary adrenal insufficiency (AI), or Addison’s disease, which precedes cerebral manifestations of ALD, occurs with an estimated prevalence of 43% in asymptomatic boys with X-ALD [82]. In our center’s experience, 7 boys who have been evaluated for transplantation for cerebral ALD since 2002 had previously been diagnosed with adrenal insufficiency, but VLCFA testing was not performed expeditiously, resulting in a delay in diagnosis and presumably disease progression that either rendered the patient ineligible for transplantation or put him at higher risk for a poor outcome (Polgreen et al., unpublished observations). 

Transplantation early in the course of cerebral ALD has been shown to stabilize the disease process, although it is clear that in more advanced patients the outcome is inferior [4]. An MRI scoring system was developed by Loes to quantitate the extent of the disease [83], and this allows the identification of patients who are at high risk for poor outcomes of transplantation. Due to the importance of the extent of disease in the ability of transplantation to arrest the disease process [84], it is recommended that boys with biochemically proven ALD be monitored with serial MRI scans, and to proceed with transplantation when patients show evidence of early progression to cerebral disease [4]. It is not known whether transplantation plays any role in preventing the evolution of other manifestations of ALD, such as the peripheral nervous system condition termed adrenomyeloneuropathy (AMN). In addition, there are no data to show that transplantation prior to the onset of cerebral ALD will prevent its occurrence. Therefore the risks of transplantation are not justified in patients without evidence of evolving cerebral ALD, as a majority of boys will not develop cerebral ALD [85]. The use of Lorenzo’s oil in patients who have not yet developed cerebral ALD may decrease the risk of its occurrence [86]. 

5. Oligosaccharidosis: Mannosidosis

Alpha-mannosidosis presents with hepatosplenomegaly, vomiting, immune deficiency, and dysostosis multiplex. Affected patients also have mental retardation and ocular clouding. Approximately 20 patients have been transplanted to date, some of whom had pulmonary and airway complications during the first several months after HCT. Remarkably, the mental development as well as cardiopulmonary function appear to have been preserved, suggesting that HCT is a valid treatment option for alpha-mannosidosis [87].

6. Enzyme localization defect: Mucolipidosis Type II (I-Cell Disease)

Mucolipidosis Type II results from a defect in a phosphotransferase that is integral to the localization of numerous lysosomal hydrolyses. In the absence of this targeting mechanism, these lysosomal enzymes are secreted rather than retained in the lysosome. This results in lysosomal substrate accumulation, while extremely high serum levels of these enzymes are observed in the plasma. The phenotype resembles MPS I, but the response to HCT has been much less favorable [88]. It remains to be determined whether early identification of these patients, before the damage to visceral and neuronal tissue is irreversible and profound, and expedient transplantation may improve outcomes. 

7. Late effects after HCT for Metabolic Storage Disease

As discussed previously, the majority of patients with IEM who undergo HCT do so following traditional high-dose, chemotherapy-based conditioning regimens. The combination of busulfan and cyclophosphamide is the most common regimen utilized. Patients with IEM are unique, however, in that they also have to face the potential of long-term complications related to their underlying disease that may not be reversed or prevented by successful HCT. One can assume that they are at the same risk as other patients going through HCT for the common conditions seen after exposure to high-dose chemotherapy in the conditioning regimen, but there are little data that describe those findings. Additionally, there may be unique long-term effects of some of the preparative regimens in patients with IEM, but again for the most part these have not been reported to date. Limited long-term follow-up data in some subsets of IEM patients (Hurler’s syndrome in particular) related to amelioration of disease-associated conditions are available and will be briefly summarized. 

Endocrine issues. There are minimal IEM-specific data, but some patients have been found to have primary ovarian failure [19]. It is unclear if this is related to the disease or HCT since both may contribute. Other endocrine issues seen in children after HCT include gonadal failure in males, hypothyroidism, and growth failure. While some of these conditions may be more frequently encountered after exposure to TBI, they can also be seen with non-TBI containing regimens. Patients with Hurler’s syndrome have growth problems to begin with, and while some reports suggest that linear growth may be maintained early after HCT, others suggest growth may not be maintained on a long-term basis [19, 89]. 

Pulmonary. Patients with IEM have high rates of pulmonary complications during HCT that may be related to a pro-inflammatory state within the lung [90]. While busulfan can lead to pulmonary fibrosis, this is not a common complication in children after HCT. In patients with Hurler’s it has been demonstrated that they do have relief of their obstructive airway symptoms and improvement in sleep apnea with improved pulmonary function [19, 91]. A reduction in the risk of pulmonary deterioration in a patient successfully transplanted for I-cell disease has also been reported [92].

Cardiac. Long-term cardiovascular complications are rarely associated with exposure to cyclophosphamide and busulfan alone. Certainly for several of the IEM disorders, progressive cardiac dysfunction is common. For patients with Hurler’s, long-term follow-up after HCT has shown that myocardial function is preserved and hypertrophy has been seen to regress, and patients have not developed heart failure or coronary artery disease. However, mitral and aortic valve deformities have persisted and frequently progressed [93].

Neuropsychological and cognitive function. In the absence of exposure to radiation during conditioning, children typically do not have significant neuropsychological sequelae secondary to HCT. In the case of children with IEM, post-HCT neurologic outcome depends upon the specific disease, age at time of HCT, specific genotype of the disease, cognitive status at the time of HCT, engraftment status, and donor enzyme activity after HCT. The goal, of course, is to perform HCT early in the course of the disease before any extensive neurologic damage or deterioration has occurred. When this can be done, neurocognitive function can be stabilized (or in some cases improved) and further progressive neurologic deterioration can be prevented [5, 19, 89,91, 94].
 
Bone and joints. HCT conditioning can affect bone health leading to osteopenia and osteoporosis. This may be reversible on its own over time or may require further intervention with vitamin D and calcium supplementation or occasionally treatment with bisphosphonates. These effects have not been studied to date in children with IEM. Other disease-specific orthopedic complications, such as odontoid dysplasia in patients with Hurler’s, have been shown to improve over time [95]. However, other  complications such as genu valgum, carpel tunnel syndrome, and acetabular dysplasia have not improved after HCT and frequently require surgical intervention [96-97].
 
Post-transplant malignancies. It has been well described that patients after HCT are at life-long increased risk of developing malignancies that is estimated at nearly 10-fold greater than that in the general population [98-99]. Whether this same risk applies to patients with IEM is not known, but we are aware of some patients who have developed malignancies years after HCT. 

Late Mortality. After allogeneic HCT patients have twice the risk of mortality of the general population [100]. Data submitted for publication from the Center for International Blood and Marrow Transplant Research demonstrate that patients with IEM have a higher risk of mortality between 2–6 yrs after HCT and that this increased risk persists even 6 yrs after HCT. This increased risk is highest in patients who have received unrelated or HLA non-identical related donor transplants. Causes of death include GVHD, infection, and organ failure. 

Summary

Obtaining clear data regarding the outcomes of transplantation in patients with IEM has proven difficult due to the rarity of these diseases, their variable phenotypes/genotypes, and differences in stem cell sources, preparative regimens, supportive therapy, and assessment of “successful” outcomes. Multi-institution trials with a common approach and outcome measures will be important in this regard. In earlier years HCT in these populations used standardized regimens designed for patients with malignant disorders. For disorders such as Hurler’s syndrome and early cerebral ALD, this approach has been successful. However, for other disorders, the ability to achieve satisfactory outcomes with standard transplant regimens has proven elusive. Reduced-intensity conditioning strategies may prove more successful in decreasing morbidity and mortality, particularly in patients with ongoing neurologic injury. It is anticipated that future investigations will test the use of combination therapy with or without transplantation, including substrate inhibition [101-102], chaperone therapy [103-105], enzyme replacement [24, 106], modification of anti-inflammatory therapy [107], or biologic response modifiers [108-110]. In addition, the interest in neonatal screening will provide the opportunity to intervene early in the course of these diseases, as this appears critical in achieving optimal outcomes [4, 111-114]. Finally, modifying the transplant procedure, using selectively expanded cell populations, or using cytokine manipulation may enhance microglial engraftment [115-118], which could make a substantial difference in the delivery of enzyme to the CNS. Significant progress is required to enhance transplant results and to determine optimal therapy in individuals with these devastating congenital disorders. 

References

1. Fratantoni JC, Hall CW, Neufeld EF. Hurler and Hunter syndromes: mutual correction of the defect in cultured fibroblasts. Science. 1968;162:570-572.

2. Hobbs JR, Hugh-Jones K, Barrett AJ, et al. Reversal of clinical features of Hurler's disease and biochemical improvement after treatment by bone-marrow transplantation. Lancet. 1981;2:709-712.

3. Jacobson P, Park JJ, DeFor TE, et al. Oral busulfan pharmacokinetics and engraftment in children with Hurler syndrome and other inherited metabolic storage diseases undergoing hematopoietic cell transplantation. Bone Marrow Transplant. 2001;27:855-861.

4. Peters C, Charnas LR, Tan Y, et al. Cerebral X-linked adrenoleukodystrophy: the international hematopoietic cell transplantation experience from 1982 to 1999. Blood. 2004;104:881-888.

5. Peters C, Shapiro EG, Anderson J, et al. Hurler syndrome: II. Outcome of HLA-genotypically identical sibling and HLA-haploidentical related donor bone marrow transplantation in fifty-four children. The Storage Disease Collaborative Study Group. Blood. 1998;91:2601-2608.

6. Peters C, Balthazor M, Shapiro EG, et al. Outcome of unrelated donor bone marrow transplantation in 40 children with Hurler syndrome. Blood. 1996;87:4894-4902.

7. Orchard PJ, Milla C, Braunlin E, et al. Pre-transplant risk factors affecting outcome in Hurler syndrome. Bone Marrow Transplant. 2009.

8. Storb R, Yu C, Wagner JL, et al. Stable mixed hematopoietic chimerism in DLA-identical littermate dogs given sublethal total body irradiation before and pharmacological immunosuppression after marrow transplantation. Blood. 1997;89:3048-3054.

9. McCarthy NJ, Bishop MR. Nonmyeloablative allogeneic stem cell transplantation: early promise and limitations. Oncologist. 2000;5:487-496.

10. Neufeld EF. Lysosomal storage diseases. Annu Rev Biochem. 1991;60:257-280.

11. Muenzer J. The mucopolysaccharidoses: a heterogeneous group of disorders with variable pediatric presentations. J Pediatr. 2004;144:S27-34.

12. Orchard PJ, Blazar BR, Wagner J, Charnas L, Krivit W, Tolar J. Hematopoietic cell therapy for metabolic disease. J Pediatr. 2007;151:340-346.

13. Kakkis ED, Muenzer J, Tiller GE, et al. Enzyme-replacement therapy in mucopolysaccharidosis I. N Engl J Med. 2001;344:182-188.

14. Boelens JJ, Rocha V, Aldenhoven M, et al. Risk factor analysis of outcomes after unrelated cord blood transplantation in patients with hurler syndrome. Biol Blood Marrow Transplant. 2009;15:618-625.

15. Aldenhoven M, Boelens JJ, de Koning TJ. The clinical outcome of Hurler syndrome after stem cell transplantation. Biol Blood Marrow Transplant. 2008;14:485-498.

16. Prasad VK, Kurtzberg J. Cord blood and bone marrow transplantation in inherited metabolic diseases: scientific basis, current status and future directions. Br J Haematol. 2009.

17. Prasad VK, Kurtzberg J. Umbilical cord blood transplantation for non-malignant diseases. Bone Marrow Transplant. 2009;44:643-651.

18. Prasad VK, Mendizabal A, Parikh SH, et al. Unrelated donor umbilical cord blood transplantation for inherited metabolic disorders in 159 pediatric patients from a single center: influence of cellular composition of the graft on transplantation outcomes. Blood. 2008;112:2979-2989.

19. Vellodi A, Young EP, Cooper A, et al. Bone marrow transplantation for mucopolysaccharidosis type I: experience of two British centres. Arch Dis Child. 1997;76:92-99.

20. Krivit W, Sung JH, Shapiro EG, Lockman LA. Microglia: the effector cell for reconstitution of the central nervous system following bone marrow transplantation for lysosomal and peroxisomal storage diseases. Cell Transplant. 1995;4:385-392.

21. Wraith JE. The first 5 years of clinical experience with laronidase enzyme replacement therapy for mucopolysaccharidosis I. Expert Opin Pharmacother. 2005;6:489-506.

22. Wynn RF, Mercer J, Page J, Carr TF, Jones S, Wraith JE. Use of enzyme replacement therapy (Laronidase) before hematopoietic stem cell transplantation for mucopolysaccharidosis I: experience in 18 patients. J Pediatr. 2009;154:135-139.

23. Cox-Brinkman J, Boelens JJ, Wraith JE, et al. Haematopoietic cell transplantation (HCT) in combination with enzyme replacement therapy (ERT) in patients with Hurler syndrome. Bone Marrow Transplant. 2006;38:17-21.

24. Tolar J, Grewal SS, Bjoraker KJ, et al. Combination of enzyme replacement and hematopoietic stem cell transplantation as therapy for Hurler syndrome. Bone Marrow Transplant. 2008;41:531-535.

25. Klein KA, Krivit W, Whitley CB, et al. Poor cognitive outcome of eleven children with Sanfilippo syndrome after bone marrow transplantation and successful engraftment. Bone Marrow Transplant. 1995;15:S176-181.

26. Krivit W. Allogeneic stem cell transplantation for the treatment of lysosomal and peroxisomal metabolic diseases. Springer Semin Immunopathol. 2004;26:119-132.

27. Peters C, Krivit W. Hematopoietic cell transplantation for mucopolysaccharidosis IIB (Hunter syndrome). Bone Marrow Transplant. 2000;25:1097-1099.

28. Platt FM, Jeyakumar M, Andersson U, Heare T, Dwek RA, Butters TD. Substrate reduction therapy in mouse models of the glycosphingolipidoses. Philos Trans R Soc Lond B Biol Sci. 2003;358:947-954.

29. Watts RW. A historical perspective of the glycosphingolipids and sphingolipidoses. Philos Trans R Soc Lond B Biol Sci. 2003;358:975-983.

30. Gieselmann V, Polten A, Kreysing J, von Figura K. Molecular genetics of metachromatic leukodystrophy. J Inherit Metab Dis. 1994;17:500-509.

31. Eng B, Nakamura LN, O'Reilly N, et al. Identification of nine novel arylsulfatase a (ARSA) gene mutations in patients with metachromatic leukodystrophy (MLD). Hum Mutat. 2003;22:418-419.

32. Heinisch U, Zlotogora J, Kafert S, Gieselmann V. Multiple mutations are responsible for the high frequency of metachromatic leukodystrophy in a small geographic area. Am J Hum Genet. 1995;56:51-57.

33. Zlotogora J, Bach G, Bosenberg C, Barak Y, von Figura K, Gieselmann V. Molecular basis of late infantile metachromatic leukodystrophy in the Habbanite Jews. Hum Mutat. 1995;5:137-143.

34. Biffi A, Lucchini G, Rovelli A, Sessa M. Metachromatic leukodystrophy: an overview of current and prospective treatments. Bone Marrow Transplant. 2008;42 Suppl 2:S2-6.

35. Scriver CR, Beaudet AL, Sly WS, Valle D. The Metabolic and Molecular Bases of Inherited Disease. Vol. III (ed 8th). New York: McGraw-Hill; 2001.

36. Sedel F, Tourbah A, Fontaine B, et al. Leukoencephalopathies associated with inborn errors of metabolism in adults. J Inherit Metab Dis. 2008;31:295-307.

37. Gieselmann V. Metachromatic leukodystrophy: genetics, pathogenesis and therapeutic options. Acta Paediatr Suppl. 2008;97:15-21.

38. Krivit W, Shapiro E, Kennedy W, et al. Treatment of late infantile metachromatic leukodystrophy by bone marrow transplantation. N Engl J Med. 1990;322:28-32.

39. Krivit W, Aubourg P, Shapiro E, Peters C. Bone marrow transplantation for globoid cell leukodystrophy, adrenoleukodystrophy, metachromatic leukodystrophy, and Hurler syndrome. Curr Opin Hematol. 1999;6:377-382.

40. Peters C, Steward CG. Hematopoietic cell transplantation for inherited metabolic diseases: an overview of outcomes and practice guidelines. Bone Marrow Transplant. 2003;31:229-239.

41. Peters C. Hematopoietic Stem Cell Transplantation for Storage Diseases. In: Appelbaum FR, Forman SJ, Negrin RS, eds. Thomas' Hematopoietic Cell Transplantation: Stem Cell Transplantation (ed 4). Oxford, UK: Wiley, John & Sons, Incorporated; 2009:1136-1162.

42. Gorg M, Wilck W, Granitzny B, et al. Stabilization of juvenile metachromatic leukodystrophy after bone marrow transplantation: a 13-year follow-up. J Child Neurol. 2007;22:1139-1142.

43. Solders G, Celsing G, Hagenfeldt L, Ljungman P, Isberg B, Ringden O. Improved peripheral nerve conduction, EEG and verbal IQ after bone marrow transplantation for adult metachromatic leukodystrophy. Bone Marrow Transplant. 1998;22:1119-1122.

44. Pierson TM, Bonnemann CG, Finkel RS, Bunin N, Tennekoon GI. Umbilical cord blood transplantation for juvenile metachromatic leukodystrophy. Ann Neurol. 2008;64:583-587.

45. Krabbe K. A new familial, infantile form of diffuse brain sclerosis. Brain. 1916;39:74-114.

46. Suzuki K, Suzuki Y. Globoid cell leucodystrophy (Krabbe's disease): deficiency of galactocerebroside beta-galactosidase. Proc Natl Acad Sci U S A. 1970;66:302-309.

47. Zlotogora J, Chakraborty S, Knowlton RG, Wenger DA. Krabbe disease locus mapped to chromosome 14 by genetic linkage. Am J Hum Genet. 1990;47:37-44.

48. Chen YQ, Rafi MA, de Gala G, Wenger DA. Cloning and expression of cDNA encoding human galactocerebrosidase, the enzyme deficient in globoid cell leukodystrophy. Hum Mol Genet. 1993;2:1841-1845.

49. Tatsumi N, Inui K, Sakai N, et al. Molecular defects in Krabbe disease. Hum Mol Genet. 1995;4:1865-1868.

50. Igisu H, Suzuki K. Progressive accumulation of toxic metabolite in a genetic leukodystrophy. Science. 1984;224:753-755.

51. Suzuki K. Twenty five years of the "psychosine hypothesis": a personal perspective of its history and present status. Neurochem Res. 1998;23:251-259.

52. White AB, Givogri MI, Lopez-Rosas A, et al. Psychosine accumulates in membrane microdomains in the brain of krabbe patients, disrupting the raft architecture. J Neurosci. 2009;29:6068-6077.

53. Krivit W, Shapiro EG, Peters C, et al. Hematopoietic stem-cell transplantation in globoid-cell leukodystrophy. N Engl J Med. 1998;338:1119-1126.

54. Escolar ML, Poe MD, Martin HR, Kurtzberg J. A staging system for infantile Krabbe disease to predict outcome after unrelated umbilical cord blood transplantation. Pediatrics. 2006;118:e879-889.

55. Duffner PK, Caviness VS, Jr., Erbe RW, et al. The long-term outcomes of presymptomatic infants transplanted for Krabbe disease: Report of the workshop held on July 11 and 12, 2008, Holiday Valley, New York. Genet Med. 2009.

56. Escolar ML, Poe MD, Provenzale JM, et al. Transplantation of umbilical-cord blood in babies with infantile Krabbe's disease. N Engl J Med. 2005;352:2069-2081.

57. Duffner PK, Caggana M, Orsini JJ, et al. Newborn screening for Krabbe disease: the New York State model. Pediatr Neurol. 2009;40:245-252; discussion 253-245.

58. Meikle PJ, Grasby DJ, Dean CJ, et al. Newborn screening for lysosomal storage disorders. Mol Genet Metab. 2006;88:307-314.

59. Kagitani-Shimono K, Mohri I, Yagi T, Taniike M, Suzuki K. Peripheral neuropathy in the twitcher mouse: accumulation of extracellular matrix in the endoneurium and aberrant expression of ion channels. Acta Neuropathol. 2008;115:577-587.

60. Kondo A, Hoogerbrugge PM, Suzuki K, Poorthuis BJ, Van Bekkum DW. Pathology of the peripheral nerve in the twitcher mouse following bone marrow transplantation. Brain Res. 1988;460:178-183.

61. Luzi P, Rafi MA, Zaka M, et al. Biochemical and pathological evaluation of long-lived mice with globoid cell leukodystrophy after bone marrow transplantation. Mol Genet Metab. 2005;86:150-159.

62. Lim ZY, Ho AY, Abrahams S, et al. Sustained neurological improvement following reduced-intensity conditioning allogeneic haematopoietic stem cell transplantation for late-onset Krabbe disease. Bone Marrow Transplant. 2008.

63. Cartier N, Aubourg P. Hematopoietic stem cell gene therapy in Hurler syndrome, globoid cell leukodystrophy, metachromatic leukodystrophy and X-adrenoleukodystrophy. Curr Opin Mol Ther. 2008;10:471-478.

64. Victor S, Coulter JB, Besley GT, et al. Niemann-Pick disease: sixteen-year follow-up of allogeneic bone marrow transplantation in a type B variant. J Inherit Metab Dis. 2003;26:775-785.

65. Shah AJ, Kapoor N, Crooks GM, et al. Successful hematopoietic stem cell transplantation for Niemann-Pick disease type B. Pediatrics. 2005;116:1022-1025.

66. Walkley SU, Suzuki K. Consequences of NPC1 and NPC2 loss of function in mammalian neurons. Biochim Biophys Acta. 2004;1685:48-62.

67. Hsu YS, Hwu WL, Huang SF, et al. Niemann-Pick disease type C (a cellular cholesterol lipidosis) treated by bone marrow transplantation. Bone Marrow Transplant. 1999;24:103-107.

68. Walkley SU. Secondary accumulation of gangliosides in lysosomal storage disorders. Semin Cell Dev Biol. 2004;15:433-444.

69. Shield JP, Stone J, Steward CG. Bone marrow transplantation correcting beta-galactosidase activity does not influence neurological outcome in juvenile GM1-gangliosidosis. J Inherit Metab Dis. 2005;28:797-798.

70. Jacobs JF, Willemsen MA, Groot-Loonen JJ, Wevers RA, Hoogerbrugge PM. Allogeneic BMT followed by substrate reduction therapy in a child with subacute Tay-Sachs disease. Bone Marrow Transplant. 2005;36:925-926.

71. Starer F, Sargent JD, Hobbs JR. Regression of the radiological changes of Gaucher's disease following bone marrow transplantation. Br J Radiol. 1987;60:1189-1195.

72. Ringden O, Groth CG, Erikson A, et al. Long-term follow-up of the first successful bone marrow transplantation in Gaucher disease. Transplantation. 1988;46:66-70.

73. Svennerholm L, Erikson A, Groth CG, Ringden O, Mansson JE. Norrbottnian type of Gaucher disease--clinical, biochemical and molecular biology aspects: successful treatment with bone marrow transplantation. Dev Neurosci. 1991;13:345-351.

74. Tsai P, Lipton JM, Sahdev I, et al. Allogenic bone marrow transplantation in severe Gaucher disease. Pediatr Res. 1992;31:503-507.

75. Goker-Alpan O, Wiggs EA, Eblan MJ, et al. Cognitive outcome in treated patients with chronic neuronopathic Gaucher disease. J Pediatr. 2008;153:89-94.

76. Krasemann EW, Meier V, Korenke GC, Hunneman DH, Hanefeld F. Identification of mutations in the ALD-gene of 20 families with adrenoleukodystrophy/adrenomyeloneuropathy. Hum Genet. 1996;97:194-197.

77. Berger J, Gartner J. X-linked adrenoleukodystrophy: clinical, biochemical and pathogenetic aspects. Biochim Biophys Acta. 2006;1763:1721-1732.

78. Ito M, Blumberg BM, Mock DJ, et al. Potential environmental and host participants in the early white matter lesion of adreno-leukodystrophy: morphologic evidence for CD8 cytotoxic T cells, cytolysis of oligodendrocytes, and CD1-mediated lipid antigen presentation. J Neuropathol Exp Neurol. 2001;60:1004-1019.

79. Powers JM, Moser HW, Moser AB, Ma CK, Elias SB, Norum RA. Pathologic findings in adrenoleukodystrophy heterozygotes. Arch Pathol Lab Med. 1987;111:151-153.

80. Eichler F, Van Haren K. Immune response in leukodystrophies. Pediatr Neurol. 2007;37:235-244.

81. Cartier N, Hacein-Bey-Abina S, Bartholomae CC, et al. Hematopoietic stem cell gene therapy with a lentiviral vector in X-linked adrenoleukodystrophy. Science. 2009;326:818-823.

82. Dubey P, Raymond GV, Moser AB, Kharkar S, Bezman L, Moser HW. Adrenal insufficiency in asymptomatic adrenoleukodystrophy patients identified by very long-chain fatty acid screening. J Pediatr. 2005;146:528-532.

83. Loes DJ, Fatemi A, Melhem ER, et al. Analysis of MRI patterns aids prediction of progression in X-linked adrenoleukodystrophy. Neurology. 2003;61:369-374.

84. Mahmood A, Raymond GV, Dubey P, Peters C, Moser HW. Survival analysis of haematopoietic cell transplantation for childhood cerebral X-linked adrenoleukodystrophy: a comparison study. Lancet Neurol. 2007;6:687-692.

85. Mahmood A, Dubey P, Moser HW, Moser A. X-linked adrenoleukodystrophy: Therapeutic approaches to distinct phenotypes. Pediatr Transplant. 2005;9:55-62.

86. Moser HW, Raymond GV, Lu SE, et al. Follow-up of 89 asymptomatic patients with adrenoleukodystrophy treated with Lorenzo's oil. Arch Neurol. 2005;62:1073-1080.

87. Grewal SS, Shapiro EG, Krivit W, et al. Effective treatment of alpha-mannosidosis by allogeneic hematopoietic stem cell transplantation. J Pediatr. 2004;144:569-573.

88. Grewal SS, Barker JN, Davies SM, Wagner JE. Unrelated donor hematopoietic cell transplantation: marrow or umbilical cord blood? Blood. 2003;101:4233-4244.

89. Souillet G, Guffon N, Maire I, et al. Outcome of 27 patients with Hurler's syndrome transplanted from either related or unrelated haematopoietic stem cell sources. Bone Marrow Transplant. 2003;31:1105-1117.

90. Kharbanda S, Panoskaltsis-Mortari A, Haddad IY, et al. Inflammatory cytokines and the development of pulmonary complications after allogeneic hematopoietic cell transplantation in patients with inherited metabolic storage disorders. Biol Blood Marrow Transplant. 2006;12:430-437.

91. Whitley CB, Belani KG, Chang PN, et al. Long-term outcome of Hurler syndrome following bone marrow transplantation. Am J Med Genet. 1993;46:209-218.

92. Grewal S, Shapiro E, Braunlin E, et al. Continued neurocognitive development and prevention of cardiopulmonary complications after successful BMT for I-cell disease: a long-term follow-up report. Bone Marrow Transplant. 2003;32:957-960.

93. Braunlin EA, Stauffer NR, Peters CH, et al. Usefulness of bone marrow transplantation in the Hurler syndrome. Am J Cardiol. 2003;92:882-886.

94. Shapiro EG, Lockman LA, Balthazor M, Krivit W. Neuropsychological outcomes of several storage diseases with and without bone marrow transplantation. J Inherit Metab Dis. 1995;18:413-429.

95. Hite SH, Peters C, Krivit W. Correction of odontoid dysplasia following bone-marrow transplantation and engraftment (in Hurler syndrome MPS 1H). Pediatr Radiol. 2000;30:464-470.

96. Field RE, Buchanan JA, Copplemans MG, Aichroth PM. Bone-marrow transplantation in Hurler's syndrome. Effect on skeletal development. J Bone Joint Surg Br. 1994;76:975-981.

97. Wraith JE, Alani SM. Carpal tunnel syndrome in the mucopolysaccharidoses and related disorders. Arch Dis Child. 1990;65:962-963.

98. Baker KS, DeFor TE, Burns LJ, Ramsay NK, Neglia JP, Robison LL. New malignancies after blood or marrow stem-cell transplantation in children and adults: incidence and risk factors. J Clin Oncol. 2003;21:1352-1358.

99. Bhatia S, Ramsay NK, Steinbuch M, et al. Malignant neoplasms following bone marrow transplantation. Blood. 1996;87:3633-3639.

100. Bhatia S, Francisco L, Carter A, et al. Late mortality after allogeneic hematopoietic cell transplantation and functional status of long-term survivors: report from the Bone Marrow Transplant Survivor Study. Blood. 2007;110:3784-3792.

101. Desnick RJ. Enzyme replacement and enhancement therapies for lysosomal diseases. J Inherit Metab Dis. 2004;27:385-410.

102. Cox TM. Substrate reduction therapy for lysosomal storage diseases. Acta Paediatr Suppl. 2005;94:69-75; discussion 57.

103. Gregersen N, Bolund L, Bross P. Protein misfolding, aggregation, and degradation in disease. Mol Biotechnol. 2005;31:141-150.

104. Desnick RJ, Schuchman EH. Enzyme replacement and enhancement therapies: lessons from lysosomal disorders. Nat Rev Genet. 2002;3:954-966.

105. Hoffmann B, Mayatepek E. Neurological manifestations in lysosomal storage disorders - from pathology to first therapeutic possibilities. Neuropediatrics. 2005;36:285-289.

106. Vellodi A. Lysosomal storage disorders. Br J Haematol. 2005;128:413-431.

107. Jeyakumar M, Thomas R, Elliot-Smith E, et al. Central nervous system inflammation is a hallmark of pathogenesis in mouse models of GM1 and GM2 gangliosidosis. Brain. 2003;126:974-987.

108. Spagnoli A, Longobardi L, O'Rear L. Cartilage disorders: potential therapeutic use of mesenchymal stem cells. Endocr Dev. 2005;9:17-30.

109. Young PP, Fantz CR, Sands MS. VEGF disrupts the neonatal blood-brain barrier and increases life span after non-ablative BMT in a murine model of congenital neurodegeneration caused by a lysosomal enzyme deficiency. Exp Neurol. 2004;188:104-114.

110. Zaka M, Rafi MA, Rao HZ, Luzi P, Wenger DA. Insulin-like growth factor-1 provides protection against psychosine-induced apoptosis in cultured mouse oligodendrocyte progenitor cells using primarily the PI3K/Akt pathway. Mol Cell Neurosci. 2005;30:398-407.

111. Li Y, Scott CR, Chamoles NA, et al. Direct multiplex assay of lysosomal enzymes in dried blood spots for newborn screening. Clin Chem. 2004;50:1785-1796.

112. Meikle PJ, Ranieri E, Simonsen H, et al. Newborn screening for lysosomal storage disorders: clinical evaluation of a two-tier strategy. Pediatrics. 2004;114:909-916.

113. Millington DS. Newborn screening for lysosomal storage disorders. Clin Chem. 2005;51:808-809.

114. Staba SL, Escolar ML, Poe M, et al. Cord-blood transplants from unrelated donors in patients with Hurler's syndrome. N Engl J Med. 2004;350:1960-1969.

115. Davoust N, Vuaillat C, Androdias G, Nataf S. From bone marrow to microglia: barriers and avenues. Trends Immunol. 2008;29:227-234.

116. D'Mello C, Le T, Swain MG. Cerebral microglia recruit monocytes into the brain in response to tumor necrosis factoralpha signaling during peripheral organ inflammation. J Neurosci. 2009;29:2089-2102.

117. Hall AA, Herrera Y, Ajmo CT, Jr., Cuevas J, Pennypacker KR. Sigma receptors suppress multiple aspects of microglial activation. Glia. 2009;57:744-754.

118. Semple BD, Bye N, Rancan M, Ziebell JM, Morganti-Kossmann MC. Role of CCL2 (MCP-1) in traumatic brain injury (TBI): evidence from severe TBI patients and CCL2-/- mice. J Cereb Blood Flow Metab. 2009.

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1. Introduction

Hematopoietic cell transplantation (HCT) is a prototypic stem cell therapy, and has been a life-saving measure for tens of thousands of patients. Over its relatively short history, the study of transplantation has shown that the transfer of relatively few cells can lead to the development of a fully functional lympho-hematopoietic system in the recipient, that bidirectional immunologic tolerance between post-natal tissues is possible, and that cancer can be eradicated by immunologic means.

After the seminal insight that cells with two different enzyme deficiencies can complement each other [1], a paradigm shift occurred, according to which stem cell transfer is applicable to equally fatal but non-malignant disorders [2]. This has translated into the establishment of transplantation as the standard of care for some of these enzyme disorders; monitoring of hundreds of patients with congenital metabolic disorders after transplantation has shown that long-lasting cross correction can be achieved. Conceptually, these benefits have been limited to congenital defects of enzymes, but there is no intellectual barrier to applying this strategy to other diseases where structural proteins are deficient, such as in extracellular matrix disorders.

In this review, we intend to present experiences with hematopoietic cell transplantation that have established its functionality and benefits for children with congenital metabolic storage diseases, and to describe some limitations and open questions regarding HCT for these conditions. 

2. Conditioning regimens and graft sources

HCT for malignant as well as non-malignant diseases has traditionally been preceded by myeloablative doses of total body irradiation (TBI) and chemotherapy, or more commonly in the non-malignant setting, with myeloablative doses of busulfan combined with cyclophosphamide [3-6]. These regimens were also originally designed to be effective in treating the underlying malignancy, particularly leukemia, as well as providing intensive immunosuppression to prevent graft rejection. Although effective at achieving durable engraftment in most patients, intensive chemotherapy leads to a significant risk of short-term morbidity and a 10–30% risk of transplant-related mortality in patients with inborn errors of metabolism (IEM) [7]. Additionally, exposure to high doses of these agents can lead to a risk of significant late effects (cataracts, endocrinopathies, pulmonary and cardiac abnormalities, and new malignancies) as discussed later in this chapter. For these reasons, many parents and non-transplant physicians have been unwilling to accept the risks of HCT for children with IEM. 

The demonstration that stable mixed chimerism could be achieved with sub-lethal doses of TBI (approximately one-sixth of the dose administered with standard TBI) and immunosuppression with cyclosporine and mycophenolate mofetil led to the widespread development of so-called non-myeloablative or reduced intensity conditioning regimens [8]. While these regimens were initially intended for patients who were ineligible for standard high dose conditioning, the fact that these regimens avoid many of the major short and long term toxicities associated with HCT has made this approach very attractive for use in children with non-malignant disorders. Fludarabine, a relatively new chemotherapeutic agent that has been widely used for conditioning, is highly immunosuppressive and has limited non-hematologic toxicity [9]. It has been used with low-dose TBI or without TBI in combination with busulfan, melphalan, or other agents. The use of these regimens in patients who are “chemotherapy naive” and who have normal immune systems, such as patients with IEM, has been very limited and associated with high rates of graft rejection. Additionally, measures commonly employed with reduced intensity conditioning to improve or boost engraftment, such as donor lymphocyte infusions, are associated with a high risk of acute and chronic graft vs. host disease (GVHD). Despite these issues, the use of reduced intensity conditioning in patients with IEM is a desirable goal, and research continues to refine these regimens with the objective of optimizing engraftment and minimizing toxicity. 

The other consideration regarding HCT for patients with IEM is graft source. Obviously the preference is for HLA-matched sibling donors, but this is an option for only a minority of patients. The availability may be even lower for this patient group because siblings can also be affected with the disease. Certainly many of the potential matched sibling donors may be carriers of the disease in question. The question as to whether an alternative donor should be used preferentially over a sibling shown to be a carrier remains unanswered. Alternative unrelated donor sources (bone marrow, peripheral blood stem cells, cord blood) have been routinely utilized with good results. Acute and chronic GVHD is the major limitation to the use of alternative donors, and in these patients with non-malignant disorders there is no benefit to be derived from GVHD. Methods employed to reduce the risk of GVHD include T cell depletion (TCD) and possibly the use of umbilical cord blood. Both of these methods appear to be effective in reducing the risk of GVHD, but each carries with it a higher risk of graft rejection as well as a higher risk of infectious complications (particularly from viruses).

3. Lysosomal storage diseases

3.1. Mucopolysaccharidoses

Mucopolysaccharidoses are autosomal recessive disorders characterized by deficiencies of enzymes needed for the stepwise catabolism of complex sugars termed glycosaminoglycans (GAG) [10-12]. Some of these conditions predominantly affect the viscera; the others are both neuronopathic and visceral. Many of them also exhibit a dynamic range from a less severe phenotype associated with hypomorphic mutations to severe ones generally associated with null mutations.

3.1.1. Mucopolysaccharidosis type I (Hurler Syndrome)

In mucopolysaccharidosis type I (MPS I), the deficiency of α-L-iduronidase (IDUA) results in lysosomal accumulation of the GAG heparan sulfate and dermatan sulfate. This in turn leads to progressive cellular and multi-organ dysfunction. While the clinical findings may be apparent at birth, the manifestations of the disease and onset of symptoms usually occur by six months of age. Multiple organ systems are affected, and many of these patients present with or develop hepatosplenomegaly, cardiac disease, umbilical or inguinal hernia, obstructive airway disease, chronic rhinitis and otitis, skeletal deformities, hydrocephalus, neurocognitive deterioration, and corneal clouding. If left untreated, death occurs between 5 and 10 years of age, primarily from cardiac causes.

Treatments focus on approaches to replace the missing IDUA. This can be achieved either by exogenous administration of IDUA or through the endogenous production of IDUA following stable engraftment of normal cells producing enzyme within the affected individual. The former is achieved by enzyme replacement therapy (ERT) available for MPS I since 2003 [13], and the latter by HCT, which was first shown to hold promise in 1980 [2]. The therapeutic basis for both treatment options is that IDUA can be taken up by recipient cells via the mannose-6-phosphate receptor and then be translocated to lysosomes where it mediates the hydrolysis of GAG.

HCT has been accepted as a standard of care for patients with severe forms of MPS I (Hurler Syndrome). Initially, unaffected HLA-genotypically-identical bone marrow donors were considered the optimal donors, but results with matched unrelated donors, and especially with cord blood, are encouraging. As a result of better availability of improved methods for HLA typing and supportive care, the early engraftment and survival rates have improved, and currently may be as high as 85% in institutions specializing in transplantation for metabolic storage diseases [5, 14-19].

Remarkably, donor-derived cells engraft even within the brain, thereby providing a source of enzyme to the central nervous system and halting the neurocognitive decline in most patients [20]. This is in addition to correction of most of the visceral signs of pathology, including cardiovascular function, organomegaly, and lung disease. In contrast, the heart valves and skeletal abnormalities are largely unaffected by this therapy.

ERT has been introduced for treatment of less severe visceral forms of MPS I, and is currently the standard of care in patients without neurologic disease, since IDUA does not cross the blood-brain barrier [21]. Recent data on a combination of ERT with HCT are encouraging, however, and appear to support the possibility that combination therapy is in fact the new standard of care for patients with Hurler Syndrome [22-24]. The rationale for this approach is based on identifying risks in the pre-transplant course that are associated with increased morbidity and mortality during and after HCT [7]. Most prominent among these risks are upper and lower lung disease. It follows that if the enzyme can be provided for a sufficient time before transplantation, GAG storage in viscera can be partially cleared, and may result in fewer complications during HCT. The possibility that pre-transplant enzyme replacement therapy will result in increased graft failure because of generation of antibodies against donor cells has not been borne out. Of note, some advocate the use of combination therapy primarily for patients with higher risk disease. We and others, however, offer combination therapy for all patients with MPS I who are considered for HCT, because of the low risks associated with enzyme therapy and the potential that it may decrease life-threatening complications after HCT. In addition, it is possible that decreases in GAG, after enzyme replacement therapy, but before the HCT, can create a more permissive environment in the bone marrow niche for donor engraftment when compared to the patients who did not receive ERT.

3.1.2. Other mucopolysaccharidoses

In contrast to Hurler Syndrome, HCT has not been shown to significantly alter the natural history of patients with severe mucopolysaccharidosis type II (Hunter Syndrome). The attenuated phenotypes may benefit from stem cell therapy, but for yet unknown reasons, children with severe MPS II phenotype do not appear to gain neurocognitive benefit from the transplant. Whether transplantation before the onset of symptoms, such as in the neonatal period, may improve outcomes is as  yet unclear. 

Similarly, early results with HCT using allogeneic grafts have not been very encouraging in patients with Sanfilippo Syndrome (MPS III). Only limited published data exist regarding transplant results, but available data suggest that, in contrast to MPS I, the neurologic deterioration of MPS III patients is not alleviated by transplantation.
Morquio Syndrome (MPS IV), is characterized by significant musculoskeletal disease with less prominent neurologic changes, and so far has not been shown to benefit from HCT.

In contrast, the visceral findings of Maroteaux-Lamy Syndrome (MPS VI) have been shown to improve with HCT. However, the availability of enzyme replacement therapy for MPS VI limits the need for HCT.

Finally, Sly Syndrome (MPS VII), which results in bone deformities, developmental delays, and organomegaly, has been treated with HCT with some positive response [25-27].

Thus, individual mucopolysaccharidoses differ substantially with regards to their responses to HCT and ERT. While HCT, especially in combination with ERT, is a standard of care for severe MPS I (Hurler Syndrome), the efficacy of standard methods of transplantation for MPS II and MPS III has not been established.

4. Sphingolipidoses

The glycosphingolipids are an important component of the cell membrane, consisting of polysaccharide bound to lipid, primarily ceramide, which is incorporated into the membrane [28]. The polysaccharide portion contributes to cell interactions, adhesion,  and signaling, in addition to other functions [29]. Degradation is accomplished through the action of lysosomal acid hydrolases, which serve to remove the carbohydrate moiety. Collectively the glycosphingolipid disorders are the most common cause of neurogenerative diseases (incidence approximately 1:18,000) in children [28]. With the exception of Fabry disease, these disorders are inherited in an autosomal recessive pattern. Based on the enzyme defect and substrate accumulation, these disorders are often divided into GM1 gangliosidosis, GM2 gangliosidoses (Tay-Sachs disease and Sandhoff disease), Fabry disease, multiple sulfatase deficiency, Gaucher disease, Niemann-Pick A and B, Farber disease, metachromatic leukodystrophy (MLD) and globoid cell leukodystrophy (GLD, also known as Krabbe disease). Most data regarding transplantation for these disorders relate to experience with MLD and GLD. These disorders will be discussed individually.

4.1. Metachromatic leukodystrophy

Metachromatic leukodystrophy (MLD) results from a decrease in arylsulfatase A (ARSA) activity, leading to the accumulation of the substrate cerebroside 3-sulfate, a component of myelin [30].  Decreased ARSA activity leads to demyelination of the white matter of the central nervous system (CNS) as well as the peripheral nerves [31].  Arylsulfatase A deficiency leading to MLD occurs with an overall incidence of approximately 1:40,000 births, while a higher frequency may be observed in specific populations [31-33]. There is significant phenotypic variation in MLD. In patients with the “late-infantile” form of the disease, neurological deterioration is initially observed within the first several years of life. Death generally ensues several years from diagnosis. Symptoms are associated with both central and peripheral demyelination, and motor-related difficulties are often apparent earlier than loss of cognition and language skills. The juvenile form of the disease has an onset from 4 years of age through adolescence [34-35]. Clinical manifestations of juvenile MLD are similar to the infantile form, although the rate of progression is slower. The adult form of the disease may become apparent as late as the seventh decade, and represents approximately 20% of cases of MLD [36]. Rather than presenting with motor-related difficulties, patients with late-onset disease may have emotional lability, progressive dementia, psychosis, and difficulties with substance abuse. There is a phenotype-genotype correlation in MLD, with more severe mutations resulting in more rapid accumulation of sulfatides and disease progression [37]. 

Krivit reported the results of the first transplant for MLD in 1990 [38]. Subsequently, reports of the success of transplantation for MLD generally have been limited to a small numbers of patients, and these data are difficult to assess due to variations in phenotype (late-infantile, juvenile, or adult forms) as well as the state of the disease at the time of transplantation [34]. Assessment of these outcomes is further limited by the lack of a universal standard for clinically assessing these patients both prior to and after transplantation. Obtaining such data will be critical to determining the utility of therapy, as asymptomatic patients or those early in their disease course are more likely to have better outcomes [16]. Similarly, those with less severe phenotypes may respond better to therapy. In regards to symptomatic late-infantile disease, while sulfatide levels decrease in urine and cerebrospinal fluid and the rate of progression may be less than observed in untreated siblings, the available data do not support the claim that transplantation has the capacity to stabilize disease [39]. The inability to deliver sufficient amounts of enzyme into the CNS is likely a primary limitation, as enzyme delivery is dependent on engraftment of cells such as the microglial population in the brain, which may take months following transplant [12, 27, 34]. In addition, despite engraftment of allogeneic cells, patients with infantile disease also appear to have progressive peripheral disease. Whether asymptomatic patients identified by neonatal screening or by family history who would be predicted to develop infantile disease can benefit from transplantation within the newborn period is debatable. Data available to address this question suggest that these patients continue to have progressive motor disabilities [34, 40-41]. In contrast, reports of the outcome of transplantation of later-onset disease (juvenile and adult forms) suggest that stabilization of the central nervous system may be achieved, even if patients are symptomatic at the time of transplantation [39,42-43]. As may be expected, the rate of decline prior to transplantation and the status of the disease at transplant are likely to affect outcomes [44]. 

4.2. Globoid cell leukodystrophy

The disorder known as globoid cell leukodystrophy (GLD) was initially described in 1916 by Krabbe, who reported infants developing spasticity and sclerosis of the brain [45]. Krabbe also described the characteristic “globoid cell” present in the white matter of affected patients. In 1970 the enzyme defect responsible for GLD was identified as the lysosomal enzyme galactocerebroside β-galactosidase (GALC) [46], also commonly referred to as galactocerebrosidase. In 1990 Zlotogora localized the gene to chromosome 14 [47], and the gene was cloned by Wenger’s laboratory in 1993 [48]. The primary substrate that accumulates in GLD is galactocerebroside, which is degraded by GALC to ceramide and galactose [49]. The metabolite psychosine accumulates as well in GLD, as it is a substrate for GALC [35]. Psychosine has been thought to contribute to cytotoxicity of cells in the CNS, including oligodendrocytes [50-52]. 

Globoid cell leukodystrophy has an incidence of 1:70,000–100,000, and presents with a varied phenotype, similar to MLD. Historically, 85–90% of patients with GLD develop symptoms as  infants [35]. Patients with infantile GLD characteristically become increasingly irritable, with increased sensitivity to stimuli, developmental arrest and subsequent regression [35]. Protein levels in the cerebro-spinal fluid are high.  Hypertonicity is apparent, with feeding difficulties and visual changes; increased deep tendon reflexes and seizures may be observed. Death generally results within a few years of the onset of symptoms. Other patients have less severe disease, and have been divided into late infantile (onset from 6 months to 3 years) and juvenile forms (ages 3–8 years), while some patients are not diagnosed until their second or third decades, and occasionally later [35]. As might be expected, these later onset patients have a less rapidly progressive disease course. 

The first description of the outcomes of GLD patients treated by allogeneic transplantation were provided by Krivit et al in 1998 [53]. Four of the 5 patients reported had late onset disease, while one had typical infantile GLD. For the older patients, the patients appeared to stabilize, or even improve, in regards to their disease. The patient with infantile disease was transplanted at 2 months of age. By now there is sufficient experience with transplantation of symptomatic patients with infantile disease to state that transplantation is not effective at arresting disease progression, although the clinical course may be attenuated [39]. In addressing this question, Escolar reported a staging system for clinically assessing patients with GLD in the pre-transplant period, and correlated this to outcomes [54]. There has recently been great interest in the outcomes of patients with presumed infantile GLD if these patients are transplanted in the neonatal period [55]. These very young and asymptomatic patients who would be predicted to have a severe phenotype, clearly have a different clinical course after transplantation than would be expected without transplantation  [56]. Based on this observation, there has been significant discussion regarding the use of newborn screening as a means of identifying these patients prior to the onset of symptoms [57, 58]. However, it remains unclear how patients who have severe genotypes and are transplanted in the first weeks of life will do as they age [55]. It is of interest that many of the difficulties these patients face are motor limitations, and this is likely at least in part due to peripheral nerve demyelination. Such a finding would be in keeping with observations in the twitcher mice, a model for GLD [59-61]. Thus far there has not been universal agreement to move towards neonatal screening for GLD with the intention of identifying and transplanting patients predicted to have severe disease soon after delivery, although screening is currently being done in New York, and is likely to be in place soon in several other US states. It should be noted that due to the severe time limitations in attempting to transplant asymptomatic neonates, a large proportion of these infants will require cord blood grafts. This has been suggested to be a preferred graft source, not only because of the expediency of moving to transplantation, but also because of the possibility of an increased ability of cord blood to transdifferentiate into a variety of non-hematopoietic stem cells or progenitor cells [16]. Additional clinical information will be required to determine if this will be the case. 

The efficacy of transplantation in patients with later onset GLD remains less well delineated than would be expected. It has previously been stated that patients with later onset disease are likely to benefit from transplantation [62]. In some cases, improvement has been reported [26]. However, data related to large series of patients focused on the function and neurocognitive outcomes are not available. It would be important to review the genotypic findings of an individual diagnosed by GALC activity to determine whether it is reasonable to pursue transplantation in an asymptomatic patient, as it is not necessarily clear what the anticipated course will be. However, if a patient with later-onset disease is early in the course of the disease, transplantation seems a reasonable option. It has been suggested that for a number of these diseases, multi-institutional trials with standard methods of analysis would prove very beneficial to the field [63], and despite the difficulties inherent in developing and funding these large trials that could require decades to complete, it is difficult to argue with this view. 

Other related lysosomal disorders have been treated with transplantation, although less data are available than for MLD and GLD. Niemann-Pick A and B result from a deficiency in sphingomyelinase. In Niemann-Pick A rapid neurologic progression is often observed. For these patients, who are severely affected and deteriorating rapidly, there are insufficient data to confirm that transplantation modifies the course of neurologic disease. In Niemann-Pick B, there is little published data, but our group and others have observed improvement in the marrow and lung pathology of these patients after transplant [64-65]. Niemann-Pick C has been shown to have 2 subtypes, both associated with accumulation of cholesterol. Niemann-Pick C1 is the most frequent form, but is not due to a lysosomal enzyme defect and therefore is less likely to respond to transplantation. In contrast, Niemann-Pick C2 disease is associated with a deficit in a lysosomal enzyme [66]. While it has been reported that there is an insufficient response of Niemann-Pick C to transplantation [67], the ability to separate the genotypes has only recently become available. Although it might be expected that type C2 may respond to transplantation, results have not been reported in individuals confirmed to have this genotype. As the C2 genotype is much less common than C1, genetic analysis prior to intervention will be of importance.

GM1 gangliosidosis is characterized by seizures and psychomotor deficits, and has infantile, juvenile, and adult onset forms [35, 68]. While little information is available regarding the utility of transplantation, a report describing a juvenile patient suggests there is little benefit from transplantation [69]. GM2 gangliosidosis disorders (Tay-Sachs and Sandhoff) are due to abnormalities within the hexosaminidase (HEX) gene [68]. In the case of Tay-Sachs, HEX A is deficient, while in Sandhoff HEX A and B are deficient. Unfortunately in most cases these disorders are rapidly progressive, and there is little information to suggest that symptomatic patients benefit from transplantation [40, 70]. However, it is as yet unclear as to whether those with late-onset disease or newborns predicted to have early-onset disease would benefit. Gaucher disease has been shown to benefit from transplantation [71-74], but as there is enzyme replacement therapy available for Gaucher, there is little enthusiasm for the morbidity and mortality associated with transplantation for this disorder. However, as the neuropathic form of Gaucher does not benefit from ERT [75], there may be interest in evaluating transplantation in patients with Gaucher who show evidence of neurologic deterioration [40]. Fabry disease is an X-linked disorder of the lysosomal enzyme α-galactosidase A, which results in accumulation of substrate in the kidneys, heart, eyes, and blood vessels, but does not have a significant neurological component. As enzyme replacement therapy is available for Fabry, there is currently no enthusiasm for transplantation [41]. 

4.3. Adrenoleukodystrophy

While GLD and MLD are autosomal recessive lysosomal enzyme deficiencies, adrenoleukodystrophy (ALD) is an X-linked disorder of the peroxisome that results in abnormal metabolism of very long chain fatty acids (VLCFA) due to decreased beta-oxidation. These VLCFA accumulate in the testes, adrenal gland, and white matter of the central nervous system [76]. For reasons that are not clear, approximately 40% of individuals with ALD under 20 years of age show a clinical course of rapid neurologic deterioration [77]. This condition, representing the cerebral form of ALD, is an inflammatory process present in the CNS, with a mixed cellular infiltrative process, although CD8+ T cells are prominent [78-79]. Eichler stated that the bulk of the inflammation occurs behind the area in which demyelination is seen, and he proposed that the infiltrative process occurs in response to demyelination rather than being its cause [80]. The beneficial effects of HCT are thought to be related at least in part to elimination of the active inflammation present in the CNS, although recent early findings of a gene therapy approach suggest that there is a corrective process provided by hematopoietically-derived cells [81]. Another important issue in regards to the early identification of ALD relates to adrenal insufficiency. Primary adrenal insufficiency (AI), or Addison’s disease, which precedes cerebral manifestations of ALD, occurs with an estimated prevalence of 43% in asymptomatic boys with X-ALD [82]. In our center’s experience, 7 boys who have been evaluated for transplantation for cerebral ALD since 2002 had previously been diagnosed with adrenal insufficiency, but VLCFA testing was not performed expeditiously, resulting in a delay in diagnosis and presumably disease progression that either rendered the patient ineligible for transplantation or put him at higher risk for a poor outcome (Polgreen et al., unpublished observations). 

Transplantation early in the course of cerebral ALD has been shown to stabilize the disease process, although it is clear that in more advanced patients the outcome is inferior [4]. An MRI scoring system was developed by Loes to quantitate the extent of the disease [83], and this allows the identification of patients who are at high risk for poor outcomes of transplantation. Due to the importance of the extent of disease in the ability of transplantation to arrest the disease process [84], it is recommended that boys with biochemically proven ALD be monitored with serial MRI scans, and to proceed with transplantation when patients show evidence of early progression to cerebral disease [4]. It is not known whether transplantation plays any role in preventing the evolution of other manifestations of ALD, such as the peripheral nervous system condition termed adrenomyeloneuropathy (AMN). In addition, there are no data to show that transplantation prior to the onset of cerebral ALD will prevent its occurrence. Therefore the risks of transplantation are not justified in patients without evidence of evolving cerebral ALD, as a majority of boys will not develop cerebral ALD [85]. The use of Lorenzo’s oil in patients who have not yet developed cerebral ALD may decrease the risk of its occurrence [86]. 

5. Oligosaccharidosis: Mannosidosis

Alpha-mannosidosis presents with hepatosplenomegaly, vomiting, immune deficiency, and dysostosis multiplex. Affected patients also have mental retardation and ocular clouding. Approximately 20 patients have been transplanted to date, some of whom had pulmonary and airway complications during the first several months after HCT. Remarkably, the mental development as well as cardiopulmonary function appear to have been preserved, suggesting that HCT is a valid treatment option for alpha-mannosidosis [87].

6. Enzyme localization defect: Mucolipidosis Type II (I-Cell Disease)

Mucolipidosis Type II results from a defect in a phosphotransferase that is integral to the localization of numerous lysosomal hydrolyses. In the absence of this targeting mechanism, these lysosomal enzymes are secreted rather than retained in the lysosome. This results in lysosomal substrate accumulation, while extremely high serum levels of these enzymes are observed in the plasma. The phenotype resembles MPS I, but the response to HCT has been much less favorable [88]. It remains to be determined whether early identification of these patients, before the damage to visceral and neuronal tissue is irreversible and profound, and expedient transplantation may improve outcomes. 

7. Late effects after HCT for Metabolic Storage Disease

As discussed previously, the majority of patients with IEM who undergo HCT do so following traditional high-dose, chemotherapy-based conditioning regimens. The combination of busulfan and cyclophosphamide is the most common regimen utilized. Patients with IEM are unique, however, in that they also have to face the potential of long-term complications related to their underlying disease that may not be reversed or prevented by successful HCT. One can assume that they are at the same risk as other patients going through HCT for the common conditions seen after exposure to high-dose chemotherapy in the conditioning regimen, but there are little data that describe those findings. Additionally, there may be unique long-term effects of some of the preparative regimens in patients with IEM, but again for the most part these have not been reported to date. Limited long-term follow-up data in some subsets of IEM patients (Hurler’s syndrome in particular) related to amelioration of disease-associated conditions are available and will be briefly summarized. 

Endocrine issues. There are minimal IEM-specific data, but some patients have been found to have primary ovarian failure [19]. It is unclear if this is related to the disease or HCT since both may contribute. Other endocrine issues seen in children after HCT include gonadal failure in males, hypothyroidism, and growth failure. While some of these conditions may be more frequently encountered after exposure to TBI, they can also be seen with non-TBI containing regimens. Patients with Hurler’s syndrome have growth problems to begin with, and while some reports suggest that linear growth may be maintained early after HCT, others suggest growth may not be maintained on a long-term basis [19, 89]. 

Pulmonary. Patients with IEM have high rates of pulmonary complications during HCT that may be related to a pro-inflammatory state within the lung [90]. While busulfan can lead to pulmonary fibrosis, this is not a common complication in children after HCT. In patients with Hurler’s it has been demonstrated that they do have relief of their obstructive airway symptoms and improvement in sleep apnea with improved pulmonary function [19, 91]. A reduction in the risk of pulmonary deterioration in a patient successfully transplanted for I-cell disease has also been reported [92].

Cardiac. Long-term cardiovascular complications are rarely associated with exposure to cyclophosphamide and busulfan alone. Certainly for several of the IEM disorders, progressive cardiac dysfunction is common. For patients with Hurler’s, long-term follow-up after HCT has shown that myocardial function is preserved and hypertrophy has been seen to regress, and patients have not developed heart failure or coronary artery disease. However, mitral and aortic valve deformities have persisted and frequently progressed [93].

Neuropsychological and cognitive function. In the absence of exposure to radiation during conditioning, children typically do not have significant neuropsychological sequelae secondary to HCT. In the case of children with IEM, post-HCT neurologic outcome depends upon the specific disease, age at time of HCT, specific genotype of the disease, cognitive status at the time of HCT, engraftment status, and donor enzyme activity after HCT. The goal, of course, is to perform HCT early in the course of the disease before any extensive neurologic damage or deterioration has occurred. When this can be done, neurocognitive function can be stabilized (or in some cases improved) and further progressive neurologic deterioration can be prevented [5, 19, 89,91, 94].
 
Bone and joints. HCT conditioning can affect bone health leading to osteopenia and osteoporosis. This may be reversible on its own over time or may require further intervention with vitamin D and calcium supplementation or occasionally treatment with bisphosphonates. These effects have not been studied to date in children with IEM. Other disease-specific orthopedic complications, such as odontoid dysplasia in patients with Hurler’s, have been shown to improve over time [95]. However, other  complications such as genu valgum, carpel tunnel syndrome, and acetabular dysplasia have not improved after HCT and frequently require surgical intervention [96-97].
 
Post-transplant malignancies. It has been well described that patients after HCT are at life-long increased risk of developing malignancies that is estimated at nearly 10-fold greater than that in the general population [98-99]. Whether this same risk applies to patients with IEM is not known, but we are aware of some patients who have developed malignancies years after HCT. 

Late Mortality. After allogeneic HCT patients have twice the risk of mortality of the general population [100]. Data submitted for publication from the Center for International Blood and Marrow Transplant Research demonstrate that patients with IEM have a higher risk of mortality between 2–6 yrs after HCT and that this increased risk persists even 6 yrs after HCT. This increased risk is highest in patients who have received unrelated or HLA non-identical related donor transplants. Causes of death include GVHD, infection, and organ failure. 

Summary

Obtaining clear data regarding the outcomes of transplantation in patients with IEM has proven difficult due to the rarity of these diseases, their variable phenotypes/genotypes, and differences in stem cell sources, preparative regimens, supportive therapy, and assessment of “successful” outcomes. Multi-institution trials with a common approach and outcome measures will be important in this regard. In earlier years HCT in these populations used standardized regimens designed for patients with malignant disorders. For disorders such as Hurler’s syndrome and early cerebral ALD, this approach has been successful. However, for other disorders, the ability to achieve satisfactory outcomes with standard transplant regimens has proven elusive. Reduced-intensity conditioning strategies may prove more successful in decreasing morbidity and mortality, particularly in patients with ongoing neurologic injury. It is anticipated that future investigations will test the use of combination therapy with or without transplantation, including substrate inhibition [101-102], chaperone therapy [103-105], enzyme replacement [24, 106], modification of anti-inflammatory therapy [107], or biologic response modifiers [108-110]. In addition, the interest in neonatal screening will provide the opportunity to intervene early in the course of these diseases, as this appears critical in achieving optimal outcomes [4, 111-114]. Finally, modifying the transplant procedure, using selectively expanded cell populations, or using cytokine manipulation may enhance microglial engraftment [115-118], which could make a substantial difference in the delivery of enzyme to the CNS. Significant progress is required to enhance transplant results and to determine optimal therapy in individuals with these devastating congenital disorders. 

References

1. Fratantoni JC, Hall CW, Neufeld EF. Hurler and Hunter syndromes: mutual correction of the defect in cultured fibroblasts. Science. 1968;162:570-572.

2. Hobbs JR, Hugh-Jones K, Barrett AJ, et al. Reversal of clinical features of Hurler's disease and biochemical improvement after treatment by bone-marrow transplantation. Lancet. 1981;2:709-712.

3. Jacobson P, Park JJ, DeFor TE, et al. Oral busulfan pharmacokinetics and engraftment in children with Hurler syndrome and other inherited metabolic storage diseases undergoing hematopoietic cell transplantation. Bone Marrow Transplant. 2001;27:855-861.

4. Peters C, Charnas LR, Tan Y, et al. Cerebral X-linked adrenoleukodystrophy: the international hematopoietic cell transplantation experience from 1982 to 1999. Blood. 2004;104:881-888.

5. Peters C, Shapiro EG, Anderson J, et al. Hurler syndrome: II. Outcome of HLA-genotypically identical sibling and HLA-haploidentical related donor bone marrow transplantation in fifty-four children. The Storage Disease Collaborative Study Group. Blood. 1998;91:2601-2608.

6. Peters C, Balthazor M, Shapiro EG, et al. Outcome of unrelated donor bone marrow transplantation in 40 children with Hurler syndrome. Blood. 1996;87:4894-4902.

7. Orchard PJ, Milla C, Braunlin E, et al. Pre-transplant risk factors affecting outcome in Hurler syndrome. Bone Marrow Transplant. 2009.

8. Storb R, Yu C, Wagner JL, et al. Stable mixed hematopoietic chimerism in DLA-identical littermate dogs given sublethal total body irradiation before and pharmacological immunosuppression after marrow transplantation. Blood. 1997;89:3048-3054.

9. McCarthy NJ, Bishop MR. Nonmyeloablative allogeneic stem cell transplantation: early promise and limitations. Oncologist. 2000;5:487-496.

10. Neufeld EF. Lysosomal storage diseases. Annu Rev Biochem. 1991;60:257-280.

11. Muenzer J. The mucopolysaccharidoses: a heterogeneous group of disorders with variable pediatric presentations. J Pediatr. 2004;144:S27-34.

12. Orchard PJ, Blazar BR, Wagner J, Charnas L, Krivit W, Tolar J. Hematopoietic cell therapy for metabolic disease. J Pediatr. 2007;151:340-346.

13. Kakkis ED, Muenzer J, Tiller GE, et al. Enzyme-replacement therapy in mucopolysaccharidosis I. N Engl J Med. 2001;344:182-188.

14. Boelens JJ, Rocha V, Aldenhoven M, et al. Risk factor analysis of outcomes after unrelated cord blood transplantation in patients with hurler syndrome. Biol Blood Marrow Transplant. 2009;15:618-625.

15. Aldenhoven M, Boelens JJ, de Koning TJ. The clinical outcome of Hurler syndrome after stem cell transplantation. Biol Blood Marrow Transplant. 2008;14:485-498.

16. Prasad VK, Kurtzberg J. Cord blood and bone marrow transplantation in inherited metabolic diseases: scientific basis, current status and future directions. Br J Haematol. 2009.

17. Prasad VK, Kurtzberg J. Umbilical cord blood transplantation for non-malignant diseases. Bone Marrow Transplant. 2009;44:643-651.

18. Prasad VK, Mendizabal A, Parikh SH, et al. Unrelated donor umbilical cord blood transplantation for inherited metabolic disorders in 159 pediatric patients from a single center: influence of cellular composition of the graft on transplantation outcomes. Blood. 2008;112:2979-2989.

19. Vellodi A, Young EP, Cooper A, et al. Bone marrow transplantation for mucopolysaccharidosis type I: experience of two British centres. Arch Dis Child. 1997;76:92-99.

20. Krivit W, Sung JH, Shapiro EG, Lockman LA. Microglia: the effector cell for reconstitution of the central nervous system following bone marrow transplantation for lysosomal and peroxisomal storage diseases. Cell Transplant. 1995;4:385-392.

21. Wraith JE. The first 5 years of clinical experience with laronidase enzyme replacement therapy for mucopolysaccharidosis I. Expert Opin Pharmacother. 2005;6:489-506.

22. Wynn RF, Mercer J, Page J, Carr TF, Jones S, Wraith JE. Use of enzyme replacement therapy (Laronidase) before hematopoietic stem cell transplantation for mucopolysaccharidosis I: experience in 18 patients. J Pediatr. 2009;154:135-139.

23. Cox-Brinkman J, Boelens JJ, Wraith JE, et al. Haematopoietic cell transplantation (HCT) in combination with enzyme replacement therapy (ERT) in patients with Hurler syndrome. Bone Marrow Transplant. 2006;38:17-21.

24. Tolar J, Grewal SS, Bjoraker KJ, et al. Combination of enzyme replacement and hematopoietic stem cell transplantation as therapy for Hurler syndrome. Bone Marrow Transplant. 2008;41:531-535.

25. Klein KA, Krivit W, Whitley CB, et al. Poor cognitive outcome of eleven children with Sanfilippo syndrome after bone marrow transplantation and successful engraftment. Bone Marrow Transplant. 1995;15:S176-181.

26. Krivit W. Allogeneic stem cell transplantation for the treatment of lysosomal and peroxisomal metabolic diseases. Springer Semin Immunopathol. 2004;26:119-132.

27. Peters C, Krivit W. Hematopoietic cell transplantation for mucopolysaccharidosis IIB (Hunter syndrome). Bone Marrow Transplant. 2000;25:1097-1099.

28. Platt FM, Jeyakumar M, Andersson U, Heare T, Dwek RA, Butters TD. Substrate reduction therapy in mouse models of the glycosphingolipidoses. Philos Trans R Soc Lond B Biol Sci. 2003;358:947-954.

29. Watts RW. A historical perspective of the glycosphingolipids and sphingolipidoses. Philos Trans R Soc Lond B Biol Sci. 2003;358:975-983.

30. Gieselmann V, Polten A, Kreysing J, von Figura K. Molecular genetics of metachromatic leukodystrophy. J Inherit Metab Dis. 1994;17:500-509.

31. Eng B, Nakamura LN, O'Reilly N, et al. Identification of nine novel arylsulfatase a (ARSA) gene mutations in patients with metachromatic leukodystrophy (MLD). Hum Mutat. 2003;22:418-419.

32. Heinisch U, Zlotogora J, Kafert S, Gieselmann V. Multiple mutations are responsible for the high frequency of metachromatic leukodystrophy in a small geographic area. Am J Hum Genet. 1995;56:51-57.

33. Zlotogora J, Bach G, Bosenberg C, Barak Y, von Figura K, Gieselmann V. Molecular basis of late infantile metachromatic leukodystrophy in the Habbanite Jews. Hum Mutat. 1995;5:137-143.

34. Biffi A, Lucchini G, Rovelli A, Sessa M. Metachromatic leukodystrophy: an overview of current and prospective treatments. Bone Marrow Transplant. 2008;42 Suppl 2:S2-6.

35. Scriver CR, Beaudet AL, Sly WS, Valle D. The Metabolic and Molecular Bases of Inherited Disease. Vol. III (ed 8th). New York: McGraw-Hill; 2001.

36. Sedel F, Tourbah A, Fontaine B, et al. Leukoencephalopathies associated with inborn errors of metabolism in adults. J Inherit Metab Dis. 2008;31:295-307.

37. Gieselmann V. Metachromatic leukodystrophy: genetics, pathogenesis and therapeutic options. Acta Paediatr Suppl. 2008;97:15-21.

38. Krivit W, Shapiro E, Kennedy W, et al. Treatment of late infantile metachromatic leukodystrophy by bone marrow transplantation. N Engl J Med. 1990;322:28-32.

39. Krivit W, Aubourg P, Shapiro E, Peters C. Bone marrow transplantation for globoid cell leukodystrophy, adrenoleukodystrophy, metachromatic leukodystrophy, and Hurler syndrome. Curr Opin Hematol. 1999;6:377-382.

40. Peters C, Steward CG. Hematopoietic cell transplantation for inherited metabolic diseases: an overview of outcomes and practice guidelines. Bone Marrow Transplant. 2003;31:229-239.

41. Peters C. Hematopoietic Stem Cell Transplantation for Storage Diseases. In: Appelbaum FR, Forman SJ, Negrin RS, eds. Thomas' Hematopoietic Cell Transplantation: Stem Cell Transplantation (ed 4). Oxford, UK: Wiley, John & Sons, Incorporated; 2009:1136-1162.

42. Gorg M, Wilck W, Granitzny B, et al. Stabilization of juvenile metachromatic leukodystrophy after bone marrow transplantation: a 13-year follow-up. J Child Neurol. 2007;22:1139-1142.

43. Solders G, Celsing G, Hagenfeldt L, Ljungman P, Isberg B, Ringden O. Improved peripheral nerve conduction, EEG and verbal IQ after bone marrow transplantation for adult metachromatic leukodystrophy. Bone Marrow Transplant. 1998;22:1119-1122.

44. Pierson TM, Bonnemann CG, Finkel RS, Bunin N, Tennekoon GI. Umbilical cord blood transplantation for juvenile metachromatic leukodystrophy. Ann Neurol. 2008;64:583-587.

45. Krabbe K. A new familial, infantile form of diffuse brain sclerosis. Brain. 1916;39:74-114.

46. Suzuki K, Suzuki Y. Globoid cell leucodystrophy (Krabbe's disease): deficiency of galactocerebroside beta-galactosidase. Proc Natl Acad Sci U S A. 1970;66:302-309.

47. Zlotogora J, Chakraborty S, Knowlton RG, Wenger DA. Krabbe disease locus mapped to chromosome 14 by genetic linkage. Am J Hum Genet. 1990;47:37-44.

48. Chen YQ, Rafi MA, de Gala G, Wenger DA. Cloning and expression of cDNA encoding human galactocerebrosidase, the enzyme deficient in globoid cell leukodystrophy. Hum Mol Genet. 1993;2:1841-1845.

49. Tatsumi N, Inui K, Sakai N, et al. Molecular defects in Krabbe disease. Hum Mol Genet. 1995;4:1865-1868.

50. Igisu H, Suzuki K. Progressive accumulation of toxic metabolite in a genetic leukodystrophy. Science. 1984;224:753-755.

51. Suzuki K. Twenty five years of the "psychosine hypothesis": a personal perspective of its history and present status. Neurochem Res. 1998;23:251-259.

52. White AB, Givogri MI, Lopez-Rosas A, et al. Psychosine accumulates in membrane microdomains in the brain of krabbe patients, disrupting the raft architecture. J Neurosci. 2009;29:6068-6077.

53. Krivit W, Shapiro EG, Peters C, et al. Hematopoietic stem-cell transplantation in globoid-cell leukodystrophy. N Engl J Med. 1998;338:1119-1126.

54. Escolar ML, Poe MD, Martin HR, Kurtzberg J. A staging system for infantile Krabbe disease to predict outcome after unrelated umbilical cord blood transplantation. Pediatrics. 2006;118:e879-889.

55. Duffner PK, Caviness VS, Jr., Erbe RW, et al. The long-term outcomes of presymptomatic infants transplanted for Krabbe disease: Report of the workshop held on July 11 and 12, 2008, Holiday Valley, New York. Genet Med. 2009.

56. Escolar ML, Poe MD, Provenzale JM, et al. Transplantation of umbilical-cord blood in babies with infantile Krabbe's disease. N Engl J Med. 2005;352:2069-2081.

57. Duffner PK, Caggana M, Orsini JJ, et al. Newborn screening for Krabbe disease: the New York State model. Pediatr Neurol. 2009;40:245-252; discussion 253-245.

58. Meikle PJ, Grasby DJ, Dean CJ, et al. Newborn screening for lysosomal storage disorders. Mol Genet Metab. 2006;88:307-314.

59. Kagitani-Shimono K, Mohri I, Yagi T, Taniike M, Suzuki K. Peripheral neuropathy in the twitcher mouse: accumulation of extracellular matrix in the endoneurium and aberrant expression of ion channels. Acta Neuropathol. 2008;115:577-587.

60. Kondo A, Hoogerbrugge PM, Suzuki K, Poorthuis BJ, Van Bekkum DW. Pathology of the peripheral nerve in the twitcher mouse following bone marrow transplantation. Brain Res. 1988;460:178-183.

61. Luzi P, Rafi MA, Zaka M, et al. Biochemical and pathological evaluation of long-lived mice with globoid cell leukodystrophy after bone marrow transplantation. Mol Genet Metab. 2005;86:150-159.

62. Lim ZY, Ho AY, Abrahams S, et al. Sustained neurological improvement following reduced-intensity conditioning allogeneic haematopoietic stem cell transplantation for late-onset Krabbe disease. Bone Marrow Transplant. 2008.

63. Cartier N, Aubourg P. Hematopoietic stem cell gene therapy in Hurler syndrome, globoid cell leukodystrophy, metachromatic leukodystrophy and X-adrenoleukodystrophy. Curr Opin Mol Ther. 2008;10:471-478.

64. Victor S, Coulter JB, Besley GT, et al. Niemann-Pick disease: sixteen-year follow-up of allogeneic bone marrow transplantation in a type B variant. J Inherit Metab Dis. 2003;26:775-785.

65. Shah AJ, Kapoor N, Crooks GM, et al. Successful hematopoietic stem cell transplantation for Niemann-Pick disease type B. Pediatrics. 2005;116:1022-1025.

66. Walkley SU, Suzuki K. Consequences of NPC1 and NPC2 loss of function in mammalian neurons. Biochim Biophys Acta. 2004;1685:48-62.

67. Hsu YS, Hwu WL, Huang SF, et al. Niemann-Pick disease type C (a cellular cholesterol lipidosis) treated by bone marrow transplantation. Bone Marrow Transplant. 1999;24:103-107.

68. Walkley SU. Secondary accumulation of gangliosides in lysosomal storage disorders. Semin Cell Dev Biol. 2004;15:433-444.

69. Shield JP, Stone J, Steward CG. Bone marrow transplantation correcting beta-galactosidase activity does not influence neurological outcome in juvenile GM1-gangliosidosis. J Inherit Metab Dis. 2005;28:797-798.

70. Jacobs JF, Willemsen MA, Groot-Loonen JJ, Wevers RA, Hoogerbrugge PM. Allogeneic BMT followed by substrate reduction therapy in a child with subacute Tay-Sachs disease. Bone Marrow Transplant. 2005;36:925-926.

71. Starer F, Sargent JD, Hobbs JR. Regression of the radiological changes of Gaucher's disease following bone marrow transplantation. Br J Radiol. 1987;60:1189-1195.

72. Ringden O, Groth CG, Erikson A, et al. Long-term follow-up of the first successful bone marrow transplantation in Gaucher disease. Transplantation. 1988;46:66-70.

73. Svennerholm L, Erikson A, Groth CG, Ringden O, Mansson JE. Norrbottnian type of Gaucher disease--clinical, biochemical and molecular biology aspects: successful treatment with bone marrow transplantation. Dev Neurosci. 1991;13:345-351.

74. Tsai P, Lipton JM, Sahdev I, et al. Allogenic bone marrow transplantation in severe Gaucher disease. Pediatr Res. 1992;31:503-507.

75. Goker-Alpan O, Wiggs EA, Eblan MJ, et al. Cognitive outcome in treated patients with chronic neuronopathic Gaucher disease. J Pediatr. 2008;153:89-94.

76. Krasemann EW, Meier V, Korenke GC, Hunneman DH, Hanefeld F. Identification of mutations in the ALD-gene of 20 families with adrenoleukodystrophy/adrenomyeloneuropathy. Hum Genet. 1996;97:194-197.

77. Berger J, Gartner J. X-linked adrenoleukodystrophy: clinical, biochemical and pathogenetic aspects. Biochim Biophys Acta. 2006;1763:1721-1732.

78. Ito M, Blumberg BM, Mock DJ, et al. Potential environmental and host participants in the early white matter lesion of adreno-leukodystrophy: morphologic evidence for CD8 cytotoxic T cells, cytolysis of oligodendrocytes, and CD1-mediated lipid antigen presentation. J Neuropathol Exp Neurol. 2001;60:1004-1019.

79. Powers JM, Moser HW, Moser AB, Ma CK, Elias SB, Norum RA. Pathologic findings in adrenoleukodystrophy heterozygotes. Arch Pathol Lab Med. 1987;111:151-153.

80. Eichler F, Van Haren K. Immune response in leukodystrophies. Pediatr Neurol. 2007;37:235-244.

81. Cartier N, Hacein-Bey-Abina S, Bartholomae CC, et al. Hematopoietic stem cell gene therapy with a lentiviral vector in X-linked adrenoleukodystrophy. Science. 2009;326:818-823.

82. Dubey P, Raymond GV, Moser AB, Kharkar S, Bezman L, Moser HW. Adrenal insufficiency in asymptomatic adrenoleukodystrophy patients identified by very long-chain fatty acid screening. J Pediatr. 2005;146:528-532.

83. Loes DJ, Fatemi A, Melhem ER, et al. Analysis of MRI patterns aids prediction of progression in X-linked adrenoleukodystrophy. Neurology. 2003;61:369-374.

84. Mahmood A, Raymond GV, Dubey P, Peters C, Moser HW. Survival analysis of haematopoietic cell transplantation for childhood cerebral X-linked adrenoleukodystrophy: a comparison study. Lancet Neurol. 2007;6:687-692.

85. Mahmood A, Dubey P, Moser HW, Moser A. X-linked adrenoleukodystrophy: Therapeutic approaches to distinct phenotypes. Pediatr Transplant. 2005;9:55-62.

86. Moser HW, Raymond GV, Lu SE, et al. Follow-up of 89 asymptomatic patients with adrenoleukodystrophy treated with Lorenzo's oil. Arch Neurol. 2005;62:1073-1080.

87. Grewal SS, Shapiro EG, Krivit W, et al. Effective treatment of alpha-mannosidosis by allogeneic hematopoietic stem cell transplantation. J Pediatr. 2004;144:569-573.

88. Grewal SS, Barker JN, Davies SM, Wagner JE. Unrelated donor hematopoietic cell transplantation: marrow or umbilical cord blood? Blood. 2003;101:4233-4244.

89. Souillet G, Guffon N, Maire I, et al. Outcome of 27 patients with Hurler's syndrome transplanted from either related or unrelated haematopoietic stem cell sources. Bone Marrow Transplant. 2003;31:1105-1117.

90. Kharbanda S, Panoskaltsis-Mortari A, Haddad IY, et al. Inflammatory cytokines and the development of pulmonary complications after allogeneic hematopoietic cell transplantation in patients with inherited metabolic storage disorders. Biol Blood Marrow Transplant. 2006;12:430-437.

91. Whitley CB, Belani KG, Chang PN, et al. Long-term outcome of Hurler syndrome following bone marrow transplantation. Am J Med Genet. 1993;46:209-218.

92. Grewal S, Shapiro E, Braunlin E, et al. Continued neurocognitive development and prevention of cardiopulmonary complications after successful BMT for I-cell disease: a long-term follow-up report. Bone Marrow Transplant. 2003;32:957-960.

93. Braunlin EA, Stauffer NR, Peters CH, et al. Usefulness of bone marrow transplantation in the Hurler syndrome. Am J Cardiol. 2003;92:882-886.

94. Shapiro EG, Lockman LA, Balthazor M, Krivit W. Neuropsychological outcomes of several storage diseases with and without bone marrow transplantation. J Inherit Metab Dis. 1995;18:413-429.

95. Hite SH, Peters C, Krivit W. Correction of odontoid dysplasia following bone-marrow transplantation and engraftment (in Hurler syndrome MPS 1H). Pediatr Radiol. 2000;30:464-470.

96. Field RE, Buchanan JA, Copplemans MG, Aichroth PM. Bone-marrow transplantation in Hurler's syndrome. Effect on skeletal development. J Bone Joint Surg Br. 1994;76:975-981.

97. Wraith JE, Alani SM. Carpal tunnel syndrome in the mucopolysaccharidoses and related disorders. Arch Dis Child. 1990;65:962-963.

98. Baker KS, DeFor TE, Burns LJ, Ramsay NK, Neglia JP, Robison LL. New malignancies after blood or marrow stem-cell transplantation in children and adults: incidence and risk factors. J Clin Oncol. 2003;21:1352-1358.

99. Bhatia S, Ramsay NK, Steinbuch M, et al. Malignant neoplasms following bone marrow transplantation. Blood. 1996;87:3633-3639.

100. Bhatia S, Francisco L, Carter A, et al. Late mortality after allogeneic hematopoietic cell transplantation and functional status of long-term survivors: report from the Bone Marrow Transplant Survivor Study. Blood. 2007;110:3784-3792.

101. Desnick RJ. Enzyme replacement and enhancement therapies for lysosomal diseases. J Inherit Metab Dis. 2004;27:385-410.

102. Cox TM. Substrate reduction therapy for lysosomal storage diseases. Acta Paediatr Suppl. 2005;94:69-75; discussion 57.

103. Gregersen N, Bolund L, Bross P. Protein misfolding, aggregation, and degradation in disease. Mol Biotechnol. 2005;31:141-150.

104. Desnick RJ, Schuchman EH. Enzyme replacement and enhancement therapies: lessons from lysosomal disorders. Nat Rev Genet. 2002;3:954-966.

105. Hoffmann B, Mayatepek E. Neurological manifestations in lysosomal storage disorders - from pathology to first therapeutic possibilities. Neuropediatrics. 2005;36:285-289.

106. Vellodi A. Lysosomal storage disorders. Br J Haematol. 2005;128:413-431.

107. Jeyakumar M, Thomas R, Elliot-Smith E, et al. Central nervous system inflammation is a hallmark of pathogenesis in mouse models of GM1 and GM2 gangliosidosis. Brain. 2003;126:974-987.

108. Spagnoli A, Longobardi L, O'Rear L. Cartilage disorders: potential therapeutic use of mesenchymal stem cells. Endocr Dev. 2005;9:17-30.

109. Young PP, Fantz CR, Sands MS. VEGF disrupts the neonatal blood-brain barrier and increases life span after non-ablative BMT in a murine model of congenital neurodegeneration caused by a lysosomal enzyme deficiency. Exp Neurol. 2004;188:104-114.

110. Zaka M, Rafi MA, Rao HZ, Luzi P, Wenger DA. Insulin-like growth factor-1 provides protection against psychosine-induced apoptosis in cultured mouse oligodendrocyte progenitor cells using primarily the PI3K/Akt pathway. Mol Cell Neurosci. 2005;30:398-407.

111. Li Y, Scott CR, Chamoles NA, et al. Direct multiplex assay of lysosomal enzymes in dried blood spots for newborn screening. Clin Chem. 2004;50:1785-1796.

112. Meikle PJ, Ranieri E, Simonsen H, et al. Newborn screening for lysosomal storage disorders: clinical evaluation of a two-tier strategy. Pediatrics. 2004;114:909-916.

113. Millington DS. Newborn screening for lysosomal storage disorders. Clin Chem. 2005;51:808-809.

114. Staba SL, Escolar ML, Poe M, et al. Cord-blood transplants from unrelated donors in patients with Hurler's syndrome. N Engl J Med. 2004;350:1960-1969.

115. Davoust N, Vuaillat C, Androdias G, Nataf S. From bone marrow to microglia: barriers and avenues. Trends Immunol. 2008;29:227-234.

116. D'Mello C, Le T, Swain MG. Cerebral microglia recruit monocytes into the brain in response to tumor necrosis factoralpha signaling during peripheral organ inflammation. J Neurosci. 2009;29:2089-2102.

117. Hall AA, Herrera Y, Ajmo CT, Jr., Cuevas J, Pennypacker KR. Sigma receptors suppress multiple aspects of microglial activation. Glia. 2009;57:744-754.

118. Semple BD, Bye N, Rancan M, Ziebell JM, Morganti-Kossmann MC. Role of CCL2 (MCP-1) in traumatic brain injury (TBI): evidence from severe TBI patients and CCL2-/- mice. J Cereb Blood Flow Metab. 2009.

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Обсуждаются как миелоаблативные, так и менее интенсивные режимы кондиционирования. Показана выгода стандартизированного подхода к ТГСК при болезни Хурлера и ранней адренолейкодистрофии (АЛД) головного мозга. Режимы кондиционирования со сниженной интенсивностью могут оказаться более успешными в плане снижения смертности и развития осложнений, особенно у больных с развивающимся неврологическим дефектом. В ситуациях с ТГСК при наследственных заболеваниях можно ожидать, что потенциальные доноры-сибсы могут быть носителями мутации данного гена. Нерешенная проблема состоит в том, может ли альтернативный донор иметь преимущество в сравнении с сибсом, который может быть носителем заболевания. Обычно применяют стволовые неродственные донорские клетки из различных источников (костного мозга, периферических клеток, пуповинной крови) с хорошими результатами. 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Орчард</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(81) "

Якуб Толар, К.Скотт Бэйкер, Пол Дж. Орчард

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Обсуждаются как миелоаблативные, так и менее интенсивные режимы кондиционирования. Показана выгода стандартизированного подхода к ТГСК при болезни Хурлера и ранней адренолейкодистрофии (АЛД) головного мозга. Режимы кондиционирования со сниженной интенсивностью могут оказаться более успешными в плане снижения смертности и развития осложнений, особенно у больных с развивающимся неврологическим дефектом. В ситуациях с ТГСК при наследственных заболеваниях можно ожидать, что потенциальные доноры-сибсы могут быть носителями мутации данного гена. Нерешенная проблема состоит в том, может ли альтернативный донор иметь преимущество в сравнении с сибсом, который может быть носителем заболевания. Обычно применяют стволовые неродственные донорские клетки из различных источников (костного мозга, периферических клеток, пуповинной крови) с хорошими результатами. Рассматривается эффективность энзим-заместительной терапии по сравнению с ТГСК в качестве подходящего лечения при менее тяжелых формах мукополисахаридозов (МПС), и ТГСК признано стандартом терапии для больных с тяжелыми клиническими формами МПС типа I. В противоположность синдрому Хурлера, ТГСК не выявила существенного влияния у больных с тяжелым МПС типа II (синдром Хантера), т.е. дети с тяжелой формой МПС типа II, по-видимому, не имеют преимуществ в нейрокогнитивном развитии при ТГСК. Что касается метахроматической или глобоидноклеточной лейкодистрофии, то данные об эффективности ТГСК здесь более скудные. Получение четких данных об исходах ТГСК  у больных с ВМБН оказалось сложной задачей из-за редкости этих заболеваний, вариабельности их генотипов и фенотипов, различий в источниках стволовых клеток, кондиционирующих режимах и оценке «успешных» результатов. Дальнейшие исследования установят полезность комбинированной терапии с/без трансплантации, включая субстратное ингибирование, терапию шаперонами, энзимотерапию и т.д. Кроме того, интерес к неонатальному скринингу обеспечит раннее вмешательство в течение этих болезней, т.к. это очень важно для получения оптимальных результатов. Наконец, модификация процедуры ТГСК или применение селективно размножающихся клеточных популяций, или обработка цитокинами могут усилить приживление микроглии, что может существенно облегчить достаку энзимов в центральную нервную систему. В это отношении будут важны многоцентровые исследования с общим подходом и оценкой клинических исходов. </p> <h3>Ключевые слова</h3> <p>наследственные болезни накопления, мукополисахаридозы, трансплантация гемопоэтических клеток, режимы кондиционирования, клинический эффект </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(5197) "

В данной обзорной статье представлены сведения о трансплантации гемопоэтических стволовых клеток (ТГСК) у детей с врожденными метаболическими болезнями накопления (ВМБН), и о нерешенных вопросах ТГСК при этих состояниях. Обсуждаются как миелоаблативные, так и менее интенсивные режимы кондиционирования. Показана выгода стандартизированного подхода к ТГСК при болезни Хурлера и ранней адренолейкодистрофии (АЛД) головного мозга. Режимы кондиционирования со сниженной интенсивностью могут оказаться более успешными в плане снижения смертности и развития осложнений, особенно у больных с развивающимся неврологическим дефектом. В ситуациях с ТГСК при наследственных заболеваниях можно ожидать, что потенциальные доноры-сибсы могут быть носителями мутации данного гена. Нерешенная проблема состоит в том, может ли альтернативный донор иметь преимущество в сравнении с сибсом, который может быть носителем заболевания. Обычно применяют стволовые неродственные донорские клетки из различных источников (костного мозга, периферических клеток, пуповинной крови) с хорошими результатами. Рассматривается эффективность энзим-заместительной терапии по сравнению с ТГСК в качестве подходящего лечения при менее тяжелых формах мукополисахаридозов (МПС), и ТГСК признано стандартом терапии для больных с тяжелыми клиническими формами МПС типа I. В противоположность синдрому Хурлера, ТГСК не выявила существенного влияния у больных с тяжелым МПС типа II (синдром Хантера), т.е. дети с тяжелой формой МПС типа II, по-видимому, не имеют преимуществ в нейрокогнитивном развитии при ТГСК. Что касается метахроматической или глобоидноклеточной лейкодистрофии, то данные об эффективности ТГСК здесь более скудные. Получение четких данных об исходах ТГСК  у больных с ВМБН оказалось сложной задачей из-за редкости этих заболеваний, вариабельности их генотипов и фенотипов, различий в источниках стволовых клеток, кондиционирующих режимах и оценке «успешных» результатов. Дальнейшие исследования установят полезность комбинированной терапии с/без трансплантации, включая субстратное ингибирование, терапию шаперонами, энзимотерапию и т.д. Кроме того, интерес к неонатальному скринингу обеспечит раннее вмешательство в течение этих болезней, т.к. это очень важно для получения оптимальных результатов. Наконец, модификация процедуры ТГСК или применение селективно размножающихся клеточных популяций, или обработка цитокинами могут усилить приживление микроглии, что может существенно облегчить достаку энзимов в центральную нервную систему. В это отношении будут важны многоцентровые исследования с общим подходом и оценкой клинических исходов.

Ключевые слова

наследственные болезни накопления, мукополисахаридозы, трансплантация гемопоэтических клеток, режимы кондиционирования, клинический эффект

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Jakub Tolar, M.D., Ph.D.1, K. Scott Baker, M.D.2, Paul J. Orchard, M.D.1

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1Division of Hematology/Oncology and Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota, Minneapolis, USA; 2Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Organization" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_EN"]=> array(36) { ["ID"]=> string(2) "39" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Description / Summary" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "39" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "19007" ["VALUE"]=> array(2) { ["TEXT"]=> string(1514) "<p class="bodytext">Almost thirty years of hematopoietic cell transplantation for congenital enzymopathies have revealed that the transfer of relatively few hematopoietic stem cells is able to fully reconstitute the lymphohematopoietic system in conditioned recipients and to maintain long term complementation of the enzyme defect in the recipient. Despite decades of effort to illuminate the mechanisms whereby the cross correction occurs, it remains unclear why hematopoietic cell transplantation is adequate only in some enzyme deficiencies. Here we review both biochemical and clinical data on the metabolic storage diseases in which the natural history and quality of life have been changed after hematopoietic cell transplantation. The challenge ahead is to understand the pathophysiology of congenital enzymopathies resistant to correction with hematopoietic cell transplantation, and to test whether the advances in stem cell therapy and gene correction can be translated into less toxic and even more effective therapy of metabolic storage diseases for which hematopoietic cell transplantation is a standard of care today.</p> <h3>Keywords</h3> <p> hematopoietic cell transplantation, conditioning regimen for hematopoietic cell transplantation, mucopolysaccharidosis, Hurler syndrome, metachromatic leukodystrophy, globoid cell leukodystrophy, Krabbe disease, adrenoleukodystrophy, mannosidosis, late effects after hematopoietic cell transplantation </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(1468) "

Almost thirty years of hematopoietic cell transplantation for congenital enzymopathies have revealed that the transfer of relatively few hematopoietic stem cells is able to fully reconstitute the lymphohematopoietic system in conditioned recipients and to maintain long term complementation of the enzyme defect in the recipient. Despite decades of effort to illuminate the mechanisms whereby the cross correction occurs, it remains unclear why hematopoietic cell transplantation is adequate only in some enzyme deficiencies. Here we review both biochemical and clinical data on the metabolic storage diseases in which the natural history and quality of life have been changed after hematopoietic cell transplantation. The challenge ahead is to understand the pathophysiology of congenital enzymopathies resistant to correction with hematopoietic cell transplantation, and to test whether the advances in stem cell therapy and gene correction can be translated into less toxic and even more effective therapy of metabolic storage diseases for which hematopoietic cell transplantation is a standard of care today.

Keywords

hematopoietic cell transplantation, conditioning regimen for hematopoietic cell transplantation, mucopolysaccharidosis, Hurler syndrome, metachromatic leukodystrophy, globoid cell leukodystrophy, Krabbe disease, adrenoleukodystrophy, mannosidosis, late effects after hematopoietic cell transplantation

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Jakub Tolar, M.D., Ph.D.1, K. Scott Baker, M.D.2, Paul J. Orchard, M.D.1

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Jakub Tolar, M.D., Ph.D.1, K. Scott Baker, M.D.2, Paul J. Orchard, M.D.1

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Almost thirty years of hematopoietic cell transplantation for congenital enzymopathies have revealed that the transfer of relatively few hematopoietic stem cells is able to fully reconstitute the lymphohematopoietic system in conditioned recipients and to maintain long term complementation of the enzyme defect in the recipient. Despite decades of effort to illuminate the mechanisms whereby the cross correction occurs, it remains unclear why hematopoietic cell transplantation is adequate only in some enzyme deficiencies. Here we review both biochemical and clinical data on the metabolic storage diseases in which the natural history and quality of life have been changed after hematopoietic cell transplantation. The challenge ahead is to understand the pathophysiology of congenital enzymopathies resistant to correction with hematopoietic cell transplantation, and to test whether the advances in stem cell therapy and gene correction can be translated into less toxic and even more effective therapy of metabolic storage diseases for which hematopoietic cell transplantation is a standard of care today.

Keywords

hematopoietic cell transplantation, conditioning regimen for hematopoietic cell transplantation, mucopolysaccharidosis, Hurler syndrome, metachromatic leukodystrophy, globoid cell leukodystrophy, Krabbe disease, adrenoleukodystrophy, mannosidosis, late effects after hematopoietic cell transplantation

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Almost thirty years of hematopoietic cell transplantation for congenital enzymopathies have revealed that the transfer of relatively few hematopoietic stem cells is able to fully reconstitute the lymphohematopoietic system in conditioned recipients and to maintain long term complementation of the enzyme defect in the recipient. Despite decades of effort to illuminate the mechanisms whereby the cross correction occurs, it remains unclear why hematopoietic cell transplantation is adequate only in some enzyme deficiencies. Here we review both biochemical and clinical data on the metabolic storage diseases in which the natural history and quality of life have been changed after hematopoietic cell transplantation. The challenge ahead is to understand the pathophysiology of congenital enzymopathies resistant to correction with hematopoietic cell transplantation, and to test whether the advances in stem cell therapy and gene correction can be translated into less toxic and even more effective therapy of metabolic storage diseases for which hematopoietic cell transplantation is a standard of care today.

Keywords

hematopoietic cell transplantation, conditioning regimen for hematopoietic cell transplantation, mucopolysaccharidosis, Hurler syndrome, metachromatic leukodystrophy, globoid cell leukodystrophy, Krabbe disease, adrenoleukodystrophy, mannosidosis, late effects after hematopoietic cell transplantation

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1Division of Hematology/Oncology and Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota, Minneapolis, USA; 2Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA

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1Division of Hematology/Oncology and Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota, Minneapolis, USA; 2Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA

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Якуб Толар, К.Скотт Бэйкер, Пол Дж. Орчард

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Якуб Толар, К.Скотт Бэйкер, Пол Дж. Орчард

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string(5) "18998" ["VALUE"]=> array(2) { ["TEXT"]=> string(5243) "<p class="bodytext">В данной обзорной статье представлены сведения о трансплантации гемопоэтических стволовых клеток (ТГСК) у детей с врожденными метаболическими болезнями накопления (ВМБН), и о нерешенных вопросах ТГСК при этих состояниях. Обсуждаются как миелоаблативные, так и менее интенсивные режимы кондиционирования. Показана выгода стандартизированного подхода к ТГСК при болезни Хурлера и ранней адренолейкодистрофии (АЛД) головного мозга. Режимы кондиционирования со сниженной интенсивностью могут оказаться более успешными в плане снижения смертности и развития осложнений, особенно у больных с развивающимся неврологическим дефектом. В ситуациях с ТГСК при наследственных заболеваниях можно ожидать, что потенциальные доноры-сибсы могут быть носителями мутации данного гена. Нерешенная проблема состоит в том, может ли альтернативный донор иметь преимущество в сравнении с сибсом, который может быть носителем заболевания. Обычно применяют стволовые неродственные донорские клетки из различных источников (костного мозга, периферических клеток, пуповинной крови) с хорошими результатами. Рассматривается эффективность энзим-заместительной терапии по сравнению с ТГСК в качестве подходящего лечения при менее тяжелых формах мукополисахаридозов (МПС), и ТГСК признано стандартом терапии для больных с тяжелыми клиническими формами МПС типа I. В противоположность синдрому Хурлера, ТГСК не выявила существенного влияния у больных с тяжелым МПС типа II (синдром Хантера), т.е. дети с тяжелой формой МПС типа II, по-видимому, не имеют преимуществ в нейрокогнитивном развитии при ТГСК. Что касается метахроматической или глобоидноклеточной лейкодистрофии, то данные об эффективности ТГСК здесь более скудные. Получение четких данных об исходах ТГСК  у больных с ВМБН оказалось сложной задачей из-за редкости этих заболеваний, вариабельности их генотипов и фенотипов, различий в источниках стволовых клеток, кондиционирующих режимах и оценке «успешных» результатов. Дальнейшие исследования установят полезность комбинированной терапии с/без трансплантации, включая субстратное ингибирование, терапию шаперонами, энзимотерапию и т.д. Кроме того, интерес к неонатальному скринингу обеспечит раннее вмешательство в течение этих болезней, т.к. это очень важно для получения оптимальных результатов. Наконец, модификация процедуры ТГСК или применение селективно размножающихся клеточных популяций, или обработка цитокинами могут усилить приживление микроглии, что может существенно облегчить достаку энзимов в центральную нервную систему. В это отношении будут важны многоцентровые исследования с общим подходом и оценкой клинических исходов. </p> <h3>Ключевые слова</h3> <p>наследственные болезни накопления, мукополисахаридозы, трансплантация гемопоэтических клеток, режимы кондиционирования, клинический эффект </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(5197) "

В данной обзорной статье представлены сведения о трансплантации гемопоэтических стволовых клеток (ТГСК) у детей с врожденными метаболическими болезнями накопления (ВМБН), и о нерешенных вопросах ТГСК при этих состояниях. Обсуждаются как миелоаблативные, так и менее интенсивные режимы кондиционирования. Показана выгода стандартизированного подхода к ТГСК при болезни Хурлера и ранней адренолейкодистрофии (АЛД) головного мозга. Режимы кондиционирования со сниженной интенсивностью могут оказаться более успешными в плане снижения смертности и развития осложнений, особенно у больных с развивающимся неврологическим дефектом. В ситуациях с ТГСК при наследственных заболеваниях можно ожидать, что потенциальные доноры-сибсы могут быть носителями мутации данного гена. Нерешенная проблема состоит в том, может ли альтернативный донор иметь преимущество в сравнении с сибсом, который может быть носителем заболевания. Обычно применяют стволовые неродственные донорские клетки из различных источников (костного мозга, периферических клеток, пуповинной крови) с хорошими результатами. Рассматривается эффективность энзим-заместительной терапии по сравнению с ТГСК в качестве подходящего лечения при менее тяжелых формах мукополисахаридозов (МПС), и ТГСК признано стандартом терапии для больных с тяжелыми клиническими формами МПС типа I. В противоположность синдрому Хурлера, ТГСК не выявила существенного влияния у больных с тяжелым МПС типа II (синдром Хантера), т.е. дети с тяжелой формой МПС типа II, по-видимому, не имеют преимуществ в нейрокогнитивном развитии при ТГСК. Что касается метахроматической или глобоидноклеточной лейкодистрофии, то данные об эффективности ТГСК здесь более скудные. Получение четких данных об исходах ТГСК  у больных с ВМБН оказалось сложной задачей из-за редкости этих заболеваний, вариабельности их генотипов и фенотипов, различий в источниках стволовых клеток, кондиционирующих режимах и оценке «успешных» результатов. Дальнейшие исследования установят полезность комбинированной терапии с/без трансплантации, включая субстратное ингибирование, терапию шаперонами, энзимотерапию и т.д. Кроме того, интерес к неонатальному скринингу обеспечит раннее вмешательство в течение этих болезней, т.к. это очень важно для получения оптимальных результатов. Наконец, модификация процедуры ТГСК или применение селективно размножающихся клеточных популяций, или обработка цитокинами могут усилить приживление микроглии, что может существенно облегчить достаку энзимов в центральную нервную систему. В это отношении будут важны многоцентровые исследования с общим подходом и оценкой клинических исходов.

Ключевые слова

наследственные болезни накопления, мукополисахаридозы, трансплантация гемопоэтических клеток, режимы кондиционирования, клинический эффект

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В данной обзорной статье представлены сведения о трансплантации гемопоэтических стволовых клеток (ТГСК) у детей с врожденными метаболическими болезнями накопления (ВМБН), и о нерешенных вопросах ТГСК при этих состояниях. Обсуждаются как миелоаблативные, так и менее интенсивные режимы кондиционирования. Показана выгода стандартизированного подхода к ТГСК при болезни Хурлера и ранней адренолейкодистрофии (АЛД) головного мозга. Режимы кондиционирования со сниженной интенсивностью могут оказаться более успешными в плане снижения смертности и развития осложнений, особенно у больных с развивающимся неврологическим дефектом. В ситуациях с ТГСК при наследственных заболеваниях можно ожидать, что потенциальные доноры-сибсы могут быть носителями мутации данного гена. Нерешенная проблема состоит в том, может ли альтернативный донор иметь преимущество в сравнении с сибсом, который может быть носителем заболевания. Обычно применяют стволовые неродственные донорские клетки из различных источников (костного мозга, периферических клеток, пуповинной крови) с хорошими результатами. Рассматривается эффективность энзим-заместительной терапии по сравнению с ТГСК в качестве подходящего лечения при менее тяжелых формах мукополисахаридозов (МПС), и ТГСК признано стандартом терапии для больных с тяжелыми клиническими формами МПС типа I. В противоположность синдрому Хурлера, ТГСК не выявила существенного влияния у больных с тяжелым МПС типа II (синдром Хантера), т.е. дети с тяжелой формой МПС типа II, по-видимому, не имеют преимуществ в нейрокогнитивном развитии при ТГСК. Что касается метахроматической или глобоидноклеточной лейкодистрофии, то данные об эффективности ТГСК здесь более скудные. Получение четких данных об исходах ТГСК  у больных с ВМБН оказалось сложной задачей из-за редкости этих заболеваний, вариабельности их генотипов и фенотипов, различий в источниках стволовых клеток, кондиционирующих режимах и оценке «успешных» результатов. Дальнейшие исследования установят полезность комбинированной терапии с/без трансплантации, включая субстратное ингибирование, терапию шаперонами, энзимотерапию и т.д. Кроме того, интерес к неонатальному скринингу обеспечит раннее вмешательство в течение этих болезней, т.к. это очень важно для получения оптимальных результатов. Наконец, модификация процедуры ТГСК или применение селективно размножающихся клеточных популяций, или обработка цитокинами могут усилить приживление микроглии, что может существенно облегчить достаку энзимов в центральную нервную систему. В это отношении будут важны многоцентровые исследования с общим подходом и оценкой клинических исходов.

Ключевые слова

наследственные болезни накопления, мукополисахаридозы, трансплантация гемопоэтических клеток, режимы кондиционирования, клинический эффект

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Introduction

The distribution of thalassemia used to be confined to areas from the Mediterranean across the Middle East through Southern Asia to Southeast Asia: the so-called thalassemia belt [1]. At present, migration of people has spread thalassemia throughout the world. Furthermore, with the improvement of medical care, including developing countries, thalassemic children can now survive the early months of life and live long enough to require treatment. Thalassemia is, therefore, now considered to be a global health problem [2].

In Thailand, both α- and β-thalassemias as well as Hb E and Hb Constant Spring are prevalent [3]. There are more than 60 clinical syndromes resulting from various gene interactions, giving 12,000 annual births of thalassemic children. Among them, the common severe thalassemic syndromes with which patients can survive are homozygous β-thalassemia or thalassemia major, and Hb E/β-thalassemia. Hb E/β-thalassemia is the most common severe clinical syndrome in adults and is found more frequently than homozygous β-thalassemia in Thailand [4]. This syndrome is unique to Southeast Asia in general and to Thailand in particular. Clinical manifestations of this syndrome are heterogeneous:  at one end, symptoms may be as severe as with thalassemia major, at the other end, patients may have only mild anemia [4]. However, those who show symptoms related to anemia during the first year of life usually have severe manifestations later on.  

Therapy of severe thalassemia with regular hypertransfusion and iron chelation has dramatically improved life expectancy [5, 6], but there remain many problems related to quality of life, compliance, and expense. Hematopoietic stem cell transplantation is at present the only modality with the potential to cure thalassemia [7]. The objective of allogeneic transplantation for thalassemia is to replace thalassemic hematopoiesis by normal hematopoiesis through allogeneic stem cell transplantation. Patients require “conditioning” to eradicate thalassemic stem cells and to overcome the immunological barriers (histoincompatibility and transfusion-associated allosensitization).

Bone marrow transplantation from HLA-identical siblings in children with thalassemia

The first successful treatment of thalassemia with bone marrow transplantation from HLA-identical sibling donors was performed in 1981 in Seattle [8]. Most subsequent experience, however, has been reported by the Pesaro group [9-14], and other case series have been presented [15-23]. Most transplants for thalassemia have employed bone marrow from unaffected HLA-identical sibling donors. However, only 25–30% of patients have an HLA-matched sibling donor.

By using conditioning with busulfan, 14 mg/kg given over 4 days, followed by cyclophosphamide, 200 mg/kg over the next 4 days, the Pesaro group reported successful bone marrow transplantation in large numbers of children and identified three risk factors, which predicted outcome after transplantation [9]. These risk factors include hepatomegaly of more than 2 cm, liver histology showing portal fibrosis, and irregular (and therefore ineffective) iron chelation. On that basis patients can be classified into three risk categories: class 1 without any risk factors, class 2 with one or two risk factors, and class 3 with all risk factors.

Results in class 1 and 2 patients

The majority of transplants were performed in children in the class 1 and 2 risk groups using bone marrow from HLA-identical siblings. Overall survival was 87–90% and thalassemia-free survival 85–87% [9, 11, 15-23]. The incidence of graft rejection and transplant-related mortality was 3% and 10–13%, respectively. On the basis of these recommendations, children with severe thalassemia should undergo bone marrow transplantation if they have HLA-identical siblings, as early in life  as possible.

Class 3 patients

By using busulfan at 14 mg/kg and cyclophosphamide at 200 mg/kg as conditioning, the Pesaro group reported lower overall survival (61%), thalassemia-free survival (53%) and higher transplant-related mortality (47%) [12] than that observed in class 1 and 2 patients. Conditioning comprising busulfan 14 mg/kg and lower dose of cyclophosphamide (160 or 120 mg/kg) improved the overall survival to 80%; however, the graft rejection rate was increased to 33%, giving a thalassemia-free survival of 56% [12]. This conditioning regimen is, therefore, inadequate to eradicate the marrow erythroid hyperplasia related to the disease.

A new preparative regimen was developed by the Pesaro group in an attempt to eradicate more effectively thalassemic marrow erythropoiesis [14]. This protocol comprises intensified preparation with hydroxyurea 30 mg/kg and azathioprine 3 mg/kg daily on day -45 to day -11, followed by fludarabine 20 mg/m^2/day from day -17 to day 11, and busulfan at, 14 mg/kg and cyclophosphamide at 160 mg/kg . With this approach overall survival, thalassemia-free survival, graft rejection and transplant-related mortality were 93%, 85%, 8% and 6%, respectively. Thus, the use of this regimen has improved outcome in class 3 patients to the level observed in class 1 and class 2 patients conditioned with a less intensive regimen.

Transplantation in adult patients

Early trials from the Pesaro group showed unfavorable results in adult patients, who typically had more advanced disease with marked erythroid expansion and therapy-related organ complications. With conditioning regimens comprising busulfan 14 mg/kg and cyclophosphamide 200 mg/kg in class 2, and busulfan 14–16 mg/kg and cyclophosphamide 120–160 mg/kg in class 3 patients, the overall survival, thalassemia-free survival, rejection, and transplant-related mortality were 66%, 62%, 4%, and 37%, respectively.

By using a new preparative regimen similar to that used for children with class 3 risk (cyclophosphamide dose lowered to 90 mg/kg), the overall survival, thalassemia-free survival, rejection, and transplant-related mortality were 65%, 65%, 7%, and 28%, respectively [14]. Thus, this strategy has improved transplant results in adult patients with thalassemia; however, transplant-related mortality is still significant.

Bone marrow transplantation for thalassemia in Thailand

The first successful bone marrow transplant for thalassemia in Thailand was performed in 1988 at Siriraj Hospital, Mahidol University. Subsequently, transplant programs were also developed at Ramathibodi and Chulalongkorn hospitals. By 2008, 241 patients with thalassemia had undergone bone marrow transplantation in Thailand. Of these, 48 (22%) had homozygous β-thalassemia, and 155 (72%) had severe Hb E/β-thalassemia. Patients with Hb E/β-thalassemia with anemic symptoms for the first time during the first year of life are considered to have severe disease and should undergo bone marrow transplantation if they have HLA-identical siblings. Only a few patients received hypertransfusion and iron chelation. The results showed that overall survival and thalassemia-free survival in class 1 and 2 children were 89% and 80%, respectively. However, results in class 3 children were unfavorable. By using modified conditioning with busulfan 600 mg/m2 and cyclophosphamide 200 mg/kg, outcome was improved to 90% overall survival, and 85% thalassemia-free survival [15].

Cord blood transplantation from related donors

We reported the first successful use of cord blood from an unaffected younger sibling to transplant a child with Hb E/β-thalassemia [24]. The use of cord blood circumvents the need for a donor bone marrow harvest, is associated with a lower incidence of GvHD, and allows for prompt transplantation. So far, 14 patients have undergone cord blood transplantation for thalassemia at our institution. Three patients had homozygous β-thalassemia, and 11 had Hb E/β-thalassemia. Patients were 1 to 8 (a median of 4) years old, 8 were males and 6 were females. One patient died early, and one patient failed to engraft. Twelve patients had documented engraftment, and 10 of them are surviving thalassemia-free. Two patients, both in risk class 3, rejected their grafts. Based on our experience from a single institution, we recommend that sibling cord blood transplantation should be performed only in children with class 1 or 2, not in advanced disease. An adequate cell dose of cord blood is important to guarantee success.

Data from Eurocord show a high survival rate (100%) and thalassemia-free survival of 89% for class 1, and 62% for class 2 patients [25]; however, graft rejection was high (21%), presumably reflecting  the importance of cell dose, although cell dose did not predict engraftment. Graft rejection was decreased when thiotepa was added to the conditioning regimen, and when methotrexate was omitted from  GvHD prophylaxis.

Transplants from donors other than HLA- identical siblings

Only 25–30% of patients have an unaffected HLA-identical sibling donor. The remaining patients may receive stem cells from alternative donors including matched unrelated donors, unrelated cord blood, and haploidentical donors. However, it should be emphasized that thalassemia is not a malignant disease, and although bone marrow transplantation can cure the disease, patients can live a long time with a satisfactory quality of life with hypertransfusion and iron chelation, and without transplantation. Transplants from donors other than HLA-identical siblings should be considered only when patients and their parents fully understand the potential risks and benefits and are motivated to perform transplantation.

Marrow transplantation from HLA-matched unrelated donors
The outcome of matched unrelated donor transplantation has improved substantially, primarily due to more refined histocompatibility typing and selection of donors on the basis of matching at the molecular level. Earlier reports using conditioning with busulfan and cyclophosphamide with or without thiotepa showed thalassemia-free survival of 66%, graft rejection of 12%, and transplant-related mortality of 19% [26]. Favorable results were also obtained in adult patients with overall survival, thalassemia-free survival, graft rejection, and transplant-related mortality of 70%, 70%, 4%, and 30%, respectively [27].

A recent report from Thailand confirms this data, showing overall survival, thalassemia-free survival, graft rejection, and transplant related mortality of 82%, 71%, 13%, and 18% respectively [28]. By 2008, 53 patients had undergone matched unrelated bone marrow transplantation (40 “full” HLA matches, 13  1 or 2 antigen mismatches) in Thailand. Of these 53 patients, 28 were in class 1, 24 in class 2, and 5 in class 3.  Overall survival was 87%, and thalassemia-free survival, 80%. Thus, HLA-matched unrelated donor transplantation is an excellent option and may have success rates superior to those achieved with cord blood.

Unrelated cord blood transplantation
Unrelated cord blood transplantation is increasingly used to treat hematological malignancies [29]. The advantages of using cord blood are as follows: faster availability, acceptability of partial HLA mismatching, and low incidence of GvHD; however, engraftment is usually delayed. Recent data from 14 transplant centers showed encouraging results with overall survival and thalassemic-free survival of 77%, and 65%, respectively [30].  Results were better when transplants were performed at experienced centers (overall survival 87% and thalassemia-free survival 77%).

To overcome the cell dose barrier some centers have begun to use two partially HLA-matched cord blood units for transplantation [31].

Transplantation from haploidentical donors
Almost all patients have haploidentical donors. A recent report described a successful use of T-cell depleted CD34+ peripheral blood and bone marrow cells from haploidentical mothers in children with thalassemia [32]. However, the methodology to purify CD34+ cells and deplete T cells is sophisticated and expensive.

Graft failure and graft rejection

Graft failure and rejection is more common after transplant for thalassemia, especially in poor-risk patients, than it is in other diseases. Failure of primary engraftment with persistent aplasia is rare and has a poor prognosis, because second transplants following second course of conditioning yield poor results (overall survival 49%, thalassemia-free survival 33%) [33]. Most patients with graft rejection show  autologous recovery of thalassemic hematopoiesis resulting in recurrence of the disease. Graft rejection most often occurs within the first 6 months after transplantation [34], therefore monthly determination of chimerism is recommended for the first 6 months as patients with residual detectable host cells are likely to develop graft rejection [35]. If the proportion of donor cells is declining, withdrawal of immunosuppressive drugs may allow for enhancement of donor hematopoiesis [36].

Mixed chimerism was found in one third of thalassemia patients at 2 months after transplantation. The risks of graft rejection was nearly 100%, 41%, and 13%  when  residual host cells accounted for more than 25%, 10–25%, and less than 10% of all cells, respectively [35]. None of the patients with complete chimerism at 2 months rejected the graft [35].    

A cohort of 295 patients who underwent transplantation showed that at 2 months 95 (33%) had mixed chimerism. At 24 months 42 had become complete chimeras, 33 progressed to rejection, and 20 had persistent mixed chimerism of 30–90% donor cells [34]. These results indicated that engrafted donor cells, as evidenced by stable mixed chimerism, are adequate to cure the disease phenotype once donor-host tolerance has been established. Therefore, complete eradication of donor hematopoiesis may not be necessary for cure.

Reduced intensity conditioning and transplantation for thalassemia

The findings that stable mixed chimerism is sufficient to suppress thalassemic hematopoiesis, have provided the rationale for using reduced intensity conditioning in thalassemic patients. Such an approach can reduce the conditioning-related toxicity, especially in patients with advanced disease. Early results using reduced intensity conditioning were disappointing [37-40]. A more recent report describes the use of  busulfan, 8–12 mg/kg, fludarabine, 175–210 mg/m2, antilymphocyte globulin 20–40 mg/kg with or without thiotepa, and total lymphoid irradiation for conditioning, and cyclosporine or tacrolimus and mycophenolate mofetil for GvHD prophylaxis in 8 patients with class 3 disease [41]. Initial engraftment was observed in all patients, although two patients lost donor chimerism later on. Further studies are needed.

Conclusions

Hematopoietic stem cell transplantation is the only modality that offers the potential of cure for severe thalassemia, including homozygous β-thalassemia and severe Hb E/β-thalassemia. All children with class 1 or 2 disease should be transplanted if they have HLA-identical siblings, and transplantation should be performed as early as possible. Sibling cord blood transplantation is recommended in children with class 1 or 2 disease, if adequate numbers of cord blood cells from younger siblings are available.

Bone marrow transplantation in class 3 children and adult patients with appropriate conditioning regimen gives results that are superior to those obtained with cord blood. However, we recommend that patients and their families should discuss in detail the risks and benefits, and transplantation should be performed only in motivated patients who have a clear understanding of the entire process. There is new hope that haploidentical transplantation will be successful, but further studies are required to confirm early results.

Acknowledgement

Dr. Issaragrisil is a Senior Research Scholar of Thailand Research Fund (grant no. RTA 488-0007) and also supported by Commission on Higher Education (grant no. CHE-RES-RG-49).

References

1. Chernoff AI. The distribution of the thalassemia gene. A historical review. Blood. 1959;14:899.

2. Weatherall DJ. Thalassemia in the next millennium. Ann NY Acad Sci. 1998;850:1-9. pmid: 9668522.

3. Wasi P. Haemoglobinopathies including thalassemia. Part 1. Tropical Asia. Clin Haematol. 1981;10:702-29. pmid: 7030550.

4. Fucharoen S, Winichagoon P. Clinical and hematologic aspects of hemoglobin E β-thalassemia. Cur Opin Hematol. 2000;7:106-12. pmid: 10698297.

5. Borgna-Pignatti C, Rugolotto S, di Stefano P, et al. Survival and complications in patients with thalassemia major treated with transfusion and defroxamine. Hematologica. 2004;89:1187-93.

6. Telfer P, Coen PG, Christou S, et al. Survival of medically treated thalassemia patients in Cyprus. Trends and risk factors over the period 1980-2004. Hematologica. 2006;91:1187-92.

7. Lucarelli G, Gaziev J. Advances in the allogeneic transplantation for thalassemia. Blood Rev. 2008;22:53-63. doi:10.1016/j.blre.2007.10.001.

8. Thomas ED, Buckner CD, Sanders J, et al. Marrow transplantation for thalassemia. Lancet. 1982;ii:227-9. pmid: 6124668.

9. Lucarelli G, Galimberti M, Polchi P, et al. Bone marrow transplantation in patients with thalassemia. N Engl j Med. 1990;322:417-21. pmid: 2300104.

10. Lucarelli G, Galimberti M, Polchi P, et al. Bone marrow transplantation in adult thalassemia. Blood. 1992;80:1603-7.

11. Lucarelli G, Galimberti M, Polchi P, et al. Marrow transplantation in patients with thalassemia responsive to iron chelation therapy. N Engl J Med. 1993;329:840-4.

12. Lucarelli G, Clift R, Galimberti M, et al. Marrow transplantation for patients with thalassemia: results in class 3 patients. Blood. 1996;87:2082-8.

13. Lucarelli G, Clift RA, Galimberti M. Et al. Bone marrow transplantation in adult thalassemic patients. Blood. 1999;93:1164-7.

14. Gaziev J, Sodani P, Polchi P, Andreant M, Lucarelli G. Bone marrow transplantation in adults with thalassemia. Treatment and long-term follow-up. Ann NY Acad Sci. 2005;1054:196-205.

15. Issaragrisil S, Suvatte V, Visuthisakchai S, et al. Bone marrow and cord blood stem cell transplantation for thalassemia in Thailand. Bone Marrow Transplant. 1997;19(2):54-6.

16. Lin HP, Chan LL, Lam SK, Ariffin W, Menaka N, Looi LM. Bone marrow transplantation for thalassemia. The experience from Malaysia. Bone Marrow Transplant. 1997;19(2):74-7.

17. Dennison D, Srivastava A, Chandy M. Bone Marrow transplantation for thalassemia in India. Bone Marrow Transplant. 1997;19(2):70.

18. Ghavamzadeh A, Bahar B, Djahani M, Kokabandeh A, Shahriari A. Bone marrow transplantation of thalassemia, the experience in Tehran (Iran). Bone Marrow Transplant. 1997;19(2):71-3.

19. Clift RA, Johnson FL. Marrow transplants for thalassemia. The USA experience. Bone Marrow Transplant. 1997;19(2):57-9.

20. Argiolu F, Sanna MA, Cossu F, et al. Bone marrow transplant in thalassemia. The experience of Cagliari. Bone Marrow Transplant. 1997;19(2):65-7.

21. Li CK, Shing MK, Chik KW, Lee V, Leung TF, Cheung PMP, Yuen PMP. Hematopoietic stem cell transplantation for thalassemia major in Hong Kong: prognostic factors and outcome. Bone Marrow Transplant. 2002;29:101-5.

22. Lawson SE, Roberts IAG, Amrolia P, Dokal I, Szydio R, Darbyshire PJ. Bone marrow transplantation for β-thalassemia major: the UK experience in two paediatric centers. Brit J Hematol. 2003;120:289-95.

23. Di Bartolomeo P, Santarone S, Di Bartolomeo, et al. Long-term results of bone marrow transplantation for thalassemia major in Pescara. Blood. 2004;104:3332.    

24. Issaragrisil S, Visuthisakchai S, Suvatte V, et al. Transplantation of cord-blood stem cells into a patient with severe thalassemia. N Engl J Med. 1995;332(6):367-9.

25. Locatelli F, Rocha V, Reed W, et al. Related umbilical cord blood transplant in patients with thalassemia and sickle cell disease. Blood. 2003;101:2137-43. doi: 10.1182/blood-2002-07-2090.

26. La Nasa G, Giardini C, Argiolu F, et al. Unrelated donor bone marrow transplantation for thalassemia: the effect of extended haplotypes. Blood. 2002;99(12):4350-6.

27. La Nasa G, Gaocci G, Argiolu F, et al. Unrelated donor stem cell transplantation in adult patients with thalassemia. Bone Marrow Transplant. 2005;36:971-5. doi:10.1038/sj.bmt.1705173.

28. Hongeng S, Pakakasama S, Chuansumrit A, et al. Outcomes of transplantation with related and unrelated-donor stem cells in children with severe thalassemia. Biol Blood Marrow Transplant. 2006;12:683-7. doi: 10.1016/j.bbmt.2006.02.008.

29. Wagner JE, Barker JN, DeFor TE, et al. Transplantation of unrelated donor umbilical cord blood in 102 patients with malignant and nonmalignant diseases : influence of CD34 cell dose and HLA disparity on treatment-related mortality and survival. Blood. 2002;100:1611-8. doi: 10.1182/blood-2002-01-0294.

30. Jaing T-H, Tan P, Rosenthal J, et al. Unrelated cord blood transplantation (CBT) for thalassemia. Blood. 2006;108:11.

31. Jaing T-H, Yang C-P, Hung I-J, et al. Transplantation of unrelated donor umbilical cord blood utilizing double-unit grafts for five teenagers with transfusion-dependent thalassemia. Bone Marrow Transpl. 2007;40:307-11. doi: 10.1038/sj.bmt.1705737.

32. Sodani P, Isgro A, Gaziev J, et al. Purified T-deplated, CD34+ peripheral blood and bone marrow cell transplantation from haploidentical mother to child with thalassemia. Blood. (prepublished online Nov 6, 2009). doi: 10.1182/blood-2009-05-218982.

33. Gaziev D, Polchi P, Lucarelli G et al. Second bone marrow for graft failure in patients with thalassemia. Bone Marrow Transplant. 1999;24:1299-1306.

34. Nesci S, Manna M, Lucarelli G, et al. Mixed chimerism after bone marrow transplantation in thalassemia. Ann NY Acad Sci. 1998;850:495-7. pmid: 9668594.

35. Andreani M, Nesci S, Lucarelli G, et al. Long-term survival of ex-thalassemic patients with persistent mixed chimerism after bone marrow transplantation. Bone Marrow Transplant. 2000;25:401-4.

36. Zakrzewaki JL. Successful management of impending graft failure in a thalassemic bone marrow transplant recipient. Hematologica. 2002;87:ECR32. pmid: 12368175.

37. Iannone R, Casella JF, Fuche EJ, et al. Results of minimally toxic nonmyeloablative transplantation in patients with sickle cell anemia and β-thalassemia. Biol Blood Marrow Transplant. 2003;9:519-28. doi: 10.1016/S1083-8791(03)00192-7.

38. Horan JT, Liesveld JL, Fenton P, Blumberg N, Walters MC. Hematopoietic stem cell transplantation for multiply transfused patients with sickle cell disease and thalassemia after low-dose total body irradiation, fludarabine, and rabbit anti-thymocyte globulin. Bone Marrow Transplant. 2005;35:171-7. doi: 10.1038/sj.bmt.1704745.

39. Jacobsohn DA, Duerst R, Tse W, Kletzel M. Reduced intensity haematopoietic stem cell transplantation for treatment of non-malignant disease children. Lancet. 2004;364:156-62. pmid: 15246728.

40. Krishnamurti L, Wu CJ, Baker S, Wagner J. Stable donor engraftment following reduced intensity hematopoietic cell transplantation for sickle disease. Biol Blood Marrow Transplant. 2006;12:39.

41. Hongeng S, Pakakasama S, Chuansumrit A, et al. Reduced intensity stem cell transplantation for treatment of Class 3 Lucarelli severe thalassemia patients. Am J Hematol. 2007;82(12):1095-8. doi: 10.1002/ajh.21002.

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Introduction

The distribution of thalassemia used to be confined to areas from the Mediterranean across the Middle East through Southern Asia to Southeast Asia: the so-called thalassemia belt [1]. At present, migration of people has spread thalassemia throughout the world. Furthermore, with the improvement of medical care, including developing countries, thalassemic children can now survive the early months of life and live long enough to require treatment. Thalassemia is, therefore, now considered to be a global health problem [2].

In Thailand, both α- and β-thalassemias as well as Hb E and Hb Constant Spring are prevalent [3]. There are more than 60 clinical syndromes resulting from various gene interactions, giving 12,000 annual births of thalassemic children. Among them, the common severe thalassemic syndromes with which patients can survive are homozygous β-thalassemia or thalassemia major, and Hb E/β-thalassemia. Hb E/β-thalassemia is the most common severe clinical syndrome in adults and is found more frequently than homozygous β-thalassemia in Thailand [4]. This syndrome is unique to Southeast Asia in general and to Thailand in particular. Clinical manifestations of this syndrome are heterogeneous:  at one end, symptoms may be as severe as with thalassemia major, at the other end, patients may have only mild anemia [4]. However, those who show symptoms related to anemia during the first year of life usually have severe manifestations later on.  

Therapy of severe thalassemia with regular hypertransfusion and iron chelation has dramatically improved life expectancy [5, 6], but there remain many problems related to quality of life, compliance, and expense. Hematopoietic stem cell transplantation is at present the only modality with the potential to cure thalassemia [7]. The objective of allogeneic transplantation for thalassemia is to replace thalassemic hematopoiesis by normal hematopoiesis through allogeneic stem cell transplantation. Patients require “conditioning” to eradicate thalassemic stem cells and to overcome the immunological barriers (histoincompatibility and transfusion-associated allosensitization).

Bone marrow transplantation from HLA-identical siblings in children with thalassemia

The first successful treatment of thalassemia with bone marrow transplantation from HLA-identical sibling donors was performed in 1981 in Seattle [8]. Most subsequent experience, however, has been reported by the Pesaro group [9-14], and other case series have been presented [15-23]. Most transplants for thalassemia have employed bone marrow from unaffected HLA-identical sibling donors. However, only 25–30% of patients have an HLA-matched sibling donor.

By using conditioning with busulfan, 14 mg/kg given over 4 days, followed by cyclophosphamide, 200 mg/kg over the next 4 days, the Pesaro group reported successful bone marrow transplantation in large numbers of children and identified three risk factors, which predicted outcome after transplantation [9]. These risk factors include hepatomegaly of more than 2 cm, liver histology showing portal fibrosis, and irregular (and therefore ineffective) iron chelation. On that basis patients can be classified into three risk categories: class 1 without any risk factors, class 2 with one or two risk factors, and class 3 with all risk factors.

Results in class 1 and 2 patients

The majority of transplants were performed in children in the class 1 and 2 risk groups using bone marrow from HLA-identical siblings. Overall survival was 87–90% and thalassemia-free survival 85–87% [9, 11, 15-23]. The incidence of graft rejection and transplant-related mortality was 3% and 10–13%, respectively. On the basis of these recommendations, children with severe thalassemia should undergo bone marrow transplantation if they have HLA-identical siblings, as early in life  as possible.

Class 3 patients

By using busulfan at 14 mg/kg and cyclophosphamide at 200 mg/kg as conditioning, the Pesaro group reported lower overall survival (61%), thalassemia-free survival (53%) and higher transplant-related mortality (47%) [12] than that observed in class 1 and 2 patients. Conditioning comprising busulfan 14 mg/kg and lower dose of cyclophosphamide (160 or 120 mg/kg) improved the overall survival to 80%; however, the graft rejection rate was increased to 33%, giving a thalassemia-free survival of 56% [12]. This conditioning regimen is, therefore, inadequate to eradicate the marrow erythroid hyperplasia related to the disease.

A new preparative regimen was developed by the Pesaro group in an attempt to eradicate more effectively thalassemic marrow erythropoiesis [14]. This protocol comprises intensified preparation with hydroxyurea 30 mg/kg and azathioprine 3 mg/kg daily on day -45 to day -11, followed by fludarabine 20 mg/m^2/day from day -17 to day 11, and busulfan at, 14 mg/kg and cyclophosphamide at 160 mg/kg . With this approach overall survival, thalassemia-free survival, graft rejection and transplant-related mortality were 93%, 85%, 8% and 6%, respectively. Thus, the use of this regimen has improved outcome in class 3 patients to the level observed in class 1 and class 2 patients conditioned with a less intensive regimen.

Transplantation in adult patients

Early trials from the Pesaro group showed unfavorable results in adult patients, who typically had more advanced disease with marked erythroid expansion and therapy-related organ complications. With conditioning regimens comprising busulfan 14 mg/kg and cyclophosphamide 200 mg/kg in class 2, and busulfan 14–16 mg/kg and cyclophosphamide 120–160 mg/kg in class 3 patients, the overall survival, thalassemia-free survival, rejection, and transplant-related mortality were 66%, 62%, 4%, and 37%, respectively.

By using a new preparative regimen similar to that used for children with class 3 risk (cyclophosphamide dose lowered to 90 mg/kg), the overall survival, thalassemia-free survival, rejection, and transplant-related mortality were 65%, 65%, 7%, and 28%, respectively [14]. Thus, this strategy has improved transplant results in adult patients with thalassemia; however, transplant-related mortality is still significant.

Bone marrow transplantation for thalassemia in Thailand

The first successful bone marrow transplant for thalassemia in Thailand was performed in 1988 at Siriraj Hospital, Mahidol University. Subsequently, transplant programs were also developed at Ramathibodi and Chulalongkorn hospitals. By 2008, 241 patients with thalassemia had undergone bone marrow transplantation in Thailand. Of these, 48 (22%) had homozygous β-thalassemia, and 155 (72%) had severe Hb E/β-thalassemia. Patients with Hb E/β-thalassemia with anemic symptoms for the first time during the first year of life are considered to have severe disease and should undergo bone marrow transplantation if they have HLA-identical siblings. Only a few patients received hypertransfusion and iron chelation. The results showed that overall survival and thalassemia-free survival in class 1 and 2 children were 89% and 80%, respectively. However, results in class 3 children were unfavorable. By using modified conditioning with busulfan 600 mg/m2 and cyclophosphamide 200 mg/kg, outcome was improved to 90% overall survival, and 85% thalassemia-free survival [15].

Cord blood transplantation from related donors

We reported the first successful use of cord blood from an unaffected younger sibling to transplant a child with Hb E/β-thalassemia [24]. The use of cord blood circumvents the need for a donor bone marrow harvest, is associated with a lower incidence of GvHD, and allows for prompt transplantation. So far, 14 patients have undergone cord blood transplantation for thalassemia at our institution. Three patients had homozygous β-thalassemia, and 11 had Hb E/β-thalassemia. Patients were 1 to 8 (a median of 4) years old, 8 were males and 6 were females. One patient died early, and one patient failed to engraft. Twelve patients had documented engraftment, and 10 of them are surviving thalassemia-free. Two patients, both in risk class 3, rejected their grafts. Based on our experience from a single institution, we recommend that sibling cord blood transplantation should be performed only in children with class 1 or 2, not in advanced disease. An adequate cell dose of cord blood is important to guarantee success.

Data from Eurocord show a high survival rate (100%) and thalassemia-free survival of 89% for class 1, and 62% for class 2 patients [25]; however, graft rejection was high (21%), presumably reflecting  the importance of cell dose, although cell dose did not predict engraftment. Graft rejection was decreased when thiotepa was added to the conditioning regimen, and when methotrexate was omitted from  GvHD prophylaxis.

Transplants from donors other than HLA- identical siblings

Only 25–30% of patients have an unaffected HLA-identical sibling donor. The remaining patients may receive stem cells from alternative donors including matched unrelated donors, unrelated cord blood, and haploidentical donors. However, it should be emphasized that thalassemia is not a malignant disease, and although bone marrow transplantation can cure the disease, patients can live a long time with a satisfactory quality of life with hypertransfusion and iron chelation, and without transplantation. Transplants from donors other than HLA-identical siblings should be considered only when patients and their parents fully understand the potential risks and benefits and are motivated to perform transplantation.

Marrow transplantation from HLA-matched unrelated donors
The outcome of matched unrelated donor transplantation has improved substantially, primarily due to more refined histocompatibility typing and selection of donors on the basis of matching at the molecular level. Earlier reports using conditioning with busulfan and cyclophosphamide with or without thiotepa showed thalassemia-free survival of 66%, graft rejection of 12%, and transplant-related mortality of 19% [26]. Favorable results were also obtained in adult patients with overall survival, thalassemia-free survival, graft rejection, and transplant-related mortality of 70%, 70%, 4%, and 30%, respectively [27].

A recent report from Thailand confirms this data, showing overall survival, thalassemia-free survival, graft rejection, and transplant related mortality of 82%, 71%, 13%, and 18% respectively [28]. By 2008, 53 patients had undergone matched unrelated bone marrow transplantation (40 “full” HLA matches, 13  1 or 2 antigen mismatches) in Thailand. Of these 53 patients, 28 were in class 1, 24 in class 2, and 5 in class 3.  Overall survival was 87%, and thalassemia-free survival, 80%. Thus, HLA-matched unrelated donor transplantation is an excellent option and may have success rates superior to those achieved with cord blood.

Unrelated cord blood transplantation
Unrelated cord blood transplantation is increasingly used to treat hematological malignancies [29]. The advantages of using cord blood are as follows: faster availability, acceptability of partial HLA mismatching, and low incidence of GvHD; however, engraftment is usually delayed. Recent data from 14 transplant centers showed encouraging results with overall survival and thalassemic-free survival of 77%, and 65%, respectively [30].  Results were better when transplants were performed at experienced centers (overall survival 87% and thalassemia-free survival 77%).

To overcome the cell dose barrier some centers have begun to use two partially HLA-matched cord blood units for transplantation [31].

Transplantation from haploidentical donors
Almost all patients have haploidentical donors. A recent report described a successful use of T-cell depleted CD34+ peripheral blood and bone marrow cells from haploidentical mothers in children with thalassemia [32]. However, the methodology to purify CD34+ cells and deplete T cells is sophisticated and expensive.

Graft failure and graft rejection

Graft failure and rejection is more common after transplant for thalassemia, especially in poor-risk patients, than it is in other diseases. Failure of primary engraftment with persistent aplasia is rare and has a poor prognosis, because second transplants following second course of conditioning yield poor results (overall survival 49%, thalassemia-free survival 33%) [33]. Most patients with graft rejection show  autologous recovery of thalassemic hematopoiesis resulting in recurrence of the disease. Graft rejection most often occurs within the first 6 months after transplantation [34], therefore monthly determination of chimerism is recommended for the first 6 months as patients with residual detectable host cells are likely to develop graft rejection [35]. If the proportion of donor cells is declining, withdrawal of immunosuppressive drugs may allow for enhancement of donor hematopoiesis [36].

Mixed chimerism was found in one third of thalassemia patients at 2 months after transplantation. The risks of graft rejection was nearly 100%, 41%, and 13%  when  residual host cells accounted for more than 25%, 10–25%, and less than 10% of all cells, respectively [35]. None of the patients with complete chimerism at 2 months rejected the graft [35].    

A cohort of 295 patients who underwent transplantation showed that at 2 months 95 (33%) had mixed chimerism. At 24 months 42 had become complete chimeras, 33 progressed to rejection, and 20 had persistent mixed chimerism of 30–90% donor cells [34]. These results indicated that engrafted donor cells, as evidenced by stable mixed chimerism, are adequate to cure the disease phenotype once donor-host tolerance has been established. Therefore, complete eradication of donor hematopoiesis may not be necessary for cure.

Reduced intensity conditioning and transplantation for thalassemia

The findings that stable mixed chimerism is sufficient to suppress thalassemic hematopoiesis, have provided the rationale for using reduced intensity conditioning in thalassemic patients. Such an approach can reduce the conditioning-related toxicity, especially in patients with advanced disease. Early results using reduced intensity conditioning were disappointing [37-40]. A more recent report describes the use of  busulfan, 8–12 mg/kg, fludarabine, 175–210 mg/m2, antilymphocyte globulin 20–40 mg/kg with or without thiotepa, and total lymphoid irradiation for conditioning, and cyclosporine or tacrolimus and mycophenolate mofetil for GvHD prophylaxis in 8 patients with class 3 disease [41]. Initial engraftment was observed in all patients, although two patients lost donor chimerism later on. Further studies are needed.

Conclusions

Hematopoietic stem cell transplantation is the only modality that offers the potential of cure for severe thalassemia, including homozygous β-thalassemia and severe Hb E/β-thalassemia. All children with class 1 or 2 disease should be transplanted if they have HLA-identical siblings, and transplantation should be performed as early as possible. Sibling cord blood transplantation is recommended in children with class 1 or 2 disease, if adequate numbers of cord blood cells from younger siblings are available.

Bone marrow transplantation in class 3 children and adult patients with appropriate conditioning regimen gives results that are superior to those obtained with cord blood. However, we recommend that patients and their families should discuss in detail the risks and benefits, and transplantation should be performed only in motivated patients who have a clear understanding of the entire process. There is new hope that haploidentical transplantation will be successful, but further studies are required to confirm early results.

Acknowledgement

Dr. Issaragrisil is a Senior Research Scholar of Thailand Research Fund (grant no. RTA 488-0007) and also supported by Commission on Higher Education (grant no. CHE-RES-RG-49).

References

1. Chernoff AI. The distribution of the thalassemia gene. A historical review. Blood. 1959;14:899.

2. Weatherall DJ. Thalassemia in the next millennium. Ann NY Acad Sci. 1998;850:1-9. pmid: 9668522.

3. Wasi P. Haemoglobinopathies including thalassemia. Part 1. Tropical Asia. Clin Haematol. 1981;10:702-29. pmid: 7030550.

4. Fucharoen S, Winichagoon P. Clinical and hematologic aspects of hemoglobin E β-thalassemia. Cur Opin Hematol. 2000;7:106-12. pmid: 10698297.

5. Borgna-Pignatti C, Rugolotto S, di Stefano P, et al. Survival and complications in patients with thalassemia major treated with transfusion and defroxamine. Hematologica. 2004;89:1187-93.

6. Telfer P, Coen PG, Christou S, et al. Survival of medically treated thalassemia patients in Cyprus. Trends and risk factors over the period 1980-2004. Hematologica. 2006;91:1187-92.

7. Lucarelli G, Gaziev J. Advances in the allogeneic transplantation for thalassemia. Blood Rev. 2008;22:53-63. doi:10.1016/j.blre.2007.10.001.

8. Thomas ED, Buckner CD, Sanders J, et al. Marrow transplantation for thalassemia. Lancet. 1982;ii:227-9. pmid: 6124668.

9. Lucarelli G, Galimberti M, Polchi P, et al. Bone marrow transplantation in patients with thalassemia. N Engl j Med. 1990;322:417-21. pmid: 2300104.

10. Lucarelli G, Galimberti M, Polchi P, et al. Bone marrow transplantation in adult thalassemia. Blood. 1992;80:1603-7.

11. Lucarelli G, Galimberti M, Polchi P, et al. Marrow transplantation in patients with thalassemia responsive to iron chelation therapy. N Engl J Med. 1993;329:840-4.

12. Lucarelli G, Clift R, Galimberti M, et al. Marrow transplantation for patients with thalassemia: results in class 3 patients. Blood. 1996;87:2082-8.

13. Lucarelli G, Clift RA, Galimberti M. Et al. Bone marrow transplantation in adult thalassemic patients. Blood. 1999;93:1164-7.

14. Gaziev J, Sodani P, Polchi P, Andreant M, Lucarelli G. Bone marrow transplantation in adults with thalassemia. Treatment and long-term follow-up. Ann NY Acad Sci. 2005;1054:196-205.

15. Issaragrisil S, Suvatte V, Visuthisakchai S, et al. Bone marrow and cord blood stem cell transplantation for thalassemia in Thailand. Bone Marrow Transplant. 1997;19(2):54-6.

16. Lin HP, Chan LL, Lam SK, Ariffin W, Menaka N, Looi LM. Bone marrow transplantation for thalassemia. The experience from Malaysia. Bone Marrow Transplant. 1997;19(2):74-7.

17. Dennison D, Srivastava A, Chandy M. Bone Marrow transplantation for thalassemia in India. Bone Marrow Transplant. 1997;19(2):70.

18. Ghavamzadeh A, Bahar B, Djahani M, Kokabandeh A, Shahriari A. Bone marrow transplantation of thalassemia, the experience in Tehran (Iran). Bone Marrow Transplant. 1997;19(2):71-3.

19. Clift RA, Johnson FL. Marrow transplants for thalassemia. The USA experience. Bone Marrow Transplant. 1997;19(2):57-9.

20. Argiolu F, Sanna MA, Cossu F, et al. Bone marrow transplant in thalassemia. The experience of Cagliari. Bone Marrow Transplant. 1997;19(2):65-7.

21. Li CK, Shing MK, Chik KW, Lee V, Leung TF, Cheung PMP, Yuen PMP. Hematopoietic stem cell transplantation for thalassemia major in Hong Kong: prognostic factors and outcome. Bone Marrow Transplant. 2002;29:101-5.

22. Lawson SE, Roberts IAG, Amrolia P, Dokal I, Szydio R, Darbyshire PJ. Bone marrow transplantation for β-thalassemia major: the UK experience in two paediatric centers. Brit J Hematol. 2003;120:289-95.

23. Di Bartolomeo P, Santarone S, Di Bartolomeo, et al. Long-term results of bone marrow transplantation for thalassemia major in Pescara. Blood. 2004;104:3332.    

24. Issaragrisil S, Visuthisakchai S, Suvatte V, et al. Transplantation of cord-blood stem cells into a patient with severe thalassemia. N Engl J Med. 1995;332(6):367-9.

25. Locatelli F, Rocha V, Reed W, et al. Related umbilical cord blood transplant in patients with thalassemia and sickle cell disease. Blood. 2003;101:2137-43. doi: 10.1182/blood-2002-07-2090.

26. La Nasa G, Giardini C, Argiolu F, et al. Unrelated donor bone marrow transplantation for thalassemia: the effect of extended haplotypes. Blood. 2002;99(12):4350-6.

27. La Nasa G, Gaocci G, Argiolu F, et al. Unrelated donor stem cell transplantation in adult patients with thalassemia. Bone Marrow Transplant. 2005;36:971-5. doi:10.1038/sj.bmt.1705173.

28. Hongeng S, Pakakasama S, Chuansumrit A, et al. Outcomes of transplantation with related and unrelated-donor stem cells in children with severe thalassemia. Biol Blood Marrow Transplant. 2006;12:683-7. doi: 10.1016/j.bbmt.2006.02.008.

29. Wagner JE, Barker JN, DeFor TE, et al. Transplantation of unrelated donor umbilical cord blood in 102 patients with malignant and nonmalignant diseases : influence of CD34 cell dose and HLA disparity on treatment-related mortality and survival. Blood. 2002;100:1611-8. doi: 10.1182/blood-2002-01-0294.

30. Jaing T-H, Tan P, Rosenthal J, et al. Unrelated cord blood transplantation (CBT) for thalassemia. Blood. 2006;108:11.

31. Jaing T-H, Yang C-P, Hung I-J, et al. Transplantation of unrelated donor umbilical cord blood utilizing double-unit grafts for five teenagers with transfusion-dependent thalassemia. Bone Marrow Transpl. 2007;40:307-11. doi: 10.1038/sj.bmt.1705737.

32. Sodani P, Isgro A, Gaziev J, et al. Purified T-deplated, CD34+ peripheral blood and bone marrow cell transplantation from haploidentical mother to child with thalassemia. Blood. (prepublished online Nov 6, 2009). doi: 10.1182/blood-2009-05-218982.

33. Gaziev D, Polchi P, Lucarelli G et al. Second bone marrow for graft failure in patients with thalassemia. Bone Marrow Transplant. 1999;24:1299-1306.

34. Nesci S, Manna M, Lucarelli G, et al. Mixed chimerism after bone marrow transplantation in thalassemia. Ann NY Acad Sci. 1998;850:495-7. pmid: 9668594.

35. Andreani M, Nesci S, Lucarelli G, et al. Long-term survival of ex-thalassemic patients with persistent mixed chimerism after bone marrow transplantation. Bone Marrow Transplant. 2000;25:401-4.

36. Zakrzewaki JL. Successful management of impending graft failure in a thalassemic bone marrow transplant recipient. Hematologica. 2002;87:ECR32. pmid: 12368175.

37. Iannone R, Casella JF, Fuche EJ, et al. Results of minimally toxic nonmyeloablative transplantation in patients with sickle cell anemia and β-thalassemia. Biol Blood Marrow Transplant. 2003;9:519-28. doi: 10.1016/S1083-8791(03)00192-7.

38. Horan JT, Liesveld JL, Fenton P, Blumberg N, Walters MC. Hematopoietic stem cell transplantation for multiply transfused patients with sickle cell disease and thalassemia after low-dose total body irradiation, fludarabine, and rabbit anti-thymocyte globulin. Bone Marrow Transplant. 2005;35:171-7. doi: 10.1038/sj.bmt.1704745.

39. Jacobsohn DA, Duerst R, Tse W, Kletzel M. Reduced intensity haematopoietic stem cell transplantation for treatment of non-malignant disease children. Lancet. 2004;364:156-62. pmid: 15246728.

40. Krishnamurti L, Wu CJ, Baker S, Wagner J. Stable donor engraftment following reduced intensity hematopoietic cell transplantation for sickle disease. Biol Blood Marrow Transplant. 2006;12:39.

41. Hongeng S, Pakakasama S, Chuansumrit A, et al. Reduced intensity stem cell transplantation for treatment of Class 3 Lucarelli severe thalassemia patients. Am J Hematol. 2007;82(12):1095-8. doi: 10.1002/ajh.21002.

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Сурапол Иссарагризил

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Трансплантация гемопоэтических стволовых клеток является единственной возможностью потенциального излечения при тяжелой талассемии, в том числе при гомозиготной β-талассемии и тяжелой талассемии с гемоглобином E/β. При заболевании 1-го или 2-го классов риска всем детям должна проводиться трансплантация, если они имеют HLA-идентичных братьев или сестер, и такую трансплантацию следует осуществлять как можно раньше. Пересадка клеток пуповинной крови от братьев или сестер рекомендуется детям с заболеванием 1-го или 2-го классов риска, если имеются в наличии адекватные количества клеток пуповинной крови от младших сиблингов. 

Трансплантация костного мозга детям 3-го класса риска и взрослым больным с применением соответствующих режимов кондиционирования дает лучшие результаты по сравнению с теми, которые получаются при использовании пуповинной крови. Мы рекомендуем, однако, чтобы больные и их семьи могли обсудить в подробностях возможные факторы риска и преимущества лечения, и трансплантация должна проводиться только мотивированным пациентам, которые имеют четкое понятие обо всем процессе.  Новые надежды связаны с возможным успехом гаплоидентичной трансплантации, но требуются дальнейшие исследования для подтверждения предыдущих результатов.

Ключевые слова

талассемия, клинические факторы риска, трансплантация гемопоэтических стволовых клеток, показания, преимущества

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Surapol Issaragrisil

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(6) "Author" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["ORGANIZATION_EN"]=> array(36) { ["ID"]=> string(2) "38" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(12) "Organization" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "38" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "19035" ["VALUE"]=> array(2) { ["TEXT"]=> string(153) "<p>Bone Marrow Transplant Center, Division of Hematology, Department of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(141) "

Bone Marrow Transplant Center, Division of Hematology, Department of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Organization" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_EN"]=> array(36) { ["ID"]=> string(2) "39" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Description / Summary" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "39" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "19036" ["VALUE"]=> array(2) { ["TEXT"]=> string(1281) "<p class="bodytext">Hematopoietic stem cell transplantation is the only modality that offers the potential of cure for severe thalassemia, including homozygous β-thalassemia and severe Hb E/β-thalassemia. All children with class 1 or 2 disease should be transplanted if they have  HLA-identical siblings, and transplantation should be performed as early as possible. Sibling cord blood transplantation is recommended in children with class 1 or 2 of the disease if adequate numbers of cord blood cells from younger siblings are available.<br /><br />Bone marrow transplantation in class 3 children and adult patients with appropriate conditioning regimen gives results that are superior to those obtained with cord blood. However, we recommend that patients and their families should discuss in detail the risks and benefits, and transplantation should be performed in only motivated patients who have a clear understanding of the entire process. There is new hope that haploidentical transplantation will be successful, but further studies are required to confirm early results.</p><h3>Keywords</h3> <p> thalassemia, clinical risk factors, hematopoietic stem cell transplantation, indications, benefits </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(1223) "

Hematopoietic stem cell transplantation is the only modality that offers the potential of cure for severe thalassemia, including homozygous β-thalassemia and severe Hb E/β-thalassemia. All children with class 1 or 2 disease should be transplanted if they have  HLA-identical siblings, and transplantation should be performed as early as possible. Sibling cord blood transplantation is recommended in children with class 1 or 2 of the disease if adequate numbers of cord blood cells from younger siblings are available.

Bone marrow transplantation in class 3 children and adult patients with appropriate conditioning regimen gives results that are superior to those obtained with cord blood. However, we recommend that patients and their families should discuss in detail the risks and benefits, and transplantation should be performed in only motivated patients who have a clear understanding of the entire process. There is new hope that haploidentical transplantation will be successful, but further studies are required to confirm early results.

Keywords

thalassemia, clinical risk factors, hematopoietic stem cell transplantation, indications, benefits

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Surapol Issaragrisil

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Surapol Issaragrisil

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Hematopoietic stem cell transplantation is the only modality that offers the potential of cure for severe thalassemia, including homozygous β-thalassemia and severe Hb E/β-thalassemia. All children with class 1 or 2 disease should be transplanted if they have  HLA-identical siblings, and transplantation should be performed as early as possible. Sibling cord blood transplantation is recommended in children with class 1 or 2 of the disease if adequate numbers of cord blood cells from younger siblings are available.

Bone marrow transplantation in class 3 children and adult patients with appropriate conditioning regimen gives results that are superior to those obtained with cord blood. However, we recommend that patients and their families should discuss in detail the risks and benefits, and transplantation should be performed in only motivated patients who have a clear understanding of the entire process. There is new hope that haploidentical transplantation will be successful, but further studies are required to confirm early results.

Keywords

thalassemia, clinical risk factors, hematopoietic stem cell transplantation, indications, benefits

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Hematopoietic stem cell transplantation is the only modality that offers the potential of cure for severe thalassemia, including homozygous β-thalassemia and severe Hb E/β-thalassemia. All children with class 1 or 2 disease should be transplanted if they have  HLA-identical siblings, and transplantation should be performed as early as possible. Sibling cord blood transplantation is recommended in children with class 1 or 2 of the disease if adequate numbers of cord blood cells from younger siblings are available.

Bone marrow transplantation in class 3 children and adult patients with appropriate conditioning regimen gives results that are superior to those obtained with cord blood. However, we recommend that patients and their families should discuss in detail the risks and benefits, and transplantation should be performed in only motivated patients who have a clear understanding of the entire process. There is new hope that haploidentical transplantation will be successful, but further studies are required to confirm early results.

Keywords

thalassemia, clinical risk factors, hematopoietic stem cell transplantation, indications, benefits

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Bone Marrow Transplant Center, Division of Hematology, Department of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand

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Bone Marrow Transplant Center, Division of Hematology, Department of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand

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Сурапол Иссарагризил

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Сурапол Иссарагризил

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["PROPERTY_VALUE_ID"]=> string(5) "19039" ["VALUE"]=> array(2) { ["TEXT"]=> string(2688) "<p class="bodytext"> Трансплантация гемопоэтических стволовых клеток является единственной возможностью потенциального излечения при тяжелой талассемии, в том числе при гомозиготной β-талассемии и тяжелой талассемии с гемоглобином E/β. При заболевании 1-го или 2-го классов риска всем детям должна проводиться трансплантация, если они имеют HLA-идентичных братьев или сестер, и такую трансплантацию следует осуществлять как можно раньше. Пересадка клеток пуповинной крови от братьев или сестер рекомендуется детям с заболеванием 1-го или 2-го классов риска, если имеются в наличии адекватные количества клеток пуповинной крови от младших сиблингов.  <br> <br> Трансплантация костного мозга детям 3-го класса риска и взрослым больным с применением соответствующих режимов кондиционирования дает лучшие результаты по сравнению с теми, которые получаются при использовании пуповинной крови. Мы рекомендуем, однако, чтобы больные и их семьи могли обсудить в подробностях возможные факторы риска и преимущества лечения, и трансплантация должна проводиться только мотивированным пациентам, которые имеют четкое понятие обо всем процессе.  Новые надежды связаны с возможным успехом гаплоидентичной трансплантации, но требуются дальнейшие исследования для подтверждения предыдущих результатов. </p> <h3>Ключевые слова</h3> <p> талассемия, клинические факторы риска, трансплантация гемопоэтических стволовых клеток, показания, преимущества </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(2630) "

Трансплантация гемопоэтических стволовых клеток является единственной возможностью потенциального излечения при тяжелой талассемии, в том числе при гомозиготной β-талассемии и тяжелой талассемии с гемоглобином E/β. При заболевании 1-го или 2-го классов риска всем детям должна проводиться трансплантация, если они имеют HLA-идентичных братьев или сестер, и такую трансплантацию следует осуществлять как можно раньше. Пересадка клеток пуповинной крови от братьев или сестер рекомендуется детям с заболеванием 1-го или 2-го классов риска, если имеются в наличии адекватные количества клеток пуповинной крови от младших сиблингов. 

Трансплантация костного мозга детям 3-го класса риска и взрослым больным с применением соответствующих режимов кондиционирования дает лучшие результаты по сравнению с теми, которые получаются при использовании пуповинной крови. Мы рекомендуем, однако, чтобы больные и их семьи могли обсудить в подробностях возможные факторы риска и преимущества лечения, и трансплантация должна проводиться только мотивированным пациентам, которые имеют четкое понятие обо всем процессе.  Новые надежды связаны с возможным успехом гаплоидентичной трансплантации, но требуются дальнейшие исследования для подтверждения предыдущих результатов.

Ключевые слова

талассемия, клинические факторы риска, трансплантация гемопоэтических стволовых клеток, показания, преимущества

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Трансплантация гемопоэтических стволовых клеток является единственной возможностью потенциального излечения при тяжелой талассемии, в том числе при гомозиготной β-талассемии и тяжелой талассемии с гемоглобином E/β. При заболевании 1-го или 2-го классов риска всем детям должна проводиться трансплантация, если они имеют HLA-идентичных братьев или сестер, и такую трансплантацию следует осуществлять как можно раньше. Пересадка клеток пуповинной крови от братьев или сестер рекомендуется детям с заболеванием 1-го или 2-го классов риска, если имеются в наличии адекватные количества клеток пуповинной крови от младших сиблингов. 

Трансплантация костного мозга детям 3-го класса риска и взрослым больным с применением соответствующих режимов кондиционирования дает лучшие результаты по сравнению с теми, которые получаются при использовании пуповинной крови. Мы рекомендуем, однако, чтобы больные и их семьи могли обсудить в подробностях возможные факторы риска и преимущества лечения, и трансплантация должна проводиться только мотивированным пациентам, которые имеют четкое понятие обо всем процессе.  Новые надежды связаны с возможным успехом гаплоидентичной трансплантации, но требуются дальнейшие исследования для подтверждения предыдущих результатов.

Ключевые слова

талассемия, клинические факторы риска, трансплантация гемопоэтических стволовых клеток, показания, преимущества

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Introduction

Allogeneic hematopoietic stem cell transplantation has become one of the most frequent forms of transplantation, with currently more than 6000 transplants being performed annually. Its use is still increasing in the treatment of hematological and other malignancies. In addition there are a large number of patients with debilitating and life threatening hematological dis-eases, thalassemia, sickle cell anemia, and other non-malignant diseases that may benefit from transplantation. However, the major obstacle to the wider use of transplantation is graft-versus-host disease (GVHD); still a serious threat to these patients. However, at the same time graft-versus-host reactions directed at leukemia, lymphoma, myeloma, and other tumors of the host may be beneficial. Therefore it is necessary to understand GVHD in order to ex-ploit the potential advantages without incurring the risks. Allogeneic stem cell transplantation conveys tolerance toward organs of the donor. As a rule, immunosuppressive therapy can be discontinued after several months without the risk of rejection and GVHD. This tolerance with chimerism allows the transplantation of cells and organs of the same donor without life-long immune suppression. The success of immunotherapy with donor cells and of transplantation of solid organs from the stem cell donor depends on whether or not GVHD can be controlled.

Early observations

Mice protected from hematopoietic failure following total body irradiation by bone marrow transplantation succumbed to a “secondary disease” if the bone marrow was taken from a different strain [1]. This disease was related to an immune reaction of donor cells against the host rather than a delayed radiation syndrome: cells of diseased mice induced hepato-splenomegaly when transferred to non-irradiated newborn mice [2]. Further proof was the oc-currence of this secondary disease in F1-hybrid mice transplanted with parental marrow, but not in parental mice transplanted with F1-hybrid marrow [3]. Finally, organs containing more immunologically competent cells such as those from the spleen produced more secondary disease than bone marrow [4]. Eventually, the principle requirements for GVHD were defined by Billingham [5]: 1. the graft must contain immune reactive cells, 2. the recipient must be im-munogenetically different, and 3. the recipient cannot reject the graft. The first patients with acute GVHD were described by Mathé and colleagues [6]. A major step towards successful transplantation was the selection of marrow donors within the family according to major his-tocompatibility antigens (HLA) [7]. HLA had been previously detected in humans with pre-formed antibodies [8, 9]. Most preconditions for allogeneic transplantation in humans have been elaborated in animal experiments, particularly in dogs 10]. 

Therefore the principles for prevention of GVHD are 1. selection of a histocompatible donor, 2. adequate immune suppression for the patient before and after transplantation, and 3. ma-nipulation of the graft. In more recent years much has been learned about the regulation of the T cell response and mechanisms of tolerance, which may guide the way for immune suppression [11].

Animal models

The manifestation of GVHD in every species investigated so far involves skin, gut, and liver; primarily however hematopoietic tissue (Fig.1). Acute GVHD is a syndrome with similar fea-tures in mice, rats, monkeys, and humans; without prevention or treatment it can be rapidly fatal. Therefore pathophysiology, prevention, and treatment of acute GVHD can be studied in animal models. Chronic GVHD cannot be readily studied in animal models; it is not known why certain organs are involved and others are spared. Obviously hematopoietic cells are the primary targets, and the skin, gut, and liver may contain cells of hematopoietic origin such as dendritic cells and macrophages. These cells produce pro-inflammatory cytokines including interferon-gamma (IFN-g), tumor necrosis factor-alpha (TNF-a), interleukin 6 (IL-6), and others that stimulate donor T cells and induce expression of HLA class II antigens in host tissue (Fig.2). Dendritic cells activated by CD4 cells may stimulate CD8 cells to react against HLA class I presented peptides (Fig.3). Recent studies, however, showed that deficient production of IFN-g can increase GVHD in the skin, and failure of IFN-g induction of B7-H1 enhanced TH2 cells can produce idiopathic pneumonia [12]. TH2 cells and TH17 cells were guided to lungs and skin by the expression of chemokine receptors.

Figure 1. Host target tissues affected in the course of graft-versus-host disease

Kolb_Figure1.png

Figure 2. A proposed role of cytokine network and specific receptors of immune cells at initiation of GvHD (for details see text)

Kolb_Figure2.png

Figure 3. Dendritic cells boost CD8+ cells to react against host target tissues

Kolb_Figure3.png

GVH reactions of the graft are directed against histocompatibility antigens of the recipient that are foreign to the donor. These antigens can be defined by the major histocompatibility complex, a highly polymorphic genetic region determining class I and class II antigens. Class I antigens are present in all cells of the organism, and class II normally only in hematopoietic cells. They may be expressed in other cells if these are affected by inflammation or injury. CD4-positive T cells exert GVH reactions against cells expressing class II antigens, and CD8-positive T cells act against class I antigens [13]. Differences in both antigen classes can induce severe and rapidly fatal GVHD. Polymorphic proteins not encoded by the major histo-compatibility complex may also cause severe GVH reactions. Peptides of these proteins can be presented by MHC class I and class II antigens. In general, MHC class I presents peptides of endogenous proteins of the cell, whereas class II antigens present peptides of exogenously acquired proteins [14, 15]. Here, minor histocompatibility (mHA) directed CD8 T cells require help from CD4 T cells for expansion and generation of memory T cells [16]. Therefore, reactions against mHA require a longer phase of immune recognition and activation than reactions against MHC antigens. Class II antigens are mainly expressed in hematopoietic progenitor cells, and in the case of injury and inflammation they may be expressed in non-hematopoietic cells as well. Reactions directed against class II antigens may induce severe marrow aplasia [17].

The mechanism of initiation of acute GVHD is not entirely clear; the preconditions are given before transplantation [18]. Much has been explained and published on cytokines and the cyto-kine storm liberated by intensive conditioning treatment, including high dose radiation and chemotherapy [19]. The role of cytokine release is confirmed by the suppression of acute GVHD using TNF-a antibodies [20]. There is some evidence that the systemic release of IFN-g leads to the secretion of chemokines in organs affected by GVHD and attracts activated T cells. In transgenic mice carrying the T cell receptor for ovalbumin the distribution of T cells was dependent on whether the antigen was given alone or together with lipopolysaccharide (LPS). Intravenous injection of antigens alone homes the T cells to secondary lymphoid tissue where they produce IL2, whereas injection of a combination of antigens and LPS homes the T cells to the lung, liver, gut, and skin where they produce IFN-g [21]. Systematically activated T cells produce interferons and induce chemokines in GVHD target organs [22]. However, the “danger signal” brought about by LPS may not be necessary, since in human patients donor lymphocyte transfusion may produce GVHD without conditioning treatment and infection [23].

The host's antigen presenting cells survive the conditioning treatment for various periods of time, with the most efficient cells being dendritic cells, but B cells, macrophages and other cells present antigens as well. Whereas dendritic cells in the blood of the host are rapidly re-placed by those of the donor, data on chimerism of dendritic cells in tissues are controversial [24]. Cytokine release by the host's activated dendritic cells and the graft's T cells is part of the initiation of GVH reactions (Fig. 2), and may be powerful enough to induce fatal GVHD even in the absence of histoincompatibility [25]. In general however, histocompatibility differences are necessary to induce and maintain GVH reactions. These histocompatibility differences may be of the major histocompatibility complex (MHC) class I or class II involving CD4- or CD8-positive T cells of the graft, and minor histocompatibility differences requiring profes-sional antigen presentation by dendritic cells of the host. GVHD occurring in the skin, liver, and gut requires dendritic cells expressing class I [26]. There is a possibility of cross presenta-tion of host antigens by donor dendritic cells, but their effects are inferior to direct presentation [27].

In contrast to cases involving the transplantation of solid organs, immunosuppressive therapy can be discontinued 3–6 months after transplantation in most patients receiving hematopoietic stem cell transplants, although patients who develop chronic GVHD may require therapy for several years. The host’s immune system is continuously suppressed by the graft, and the graft becomes tolerant towards the host. The mechanism of tolerance has been related to the occurrence of non-specific and specific suppressor cells followed by clonal deletion [28-30]. In DLA-identical canine chimeras tolerance could not be abrogated by the transfusion of donor lymphocytes unless the donors were immunized against the recipient [31]. Refractoriness to donor lymphocytes inducing GVHD develops at about two months after T cell depleted transplantation [32]. It may occur earlier in dogs transplanted with marrow depleted of T cells by CD6-antibody sparing NK cells [33]. NK cells can inactivate host dendritic cells and thereby prevent GVHD in mice [34]. Besides depletion of T cells and dendritic cells in the graft and the host, responder cells to antigen stimulation may respectively be eliminated by subsequent chemotherapy with methotrexate or cyclophosphamide. Cyclophosphamide can be given in rather high doses after transplantation without jeopardizing engraftment [35]. Modulation and suppression of GVH reactions has been shown for fractions of marrow cells such as mesenchymal stromal cells [36], NK-T cells (NKT1.1) [37], and regulatory T cells [11].

The results of animal models are highly informative with respect to the principles and me-chanisms of GVHD, but they also have their limitations. Apart from species-specific regulato-ry mechanisms of hematopoiesis and the immune system, animals are mostly young, have grown up in a protected environment, and are free of disease for which clinical transplantation is undertaken. In contrast, human patients are commonly older, have a history of infections and most likely a number of latent viral infections, and are possibly allo-immunized by previous transfusions and pregnancies, as are their donors. Moreover the primary disease and its treatment have a major impact on the transplant course.

The role of the immune repertoire of donor and host is still poorly defined. Female donors produce more GVHD and GVL in male recipients; most likely due to immunization during pregnancies by antigens derived from the fetuses' father [38]. Conversely, central memory T cells produce less GVHD than naïve T cells, indicating that the GVH reaction in most cases is a primary reaction [39]. Presumably central memory T cells cannot be involved in new primary reactions; there is also a risk that central memory T cells may produce vigorous GVHD when they recognize the antigen against which they developed. Alternatively they could be regulated by regulatory T cells.

Genetics

Selecting an HLA-identical sibling as donor was the major step towards successful stem cell transplantation. Selecting the donor within a family by typing for HLA-A, -B and DR-antigens is sufficient for successful transplantation, since antigen typing defines the haplotypes inhe-rited from the parents. Unlike identity by inheritance, selection of an unrelated donor relies on the most accurate typing of as many loci as possible. In general genetic definition of alleles of 10 HLA-loci is required to select a matched donor [40]. Severe GVHD can occur with any form of mismatch, but graft failure is less serious with mismatches for HLA-alleles than for the broader HLA-antigens [41]. In multiple mismatches the impact of various HLA-loci (A, B, C, DR) was similar, with the possible exception of HLA-DQ, which was less important. Notewor-thy is a possible racial difference in the role of HLA-C; in Japanese populations HLA-C has a lesser effect on GVHD than other HLA-loci [42]. In Caucasian populations HLA-C is as impor-tant for GVHD as other HLA-antigens [43]. The linkage disequilibrium, i.e. the occurrence of two antigens together, is more frequent than expected by the antigen frequency, is high for HLA-B and -C as well as for HLA-DRB1 and DQB1; therefore isolated mismatches are infre-quent. The linkage disequilibrium of HLA-DP with HLA-DRB1 is rather low, and differences of HLA-DP do not carry an additional risk for GVHD. They may, however, have an effect on the graft-versus-leukemia activity [44].

Presently little is known about permissible HLA-mismatches that allow for the development of tolerance. There may be racial differences as shown for HLA-C in Japanese as compared to Caucasian populations. In general HLA-mismatches are more permissible in patients with advanced disease than in patients with early disease. An allele mismatch may produce se-vere GVHD in a patient in chronic phase CML, but it may not have an effect in a patient with relapse of leukemia [43]. Cytokine levels and cytokine receptors are coded for by genes of the major histocompatibility complex. Sequence polymorphisms of genes for tumor necrosis fac-tor alpha (TNF-a), IL-6 and interferon-gamma (IFN-g) are different in persons with different racial backgrounds, i.e. Caucasians, Africans, and Cubans [45]. There have been several al-leles defined for both the TNF-a locus and the TNF-a receptor II locus that are associated with an increased risk of GVHD. Contrary to the pro-inflammatory cytokine TNF-a, IL-10 has anti-inflammatory effects. Polymorphisms of the promoter of IL-10 had an impact on GVHD. High levels of IL-10 correlated with a lower risk of GVHD.

Genetic factors outside of the HLA-complex may also be involved in the pathogenesis of GVHD. In the analysis of the gene expression profiles of donor cells, a particular role of transforming growth factor beta for chronic GVHD has been found [45]. In patients transplanted for chronic myelogenous leukemia [46] polymorphic alleles of TNF-receptor in the patient and certain alleles in IL10 and IL1 receptor in donor lymphocytes were associated with an in-creased risk of GVHD and decreased survival. A genetic factor associated with inflammatory bowel disease had an impact on GVHD (NOD/Card1) [47]. However, the effect could be dimi-nished if the gut was microbiologically well decontaminated. Antimicrobial prophylaxis de-creases the risk of GVHD without the GVL effect deteriorating.

There is good evidence that minor histocompatibility antigens play a role in GVHD and GVL reactivity [48, 49]. However, a recent analysis of the role of minor antigens in HLA-matched unrelated transplants by the NMDP did not find an impact of minor HA differences on the out-come of allogeneic stem cell transplantation [50].

Clinical features

Acute GVHD

GVHD was described and classified in the '70s [51, 52], when most patients were conditioned with total body irradiation. Skin is the organ most frequently affected; a maculopapular rash is common. This rash starts frequently in the upper thorax, arms, and face, but it can occur elsewhere and spread over the whole body. Features range from a maculopapular rash to general dermatitis with blisters and epidermal necrolysis. Histological findings are degenera-tion and apoptosis of the basal cells, dyskeratosis and lymphocytic infiltration. Involvement of the gastrointestinal tract is clinically characterized by diarrhea, malaise and vomitus; diarrhea may be severe with several liters of liquid and bloody stools. Histological findings are flatten-ing of the mucosa with debris in crypts (crypt abscesses); the most frequently affected part is the ileum. GVHD of the liver is characterized by jaundice and increases of liver enzymes. Histologically the Glisson triads are infiltrated, and the bile ducts are destroyed by infiltrating lymphocytes. Unfortunately none of the histological signs are diagnostic — viral infections and drug reactions may present similar features. Nevertheless biopsies may be indicated in order to exclude other diagnoses with characteristic signs and to obtain material for microbio-logical studies.

Despite prophylactic treatment with immunosuppressive drugs the prevalence of acute GVHD of all grades of severity is high, with a rate of 40–60% in patients with an HLA-identical sibling donor and 60–90% with a matched unrelated donor. Only at a severity of grade 2 and higher is additional immunosuppressive treatment required: this equates to 40–70% of patients. Another grading system was designed by the International Bone Marrow Transplant Registry IBMTR and validated in two studies [53, 54]. This grading system does not take into account the clinical performance as does the system of H. Glucksberg [51]. No advantage of one system over the other has been shown [54]. In both grading systems microangiopathy has not been scored as a form of acute GVHD; microangiopathy is characterized by red cell fragmentation, high levels of serum lactate dehydrogenase and thrombocytopenia. It is more frequent in patients treated with calcineurin inhibitors [18] or sirolimus, and resembles thrombotic thrombocytopenic purpura, but polymers of von Willebrand factor have not been found [55].

Table I. Acute GVHD. Diagnostic criteria according to H. Glucksberg

Stage

Skin maculopapular rash

Liver bilirubin

Gut diarrhea

+

 < 25% body surface area

2 - 3 mg/dl

> 500 ml

++

25 - 505 BSA

3,1 - 6 mg/dl

> 1000 ml

+++

Generalized erythroderma

6,1 - 15 mg/dl

> 1500 ml

++++

General erythroderma with bulla formation and desquamation

> 15 mg/dl

Severe abdominal pain w/wo ileus

Cell Ther Transplant. 2012;2:e.000089.01. doi:10.3205/ctt-2012-en-000089.01-table1

Table II. Acute GVHD. Diagnostic criteria according to H. Glucksberg

Grade of aGVHD

Skin

Liver:

Gut:

Clinical performance

I

+ - ++

bilirubin < 2,0 mg/dl

No diarrhea

Ok

II

+ - +++

3,1 - 6 mg/dl

Diarrhea > 500 ml

Mild decrease

III

++ - +++

6,1 - 15 mg/dl

> 1000 ml

Marked decrease

IV

++ - ++++

> 6,1 mg/dl

> 1000 ml

Severe decrease

Cell Ther Transplant. 2012;2:e.000089.01. doi:10.3205/ctt-2012-en-000089.01-table2

Chronic GVHD

Acute GVHD may resolve completely with immunosuppressive treatment or it may lead to chronic GVHD. Chronic GVHD may also develop de novo without prior acute GVHD within a year from transplantation. Chronic GVHD involves most frequently the skin with lichenoid and sclerotic changes, the nails with dystrophy, the eyes with keratoconjunctivitis, the mouth with dryness and paradontosis, the vagina with dryness and sclerosis, liver and lungs. The clinical features of chronic GVHD resemble autoimmune diseases like lupus erythematodes, Sjögren syndrome, and biliary cirrhosis in many aspects. Characteristically there is hypogammaglo-bulinemia with loss of IgA, and lymphopenia, but there may also be hypergammaglobulinemia and eosinophilia. Thrombocytopenia is a sign of poor prognosis; another factor of poor prognosis is involvement of the lungs, which may be in the form of late interstitial pneumonitis and fibrosis or obliterating bronchiolitis. As a rule lung involvement is progressive and carries the risk of severe infections. The skeletal system may be involved in form of fasciitis, muscle dystrophy, tendinitis, and contractures. Transplant vasculopathy is a problem of solid organ transplants: in stem cell transplanted patients vasculitic changes in the CNS have been observed and vascular events can be seen in young patients [56] without other risk factors.

Overlapping GVHD

Besides the clinical features, acute and chronic GVHD have been defined by the time of oc-currence: acute GVHD in the first weeks and months, and chronic GVHD after day 100. This definition has been challenged by the introduction of cyclosporine A for immune suppression and conditioning with reduced intensity. Following discontinuation of cyclosporine A, a flare of acute GVHD may occur, and following reduced intensity conditioning, acute GVHD may occur late. Similarly, late onset of acute GVHD has been observed after prophylactic treat-ment with TNF-antibody during conditioning [20]. Obviously the activation of T cells is delayed by reduced intensity conditioning and prophylactic treatment, with TNF-antibodies leading to late acute GVHD.

Prophylaxis of GVHD

Some form of prophylaxis of GVHD is absolutely necessary even in HLA-identical sibling transplants, as hyperacute GVHD was seen in every patient with engraftment [57]. T cells are responsible for GVHD and depletion of T cells from the transplant was very successful in an-imal models [58, 59]. In the clinical setting GVHD could be prevented or suppressed [60, 61] effec-tively. Antithymocyte globulin (ATG) has a broad specificity, recognizing not only T cells, but other mononuclear cells as well. The monoclonal antibody alemtuzumab recognizes CD52, an antigen that is present in many leukocytes including lymphocytes, monocytes, and den-dritic cells; alemtuzumab has broad activities despite its specificity. In humans [62] as in dogs [63] the number of clonable T cells should be below 105/ kg body weight for effective prevention of GVHD. So far more selective depletion of T cells has not improved the overall results of transplantation [64], and depletion of CD8 has been insufficient in preventing GVHD [65]. CD6 has the advantage of sparing most of the NK cells in the transplant [64]. In dogs CD6-depleted marrow suppresses alloresponses [66] and recipients of CD6-depleted marrow tolerate donor lymphocyte transfusions earlier than recipients of marrow treated with absorbed ATG [33].

However, the advantage of ex vivo T cell depletion was offset by a high rate of graft rejection, relapse, infections, and EBV-associated post transplant lymphoproliferative disease (PTLD) [67, 68]. Treatment of the patient prior to transplantation with ATG prevents rejection; T cell anti-bodies persist in the patient for 4–5 weeks and deplete T cells of the graft in vivo. A rando-mized study comparing standard post-grafting immune suppressive treatment with and with-out ATG prior to transplantation showed lower rates of acute and chronic GVHD in the group treated with ATG [69]. A beneficial effect of ATG in the conditioning treatment for chronic GVHD has also been observed in Italian studies [70] and in retrospective analyses of non-randomized studies (own unpublished observations).

Alemtuzumab also persists in the patient for a prolonged period of time, and reconstitution of T cells is delayed for 6–9 months [71]. Severity of GVHD is low in patients treated with alemtu-zumab, but graft failures have been observed [72]. There is also an increased risk of viral infec-tions, particularly cytomegalovirus, and insufficient response of the malignant disease. These deficiencies can be compensated at least partially by the transfusion of donor lymphocytes [73].

In the last decade G-CSF mobilized peripheral blood stem cells (PBSC) have replaced mar-row in most instances. PBSC contain enormous amounts of T cells and depletion of T cells has been largely unsuccessful. Surprisingly, transplantation of PBSC is not associated with an increased risk of acute GVHD, but is instead associated with a more rapid engraftment and an increased risk of chronic GVHD [74]. PBSC may be preferable for patients with advanced disease and elderly patients. Conversely, T cell depletion and marrow transplantation may be the preferred treatment for patients with early disease, non-malignant disease, and patients who are younger.

Other approaches to prevent GVHD use specific conditioning regimens [37] or specific cells to induce transplantation tolerance. Low dose total lymphoid irradiation in combination with ATG may spare natural killer T cells in the marrow and regulatory T cells suppressing GVHD, but allow graft-versus-leukemia/lymphoma effects. The addition of regulatory T cells to the graft has suppressed GVHD without inhibiting GVL effects in mice [75] and recently in humans (Martelli F, Plenary session ASH 2009). Another immunosuppressive cell product are me-senchymal stromal cells, which have been successful in the treatment of severe GVHD [76]. Co-transplantation of mesenchymal stromal cells prevented rejection in HLA-haploidentical transplants [77] and GVHD was less severe, but the difference did not reach significance be-cause of low numbers. We have used CD6-depleted PBSC transfused 6 days after trans-plantation of unmodified marrow from HLA-haploidentical donors with a low rate of acute GVHD [78].

Post-graft immunosuppressive treatment with either methotrexate or cyclophosphamide has been used since the early days of stem cell transplantation. Both agents preferably kill proli-ferating cells and should be started early after grafting. These drugs suppress donor cells proliferating in response to host antigens as well as residual host cells responding to the graft. They sustain engraftment and suppress GVHD at the same time. They induce transplantation tolerance by killing the responsive cells, and therefore patients with incomplete responses usually take a disastrous course. A recent application of this principle is the use of large doses of cyclophosphamide 3 and 4 days after HLA-haploidentical transplantation [35, 79].

The introduction of the calcineurin inhibitors cyclosporine A and tacrolimus has also changed the outlook for these patients. Both drugs inhibit the activation and proliferation of T cells by inhibiting dephosphorylation and translocation of the nuclear factor of activated T cells (NFAT). The continuous inhibition is effective in suppressing GVHD and rejection, but the effect is not necessarily maintained after discontinuation of treatment; calcineurin inhibitors are less potent in the induction of transplantation tolerance [80]. Treatment should be started prior to transplantation in order to avoid antigen recognition and T cell activation. Tacrolimus is a somewhat stronger immunosuppressive than cyclosporine A and possibly less neurotoxic. However, in controlled studies comparing tacrolimus and cyclosporine A less severe GVHD was not associated with improved survival [81].

The combination of cyclosporine A and methotrexate is better than either drug alone [82]. It has become the gold standard of GVHD prophylaxis. In recent years mycophenolate mofetil (MMF) has been introduced to replace methotrexate [83]. MMF inhibits the purine synthesis and the de novo pathway of guanosine nucleotide synthesis; it kills not only proliferating T cells, but also T cells in the interphase. MMF produces less mucositis and less marrow toxicity than methotrexate. However the best regimen and timing (2–3 times per day) remains unknown.

Sirolimus binds to the tacrolimus binding protein FKBP12 and forms a complex with mTOR (target of rapamycin) that inhibits several signal transduction pathways including PTEN, PI3kinase and AKT as well as the JANUS kinase pathway. Thereby it produces several ef-fects including immunosuppression of T cells, anti-angiogenesis and inhibition of tumor growth [84]. Its immunosuppressive activity is presumably linked to the suppression of the second signal of T cell activation. This way T cell apoptosis and specific peripheral non-responsiveness may be induced [85]. Th1 cells and their cytokines are more affected by siroli-mus than Th2 cells and regulatory T cells [86, 87]. The sirolimus/mTOR complex inhibits the ac-tivation signals of CD28 and CD40L stimulation and thereby the second signal essential for T cell activation [88], a situation that may lead to transplantation tolerance. The combination of sirolimus and tacrolimus is synergistic and has shown little toxicity [89], but veno-occlusive dis-ease of the liver and thrombotic microangiopathy have been observed [90]. The combination of sirolimus and MMF was promising in a smaller group of patients, where VOD and TMA were not observed [91].

The goal of preventing GVHD is the induction of tolerance in both directions, the host-versus-graft and graft-versus-host direction. Contrary to transplantation of solid organs, stem cell transplantation induces self-sustained tolerance without life-long immunosuppressive therapy. As a rule, a period of 4–6 months of immunosuppressive therapy is sufficient for tolerance to become established. In clinical terms tolerance is evident by persistent chimerism without GVHD and without severe infections more than 30 days after discontinuation of immunosuppression.  

Treatment

Glucocorticoids

Despite prophylactic treatment with immunosuppressive agents, acute GVHD requiring addi-tional treatment occurs in 40–80% of patients within 3–4 weeks of transplantation [92]. Corti-costeroid therapy is the standard of treatment for acute GVHD, but the regimen and the do-sage is still under discussion. Originally, treatment with large doses was favored [93], but there are no controlled studies to support this treatment. Similarly, in organ transplantation, rejection crises are treated with bolus methylprednisolone without prospective randomized trials supporting this. Despite this general use there are only a few studies on the schedule and the dosage rates. A randomized Italian trial comparing 2mg/kg per day with 10mg/kg per day showed no advantage for the higher dose [94], however 50% of patients were switched to a high dose because of insufficient response. Recently, a retrospective study from Seattle indi-cated that even lower doses of corticosteroids (1mg/kg instead of the standard 2 mg/kg) can be given without disadvantage [95]. However the patients of the low dose group had more fa-vorable risk factors and less severe GVHD; in addition oral non-absorbable corticosteroids were given more frequently.

The mechanisms of the actions of glucocorticoids are still not fully understood, lymphopenia is mainly due to sequestration of lymphocytes, and less to lympholysis. However, glucocorti-coids exhibit strong anti-inflammatory effects in several ways including genomic and non-genomic pathways [96]. Glucocorticoids are bound to a receptor from which heat shock protein 70 is released. The glucocorticoid complex activates anti-inflammatory proteins directly and their production genomically. Inhibition of nuclear factor kB is highly sensitive to glucocortico-ids preventing the production of inflammatory proteins. Sensitivity to the treatment with glu-cocorticoids may be determined by the relative levels of glucocorticoid receptor α and ß. This may explain interpatient variation of sensitivity [97]; memory T cells [98] as well as mature den-dritic cells are less sensitive to glucocorticoids. In macrophages low doses of glucocorticoids stimulate the production of proinflammatory cytokines, whereas high doses suppress it [99]. High dose glucocorticoid therapy given for few days has shown little immune suppression in vivo [100].

Commonly treatment is started in patients with clinical grade II–IV severity of GVHD. About 40–50% of patients respond with resolution or improvement of clinical symptoms [92]. The re-mainder are classified as “steroid-refractory”. The time until refractoriness to glucocorticoids is stated may vary from 5 to 14 days [101]. Many centers increase the dose of steroids in re-fractory patients prior to the addition of other agents. We prefer to start with rather high doses of glucocorticoids (1–2mg/kg every 8 hours) and score the response after three days of treatment for refractoriness. This way we initiate secondary treatment early in refractory pa-tients. The decision to start the treatment is made by two physicians. In the case of a pro-gressive and characteristic skin rash the diagnosis is not difficult, but in cases of isolated ga-strointestinal GVHD with diarrhea and nausea or isolated hepatic GVHD the diagnosis may be more difficult. Persistent toxicity of the conditioning treatment, veno-occlusive disease of the liver, drug-induced changes and viral infections are considered as differential diagnosis. In our centre skin biopsies are regularly performed, biopsies of gut and liver are only made in patients that do not respond to the treatment. This way we obtain not only histological con-firmation of the clinical suspicion, but also information about viral infection. Concomitant vi-rostatic treatment is given to patients with biopsies positive for viral infection as well as those that are seropositive for cytomegalovirus. Another option is the use of high doses of iv immu-noglobulins that may inhibit the deleterious effects of FAS by their blockade of FAS-L [102]. Al-though their immune modulating effects are far from understood [103], 20–30% of patients with skin GVHD do respond to the treatment with iv immunoglobulins. In any case early treatment is important as delay of the start of treatment until the results of laboratory investigations are available may jeopardize the response to glucocorticoids.

The effect of systemic glucocorticoids on gastrointestinal GVHD can be improved by local treatment with beclomethasone [104] and budesonide [105].

Antibodies

In many instances the first choice in patients with steroid refractory GVHD has been immu-nosuppressive antibodies. Antithymocyte globulin (ATG) has been used in several uncon-trolled studies with some success [106], but in controlled studies a beneficial effect could not be demonstrated [107]. Similarly, OKT3 is a monoclonal antibody against CD3 on T cells: it dep-letes T cells and stimulates proliferation by its mitogenic activity. Even though many patients have responded to the treatment with OKT3 with complete remission of GVHD, better surviv-al could not be demonstrated in controlled clinical trials [108]. Alemtuzumab has been used mainly for prophylaxis of acute GVHD by treating the patient in vivo or the graft prior to transplantation ex vivo: recently beneficial outcomes of treatment of established GVHD have been reported in two uncontrolled studies [109, 110]. Viral infections may complicate treatment with alemtuzumab; therefore regular control and pre-emptive treatment is necessary. ATG and OKT3 both stimulate proliferation of lymphocytes that are not killed by cytolysis; there-fore the combination of antibody treatment with chemotherapy (methotrexate, Cyclophos-phamide, mycophenolate mofetil, etc.) may be beneficial. A humanized CD3-antibody (visili-zumab) produced good first results [111] which unfortunately were not confirmed in multicenter trials [112]. In those patients the reactivation of EBV and the incidence of post transplant lym-phoproliferative disease (PTLD) increased.

Encouraging results were also reported with ABXCBL, an antibody against CD147 that is ex-pressed in activated T cells [113]. However in a comparative study ABXCBL was not better than ATG, where survival was even inferior [114].

Antibodies against tumor necrosis factor α (TNF-a) and soluble receptors of TNF-a (etaner-cept) have been studied in the prophylaxis of GVHD [20] and the treatment of steroid refractory GVHD [115]. There has been a high rate of complete response to infliximab even in gastrointes-tinal GVHD, but this is complicated by an increased risk of fungal infections [116, 117]. Contrary to infliximab etanercept neutralizes soluble TNF-a without affecting TNF-a in phagocytic cells. Etanercept is associated with a lower risk of fungal infections. The combination of etanercept with an anti-IL2-receptor antibody showed high response rates to acute GVHD, but the long-term survival was rather poor [118]. In comparison, a pilot trial of etanercept in combination with tacrolimus and steroids gave a 75% complete response and a 50% survival rate [119]. When comparing etanercept combined with steroids to steroids alone a significantly better response to the combination was observed [120]. The combination of etanercept with ATG and tacrolimus was compared to ATG and tacrolimus alone [121]; considering the limited number of patients the response and the survival of patients given etanercept was better. Neutralization of TNF-a released by the ATG treatment by etanercept may have been contributing to the better outcome.

Antibodies against IL-2 receptor have been studied early [122] with some transient success. The importance of an early treatment start was stressed. Several studies with humanized anti-IL2-receptor antibodies were encouraging [123, 124], but a randomized study was stopped prematurely because of inferior survival of the antibody (daclizumab) group [125]. There is little doubt that the IL2- receptor antibody is effective in suppressing GVHD of the skin and the gut when started early, but it may have an adverse effect on the generation of regulatory T cells expressing high levels of the IL-2 receptor.

Alefacept is a fusion protein of the CD2-binding domain of LFA-3 and the Fc portion of IgG with specific activities against memory T cells [126]. Promising results in steroid refractory acute GVHD and in chronic GVHD have been reported, but there may be an increased risk of viral and fungal infections [127].

Recently, the role of B cells has been discussed more frequently, although the role of T cells in GVHD is not disputed. However, cytotoxic antibodies may be produced in HLA-mismatched chimeras, and depletion of B cells may prevent EBV-induced B cell lymphoma. Single patients have been reported to show a response to steroid refractory GVHD to the treatment with rituximab [128].

Drugs

As a rule the treatment given for prophylaxis is continued during the treatment of established GVHD, and includes glucocorticoids at a low level. Depending on the prophylactic regimen, cyclosporine A may be substituted by tacrolimus and new drugs may be added. In most Eu-ropean centers a calcineurin inhibitor is combined with methotrexate or mycophenolate mofe-til. In patients not treated prophylactically a trial with mycophenolate mofetil may be justified; a response rate of 47–48% has been reported in steroid refractory GVHD, but the survival at 6 and 12 months was not improved [129]. Methotrexate on a weekly basis in low doses has been helpful in single cases. Mucositis and myelosuppression are limiting factors.

Similarly, sirolimus can be used for patients not treated prophylactically, as response rates of 77% overall and 44–72% complete response have been reported [130, 131]. Again microangiopa-thy has been a problem, but could be controlled by discontinuation of the calcineurin inhibitor (CNH) or both sirolimus and CNH. A small study suggests a good response of acute GVHD to sirolimus without prior treatment with glucocorticoids [132]. Due to its anti-tumor activity siro-limus is preferred to calcineurin inhibitors and glucocorticoids by many investigators [133], par-ticularly in patients with lymphoma [134].

Pentostatin is an inhibitor of the salvage pathway of thymidine kinase that is specific for T cells. Phase I studies have shown efficacy in the treatment of steroid-refractory GVHD [135]. A retrospective analysis has shown activity comparable to other immunosuppressive regimens [136]. However, pentostatin has shown activity in the treatment of chronic GVHD [137, 138]. Pentostatin may have better effects in patients with chronic GVHD.

Thalidomide [139, 140] and more recently lenalidomide [141] have been studied in the treatment of GVHD. The initially positive results of treatment with thalidomide in chronic GVHD [139] were not confirmed in a randomized study [140]. The treatment of recurrent myeloma with lenalido-mide suggested an immune modulatory effect of lenalidomide in producing regulatory T cells [141].

Bortezomib has been tested in mice [142] and patients with HLA-mismatched unrelated donors [143]. The immunomodulatory effect has been related to the suppression of monocyte-derived dendritic cells and modified antigen presentation and release of TNF-a from CD4-positive T cells [142]. It has shown promising activity in the prophylaxis of GVHD [143].

After the description of activating antibodies against the receptor of platelet derived growth factor (PDGF) [144] in patients with systemic sclerosis similar antibodies were found in patients with sclerodermatous chronic GVHD [145] and several groups have treated sclerodermatous chronic GVHD [146, 147], as well as obliterating bronchiolitis with imatinib [148, 145]. In one study more than 70% of patients with sclerotic chronic GVHD responded with partial and complete remissions [147].

Cells

Many treatment regimens of GVHD favor the development of regulatory T cells characterized by the expression of CD 4 and CD25 in high density [149]. The suppressive activity is limited to cells of the CD4/CD25 immune phenotype that are positive for FoxP3 mRNA. Typically regulatory T cells should be negative for the IL7 receptor (CD127). Immunomagnetically selected regulatory T cells have been tested in vitro for immunosuppressive effects [149, 150], and preliminary applications for the treatment of refractory GVHD have been promising (M. Edinger, pers. comm.). The first results of preventive application have been reported (Di Ianni et al. ASH 2009); 17 of 20 evaluable patients did not produce GVHD after HLA-haploidentical stem cell transplantation despite admixture of a limited amount of conventional T cells to the CD34-selected graft.

More information is available on the treatment of refractory GVHD with mesenchymal stromal cells [76]. The results were confirmed in a multicenter study of the EBMT involving [151] 55 patients with steroid-refractory GVHD. Twenty-seven patients received one dose, 22 two doses and 6 three doses and more from HLA-mismatched or HLA-matched donors for treatment; 30 patients had a complete response, and an improvement was seen in 9 patients. Responders had a better chance of survival than non-responders. Mesenchymal stem cells have multiple properties including differentiation into bone, cartilage, tendon and muscle cells, repair of damaged tissue and modulation of immune responses [36].

UV light

Ultraviolet light has immunosuppressive properties [152]. UV-A in combination with 8-methoxypsoralen (PUVA) has been used to treat chronic GVHD [153]. UVA may be applied to the skin in combination with oral psoralen or with a bath in psoralen containing water. PUVA treatment was studied in 103 patients with steroid-resistant acute GVHD [154] with good res-ponses in GVHD of the skin and sparing of glucocorticoid doses. The treatment was well to-lerated, but it may induce a flare before lichenoid skin changes respond to the treatment. In chronic GVHD 31 of 40 patients had an improvement following PUVA treatment, but partial and complete responses were limited to the skin [155]. Best responses were seen in the liche-noid phases of chronic GVHD, and less in the sclerodermatous phases.  However, the com-bination of PUVA bath with oral isotretinoin has been effective in a small study of scleroder-matous chronic GVHD: 11 of 14 patients responded, four of these with complete remission [156].

Alternatively PUVA may be applied directly to the blood resp. leukocytes separated by a dis-continuous blood cell separator (extracorporeal photopheresis, ECP). Responses to ECP have been reported for steroid-refractory, acute GVHD [157-159] and chronic GVHD [160]. Complete resolution of acute GVHD of the skin in 82%, liver in 61% and gut in 61% of pa-tients has been reported [158]. Response was associated with better survival. In our own study of 30 patients with acute GVHD, 20 patients responded with CR and PR defined as steroid discontinuation and reduction to 10 mg or less per day respectively (unpublished). Eleven of 20 responders survived as compared to only one non-responder. Steroid treatment was a major risk factor in the treatment of acute GVHD of pediatric patients [161]. In a single centre study on steroid refractory chronic GVHD 22% of patients could discontinue steroid therapy after one year, with response to ECP and absence of thrombocytopenia being the favorable factors for survival [160]. A randomized prospective multicentre study [162] comparing standard treatment with standard treatment plus ECP showed improvement of the skin score and sig-nificant steroid sparing. ECP is a good treatment option in patients with steroid-refractory acute and chronic GVHD with little side effects. The mechanism of the immunosuppression by ECP is not completely understood as only 5–10% of all T cells may be reached by extra-corporeal irradiation. However, a shift of dendritic cells from activating DC1 to down-regulating DC2 and from Th1 to Th2 has been described in the course of ECP [163]. Ex vivo a decrease of T cells producing pro-inflammatory cytokines was described [164]. In a murine model ECP-treated T cells induced regulatory T cells in recipients with established GVHD [165]. An increase in the proportion of regulatory T cells was observed in patients that responded to ECP [166].  Therefore ECP may be one method to induce GVH-tolerance without too many side effects.

Induction of graft-versus-host tolerance

Unlike transplantation of solid organs, transplantation of hematopoietic stem cells induces transplantation tolerance, enabling immunosuppressive therapy to be discontinued. In the form of central tolerance, lymphoid progenitor cells derived from transplanted stem cells tra-vel to the thymus where T cells tolerant to the host’s tissue are produced [167-169]. However, the thymus shows progressive involution in adulthood; central tolerance may be the major form of tolerance in children and young adults. The majority of patients subjected to stem cell transplantation are older, and the thymus has shrunk to a small remnant. Therefore in the majority of our patients a peripheral form of tolerance prevails, but function of the thymus can be recovered even in elderly individuals [170]. Several studies have been performed to speed up recovery of the thymus, mostly without convincing success [171], but new agents may give better results [172, 173, 169]. However, GVHD may affect the thymus [174] and thereby may inhibit the induction of central tolerance in both young and adult patients. Peripheral tolerance is a first step and may be replaced by central tolerance with time. The mechanisms of tolerance may be similar, clonal deletion, clonal anergy, and suppression.

Clonal deletion is a mechanism of self tolerance occurring in the thymus [175]; in the case of allogeneic stem cell transplantation T cells of donor origin derived from lymphoid progenitors may be eliminated by the same mechanism and primed towards host MHC antigens in se-miallogeneic hosts [176]. Deletion in the periphery may be accomplished by the treatment with antimetabolite drugs such as methotrexate, or cycle active drugs like cyclophosphamide; both of which have been shown to induce tolerance in stem cell transplanted patients [177, 178]. The principle of selective depletion of responsive lymphocytes has been applied more recently in HLA-haploidentical transplantation [179]. Unlike these cytotoxic agents calcineurin inhibitors do not kill the responsive cells, but inhibit cytokine production and thereby the progress of the immune response. However they may not favor the induction of tolerance; flares of GVHD have been observed after discontinuation of cyclosporin A, and late rejection of marrow grafts have been reported in single patients with aplastic anemia. Activation induced cell death (AICD) is a natural decrease of the clone size by IFN-g secretion of mature Th1 T cells and death of immature T cells, which may be achieved by the external pathway.  

Clonal anergy may be the result of competitive inhibition by anergic T cells or active sup-pression by a variety of suppressor cells. Formerly, CD8-positive T cells were considered “cytotoxic/suppressor” cells, but the evidence for specific suppression was weak. Instead, several mechanisms of suppression have been described including “veto” cells suppressing the immune reaction against themselves [180]. The veto mechanism, described as the effector cells inhibiting or killing themselves has been primarily ascribed to CD8-positive T cells, but later also to other cells including stem cells. CD8-positive suppressor cells may not only func-tion as veto cells, but they may also suppress third party reactions by the secretion of FAS [181>]. Other cells with suppressor function are myeloid derived suppressor cells [182], NKT cells in the marrow [183], NK cells [184], dendritic cells type 2 [185] and mesenchymal stromal cells [76]; all of them suppress activated T cells more or less specifically. Some of these have already shown clinical effectiveness [183, 76], others are still in a developmental state. In recent years the detection of FoxP3 (forkhead transcription factors) showed suppressive function of CD4, CD25 positive T cells and even CD8 T cells [186]. Naïve CD4, CD25-positive regulatory T cells are able to down regulate allogeneic immune responses without inhibiting graft-versus-leukemia responses [75]. These may be naïve and non-specifically down regulating dendritic cells or adaptive and directed against specific antigen. Recently the Perugia group has reported the use of naïve regulatory T cells suppressing GVHD in patients given HLA-haploidentical transplants including small amounts of conventional T cells (ASH 2009, New Orleans).

Rapamycin exerts differential effects on T cells, inhibiting CD8 positive cells more than CD4 positive cells [86]; CD4 T cells spared by Rapamycin may become regulatory T cells without compromising GVL reactions [133]. Long-term observations of patients treated with Rapamycin and tacrolimus are encouraging with regard to control of acute GVHD and GVL [89]. Chronic GVHD still remains a problem despite tolerogenic effects of Rapamycin. Recently, the Milan group [187] (EBMT 2010) has reported generation of regulatory T cells in patients with HLA-haploidentical transplants. After conditioning with treosulfan, fludarabine, ATG and rituximab, and GVH prophylaxis with Rapamycin and mycophenolate mofetil, immune reconstitution was better than after transplantation of CD34-selected transplants, and regulatory T cells were detected early after transplantation.

Tolerogenic effects have also been described for the treatment with extracorporeal photo-pheresis (ECP) [188]. In acute GVHD ECP was applied with good results [158]. In most patients the effects of ECP are not immediate, but occur after some weeks. ECP has also beneficial effects against chronic GVHD [162] and may be preferable to other treatments for GVHD.

The main goal of prophylactic and therapeutic treatment of GVHD should be the induction of transplantation tolerance. Therefore treatment protocols interfering with tolerance should be avoided in protracted periods in favor of regimens allowing the development of tolerance. Glucocorticoids and calcineurin inhibitors are effective in controlling the acute disease, but they do not support the development of tolerance. Similarly, IL2-R antibodies may be effec-tive in the acute control of GVHD, but may not support the development of tolerance. Toler-ance may be achieved by depletion of mature T cells from the graft, killing of antigen respon-sive T cells with cell cycle active chemotherapy as Cyclophosphamide, methotrexate, or my-cophenolate mofetil, activating CTLA4 receptors by CTLA4-Ig or using drugs like Rapamycin that block the co-stimulatory pathway or ECP producing apoptotic cells that induce tolerance.

Future prospects

The time point to initiate treatment of acute and chronic GVHD is of paramount importance. Therefore, early diagnosis tests, before clinical diagnosis is possible, may improve the out-come significantly. Several proteins have been found in the urine of patients that developed GVHD [189]; a prospective study will help to demonstrate the value of early treatment. Similarly, elafin has been identified as a prognostic marker in the plasma of patients developing skin GVHD [190]. Early diagnosis will allow early treatment and thereby avoid the development of memory T cells or T stem cells with memory that are extremely difficult to suppress.

References

1. Barnes DHW, Loutit JF. Spleen protection: the cellular hypothesis. In: Bacq ZM and Alexander P: Radiobiology Symposium : Proceedings of the Symposium held at Liege, August-September, 1954. London: Butterworths, 1955:134-135.

2. Simonsen M, Jensen E. The graft-versus-host assay in transplantation chimeras. In: Albert F, Lejeune-Ledant G, eds. Biological problems of grafting. Oxford: Blackwell; 1959:214-236.

3. Uphoff, D. E. and Law, P. Genetic factors influencing irradiation protection by bone marrow. II. The histocompatibility 2 (H-2) locus. J Natl Cancer Inst 20, 617-624. 1958. pmid: 13539612.

4. van Bekkum, D. W. The selective elimination of immunologically competent cells from bone marrow and lymphatic cell mixtures. I.Effect of storage at 4°C. Transplantation 2, 393-404. 1964.

5. Billingham, RE. The biology of graft-versus-host reactions. Harvey Lect 1966-1967 62, 21-78. 1967. pmid: 4875305.

6. Mathé G, Amiel JL, Schwartzenberg L, et al. Successful allogeneic bone marrow transplantation in man: Chimerism, induced specific tolerance and possible antileukemic effects. Blood 1965;25:179-96. pmid: 14267694.

7. Epstein RB, Storb R, Ragde H, Thomas ED. Cytotoxic typing antisera for marrow grafting in littermate dogs. Transplantation 1968;6:45-58. pmid: 4866738.

8. Dausset J, Rapaport FT, Colombani J, Feingold N. A leucocyte group and its relationship to tissue histocompatibility in man. Transplantation 1965;3:701-705. pmid: 5324831.

9. van Rood JJ, van Leeuwen A, Eernisse JG, Frederiks E and Bosch LJ. Relationship of Leukocyte groups to tissue transplantation compatibility. Ann.N.Y.Acad.Sci. 1964;120:285-298.

10. Thomas ED, Storb R, Epstein RB, Rudolph RH. Symposium on bone marrow transplantation: experimental aspects in canines. Transplant.Proc. 1969;1:31-33. pmid: 5002661.

11. Hoffmann P, Ermann J, Edinger M, Fathman CG, Strober S. Donor-type CD4(+)CD25(+) regulatory T cells suppress lethal acute graft-versus-host disease after allogeneic bone marrow transplantation. J.Exp.Med. 2002;196:389-399.

12. Yi T, Chen Y, Wang L et al. Reciprocal differentiation and tissue-specific pathogenesis of Th1, Th2, and Th17 cells in graft-versus-host disease. Blood 2009;114:3101-3112. doi: 10.1182/blood-2009-05-219402.

13. Korngold R, Sprent J. Surface markers of T cells causing lethal graft-vs-host disease to class I vs class II H-2 differences. J Immunol. 1985;135:3004-3010. pmid: 3876371.

14. Klein J, Sato A. The HLA system. First of two parts. N Engl J Med. 2000 Sep 7;343(10):702-9 .doi: 10.1056/NEJM200009073431006.

15. Klein J, Sato A. The HLA system. Second of two parts. N Engl J Med. 2000 Sep 14;343(11):782-6. Review. Erratum in: N Engl J Med 2000 Nov 16;343(20):1504. doi: 10.1056/NEJM200009143431106.

16. Robertson, NJ, Chai J-G, Millrain, M, Scott, D, Hashim, F, Maktelov, E, Lemonnier, F, Simpson, E, and Dyson, J. Natural regulation of immunity to minor histocompatibililty antigens. J Immunol 178, 3558-3565. 2007.

17. Sprent J, Surh CD, Agus D et al. Profound atrophy of the bone marrow reflecting mature histocompatibility complex class II restricted destruction of stem cells by CD4+ cells. J.Exp.Med. 1994;180:307-317.

18. Holler E, Kolb HJ, Hiller E et al. Microangiopathy in patients on cyclosporine prophylaxis who developed acute graft-versus-host disease after HLA-identical bone marrow transplantation. Blood 1989;73:2018-2024.

19. Ferrara JLM, Deeg HJ. Graft-versus-host disease. N Engl J Med 1991;324:667-674. doi: 10.1056/NEJM199103073241005.

20. Holler E, Kolb HJ, Mittermüller J et al. Modulation of acute graft-versus-host disease after allogeneic bone marrow transplantation by tumor necrosis factor (TNF) release in the course of pretransplant conditioning: Role of conditioning regimens and prophylactic application of a monoclonal antibody neutralizing human TNF (MAK 195F). Blood 1995;86:890-899.

21. Reinhardt, RL, Khoruts A, Merica R, Zell T, and Jenkins MK. Visualizing the generation of memory CD4 T cells in the whole body. Nature 410, 101-105. 2001. doi: 10.1038/35065111.

22. Wysocki CA, Panoskaltsis-Mortari A, Blazar BR, and Serody JS. Leukocyte migration and graft-versus-host disease. Blood. 2005;105:4191-4199. doi 10.1182/blood-2004-12-4726.

23. Kolb HJ, Mittermueller J, Holler E, et al. Treatment of recurrent chronic myelogenous leukemia posttransplant with interferone alpha (INFa) and donor leukocyte transfusions [abstract]. Blut. 1990;61:122.

24. Hessel H, Mittermuller J, Zitzelsberger H, Weier HU, Bauchinger M. Combined immunophenotyping and FISH with sex chromosome-specific DNA probes for the detection of Langerhans cells after sex-mismatched bone marrow transplantation. Histochem Cell Biol. 1996;106:481-485. pmid: 8950606.

25. Teshima T, Ordemann R, Reddy P, et al. Acute graft-versus-host disease does not require alloantigen expression on host epithelium. Nat Med. 2002;8:575-581. doi: 10.1038/nm0602-575.

26. Shlomchik WD, Couzens MS, Tang CB, et al. Prevention of graft versus host disease by inactivation of host antigen-presenting cells. Science 1999;285:412-415. pmid: 10411505. PDF: Free with Registration at http://www.sciencemag.org/content/285/5426/412.long

27. Matte CC, Liu J, Cormier J, et al. Donor APCs are required for maximal GVHD but not for GVL. Nat.Med. 2004;10:987-992. doi: 10.1038/nm1089.

28. Tutschka PJ, Hess AD, Beschorner WE, Santos GW. Suppressor cells in transplantation tolerance. I. Suppressor cells in the mechanism of tolerance in radiation chimeras. Transplantation 1981;32:203-209. pmid: 6456580.

29. Tutschka PJ, Ki PF, Beschorner WE, Hess AD, Santos GW. Suppressor cells in transplantation tolerance. II. maturation of suppressor cells in the bone marrow chimera. Transplantation 1981;32:321-325. pmid: 6460354.

30. Tutschka PJ, Hess AD, Beschorner WE, Santos GW. Suppressor cells in transplantation tolerance. III. The role of antigen in the maintenance of transplantation tolerance. Transplantation 1982;33:510-514. pmid: 6211807.

31. Weiden PL, Storb R, Tsoi M-S, et al. Infusion of donor lymphocytes into stable canine radiation chimeras: Implications for mechanism of transplantation tolerance. J.Immunol. 1976;116:1212-1219. pmid: 774975.

32. Kolb HJ, Günther W, Schumm M, et al. Adoptive immunotherapy in canine chimeras. Transplantation 1997;63:430-436. pmid: 9039935.

33. Zorn J, Herber M, Schwamberger S, et al. Tolerance in DLA-haploidentical canine littermates following CD6-depleted marrow transplantation and donor lymphocyte transfusion. Exp Hematol. 2009;37:998-1006. doi: 10.1016/j.exphem.2009.05.001.

34. Ruggeri L, Capanni M, Urbani E, et al. Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Science. 2002;295:2097-2100. doi: 10.1126/science.1068440.

35. Luznik L, O'Donnell PV, Symons HJ, et al. HLA-haploidentical bone marrow transplantation for hematologic malignancies using nonmyeloablative conditioning and high-dose, posttransplantation cyclophosphamide. Biol.Blood Marrow Transplant 2008;14:641-650. doi: 10.1016/j.bbmt.2008.03.005.

36. Le BK, Ringden O. Mesenchymal stem cells: properties and role in clinical bone marrow transplantation. Curr.Opin.Immunol. 2006;18:586-591. doi: 10.1016/j.coi.2006.07.004 .

37. Lowsky R, Takahashi T, Liu YP, et al. Protective conditioning for acute graft-versus-host disease. N.Engl.J Med. 2005;353:1321-1331. doi: 10.1056/NEJMoa050642.

38. Gratwohl A, Brand R, Apperley J, et al. Graft-versus-host disease and outcome in HLA-identical sibling transplantations for chronic myeloid leukemia. Blood.doi: 10.1182/blood.V100.12.3877 2002;100:3877-3886.

39. Shlomchik WD. Graft-versus-host disease. Nat.Rev.Immunol. 2007;7:340-352. doi: 10.1038/nri2000.

40. Petersdorf EW, Malkki M. Genetics of risk factors for graft-versus-host disease. Semin.Hematol. 2006;43:11-23. doi: 10.1053/j.seminhematol.2005.09.002.

41. Petersdorf EW, Hansen JA, Martin PJ, et al. Major-histocompatibility-complex class I alleles and antigens in hematopoietic-cell transplantation. N.Engl.J Med. 2001;345:1794-1800. doi: 10.1056/NEJMoa011826.

42. Sasazuki T, Juji T, Morishima Y et al. Effect of matching of class I HLA alleles on clinical outcome after transplantation of hematopoietic stem cells from an unrelated donor. Japan Marrow Donor Program [see comments] [published erratum appears in N Engl J Med 1999 Feb 4;340(5):402]. N Engl J Med. 1998;339:1177-1185.

43. Petersdorf EW. Risk assessment in haematopoietic stem cell transplantation: histocompatibility. Best.Pract.Res.Clin.Haematol. 2007;20:155-170. doi: 10.1016/j.beha.2006.09.001.

44. Kawase T, Matsuo K, Kashiwase K et al. HLA mismatch combinations associated with decreased risk of relapse: implications for the molecular mechanism. Blood 2009;113:2851-2858. doi: 10.1182/blood-2008-08-171934.

45. Baron C, Somogyi R, Greller LD, et al. Prediction of graft-versus-host disease in humans by donor gene-expression profiling. PLoS.Med. 2007;4:e23. doi: 10.1371/journal.pmed.0040023.

46. Dickinson AM, Pearce KF, Norden J, et al. Impact of genomic risk factors on outcome after hematopoietic stem cell transplantation for patients with chronic myeloid leukemia. Haematologica. 2010.Jun;95(6):922-7. Epub 2010 Mar 19. doi: 10.3324/haematol.2009.016220.

47. Holler E, Rogler G, Herfarth H, et al. Both donor and recipient NOD2/CARD15 mutations associate with transplant-related mortality and GvHD following allogeneic stem cell transplantation. Blood. 2004;104:889-894. doi: 10.1182/blood-2003-10-3543.

48. Goulmy E. Human minor histocompatibility antigens: New concepts for marrow transplantation and adoptive immunotherapy. Immunol.Rev. 1997;157:125-140.

49. Falkenburg JH, Wafelman AR, Joosten P, et al. Complete remission of accelerated phase chronic myeloid leukemia by treatment with leukemia-reactive cytotoxic T lymphocytes. Blood. 1999;94:1201-1208.

50. Spellman S, Warden MB, Haagenson M, et al. Effects of mismatching for minor histocompatibility antigens on clinical outcomes in HLA-matched, unrelated hematopoietic stem cell transplants. Biol.Blood Marrow Transplant. 2009;15:856-863.

51. Glucksberg H, Storb R, Fefer A, et al. Clinical manifestations of graft-versus-host disease in human recipients of HL-A-matched sibling donors. Transplantation 1974;18:295-304. pmid: 4153799.

52. Kolb H, Sale GE, Lerner KG, Storb R, Thomas ED. Pathology of acute
graft-versus-host disease in the dog. An autopsy study of ninety-five dogs. Am J Pathol. 1979 Aug;96(2):581-94.

53. Rowlings PA, Przepiorka D, Klein JP, et al. IBMTR severity index for grading acute graft-versus-host disease: retrospective comparison with Glucksberg grade. Br J Haematol 1997;97:855-864.

54. Cahn JY, Klein JP, Lee SJ, et al. Prospective evaluation of 2 acute graft-versus-host (GVHD) grading systems: a joint Societe Francaise de Greffe de Moelle et Therapie Cellulaire (SFGM-TC), Dana Farber Cancer Institute (DFCI), and International Bone Marrow Transplant Registry (IBMTR) prospective study. Blood. 2005;106:1495-1500.

55. Salat C, Holler E, Kolb HJ, et al. Endothelial cell markers in bone marrow transplant recipients with and without acute graft-versus-host disease. Bone Marrow Transplant, 1997;19:909-914.

56. Tichelli A, Passweg J, Wojcik D, et al. Late cardiovascular events after allogeneic hematopoietic stem cell transplantation: a retrospective multicenter study of the Late Effects Working Party of the European Group for Blood and Marrow Transplantation. Haematologica. 2008;93:1203-1210.

57. Sullivan KM, Deeg HJ, Sanders J, et al. Hyperacute graft-v-host disease in patients not given immunosuppression after allogeneic marrow transplantation. Blood. 1986;67:1172-1175. pmid: 3513869.

58. Rodt H, Netzel B, Brehm G, Thierfelder S. Production of antibodies specific for human thymus derived lymphocytes purified from antibodies crossreacting with colony-forming cells. Blut. 1974;29:416-422. pmid: 4548852.

59. Kolb HJ, Rieder I, Rodt H, et al. Antilymphocytic antibodies and marrow transplantation. VI. Graft- versus-host tolerance in DLA-incompatible dogs after in vitro treatment of bone marrow with absorbed antithymocyte globulin. Transplantation. 1979;27:242-245. pmid: 35870.

60. Rodt H, Thierfelder S, Bender-Gotze C, et al. Serological inhibition of graft versus host disease: recent results in 28 patients with leukemia. Haematol.Blood Transfus. 1983;28:92-96. pmid: 6345300.

61. Goldman JM, Apperley J, Jones L, et al. Bone marrow transplantation for patients with chronic myeloid leukemia. N Engl J Med 1986;314:202-207. pmid: 6345300.

62. Kernan NA, Collins NJ, Juliano L, et al. Clonable T-lymphocytes in T-depleted bone marrow transplants correlate with development of graft-versus-host disease. Blood. 1986;68:770-773.

63. Schumm M, Günther W, Kolb HJ, et al. Prevention of graft-versus-host disease in DLA-haplotype mismatched dogs and hemopoietic engraftment of CD6-depleted marrow with and without cG-CSF treatment after transplantation. Tissue Antigens 1994;43:170-178. pmid:  7522357.

64. Soiffer RJ, Ritz J. Selective T cell depletion of donor allogeneic marrow with anti-CD6 monoclonal antibody: rationale and results. Bone Marrow Transplant 1993;12 Suppl 3:S7-10. pmid: 8124262.

65. Ho VT, Kim HT, Li S, et al. Partial CD8+ T-cell depletion of allogeneic peripheral blood stem cell transplantation is insufficient to prevent graft-versus-host disease. Bone Marrow Transplant. 2004;34:987-994.

66. Guenther W, Kolb HJ, Schumm M, Thierfelder S, Wilmanns W. Suppressive- and veto-effect of canine bone marrow cells [abstract]. 3rd Int Vet Immun Symp Abstractbook 1992.

67. Goldman JM, Gale RP, Horowitz MM, et al. Bone marrow transplantation for chronic myelogenous leukemia in chronic phase: Increased risk of relapse associated with T-cell depletion. Ann.Intern.Med. 1988;108:806-814. pmid: 3285744.

68. Kolb HJ, Rodt H, Netzel B, et al. In vitro treatment of marrow with ATCG or Campath 1 for prophylaxis of GVHD - Results of the AG-KMT München. Exp Hematol 1985;13:147.

69. Finke J, Bethge WA, Schmoor C, et al. Standard graft-versus-host disease prophylaxis with or without anti-T-cell globulin in haematopoietic cell transplantation from matched unrelated donors: a randomised, open-label, multicentre phase 3 trial. Lancet Oncol. 2009;10:855-864.

70. Bacigalupo A, Lamparelli T, Bruzzi P, et al. Antithymocyte globulin for graft-versus-host disease prophylaxis in transplants from unrelated donors: 2 randomized studies from Gruppo Italiano Trapianti Midollo Osseo (GITMO). Blood. 2001;98:2942-2947.

71. Morris EC, Rebello P, Thomson KJ, et al. Pharmacokinetics of alemtuzumab used for in vivo and in vitro T-cell depletion in allogeneic transplantations: relevance for early adoptive immunotherapy and infectious complications. Blood. 2003;102:404-406.

72. Peggs KS, Sureda A, Qian W, et al. Reduced-intensity conditioning for allogeneic haematopoietic stem cell transplantation in relapsed and refractory Hodgkin lymphoma: impact of alemtuzumab and donor lymphocyte infusions on long-term outcomes. Br.J Haematol. 2007;139:70-80.

73. Peggs KS, Thomson K, Hart DP, et al. Dose-escalated donor lymphocyte infusions following reduced intensity transplantation: toxicity, chimerism, and disease responses. Blood. 2004;103:1548-1556

74. Bensinger WI, Martin PJ, Storer B, et al. Transplantation of bone marrow as compared with peripheral-blood cells from HLA-identical relatives in patients with hematologic cancers. N.Engl.J.Med. 2001;344:175-181.

75. Edinger M, Hoffmann P, Ermann J, et al. CD4+CD25+ regulatory T cells preserve graft-versus-tumor activity while inhibiting graft-versus-host disease after bone marrow transplantation. Nat.Med. 2003;9:1144-1150. pmid: 12925844.

76. Le BK, Rasmusson I, Sundberg B, et al. Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells. Lancet. 2004;363:1439-1441. pmid: 15121408.

77. Ball LM, Bernardo ME, Roelofs H, et al. Cotransplantation of ex vivo expanded mesenchymal stem cells accelerates lymphocyte recovery and may reduce the risk of graft failure in haploidentical hematopoietic stem-cell transplantation. Blood. 2007;110:2764-2767.

78. Kolb HJ, Simoes B, Hoetzl F, et al. CD6-negative mobilized blood cells facilitating HLA-haploidentical marrow transplantation for the treatment of high-risk hematopoietic neoplasia. [abstract]. Blood. 2002;100:637a.

79. O'Donnell PV, Luznik L, Jones RJ, et al. Nonmyeloablative bone marrow transplantation from partially HLA-mismatched related donors using posttransplantation cyclophosphamide. Biol.Blood Marrow Transplant. 2002;8:377-386.

80. White DJ, Lim SM. The induction of tolerance by cyclosporine. Transplantation 1988;46:118S-121S. pmid: 3043793.

81. Nash RA, Antin JH, Karanes C, et al. Phase 3 study comparing methotrexate and tacrolimus with methotrexate and cyclosporine for prophylaxis of acute graft-versus-hiost disease after marrow transplantation from unrelated donors. Blood. 2002;96:2062-2068.

82. Storb R, Deeg HJ, Whitehead J, et al. Methotrexate and cyclosporine compared with  cyclosporine alone for prophylaxis of acute graft-versus-host disease after marrow transplantation for leukemia. N Engl J Med 1986;314:729-735. pmid: 3513012.

83. Bolwell B, Sobecks R, Pohlman B, et al. A prospective randomized trial comparing cyclosporine and short course methotrexate with cyclosporine and mycophenolate mofetil for GVHD prophylaxis in myeloablative allogeneic bone marrow transplantation. Bone Marrow Transplant. 2004;34:621-625.

84. Seghal SN. Sirolimus: its discovery, biological properties, and mechanism of action. Transplant Proc 2003;35:7S-14S. pmid: 12742462.

85. Wells AD, Li XC, Li Y, et al. Requirement for T-cell apoptosis in the induction of peripheral transplantation tolerance. Nat Med 1999;5:1303-1307. pmid: 10545998.

86. Blazar BR, Taylor PA, Panoskaltsis-Mortani A, Vallera DA. Rapamycin inhibits the generation of graft-versus-host disease- and graft-versus-leukemia-causing T cells by interfering with the production of Th1 or Th1 cytotoxic cytokines. J Immunol 1998;160:5355-5365.

87. Battaglia M, Stabilini A, Roncarolo MG. Rapamycin selectively expands CD4+CD25+?FoxP3+ regulatory T cells. Blood. 2005;105:4743-4748.

88. Yu X, Carpenter P, Anasetti C. Advances in transplantation tolerance. Lancet 2001;357:1959-1963. pmid: 11425437.

89. Cutler C, Li S, Ho VT, et al. Extended follow-up of methotrexate-free immunosuppression using sirolimus and tacrolimus in related and unrelated donor peripheral blood stem cell transplantation. Blood. 2007;109:3108-3114.

90. Rodriguez R, Nakamura R, Palmer JM, et al. A phase II pilot study of tacrolimus/sirolimus GVHD prophylaxis for sibling donor hematopoietic stem cell transplantation using 3 conditioning regimens. Blood. 2010;115:1098-1105.

91. Schleuning M, Judith D, Jedlickova Z, et al. Calcineurin inhibitor-free GVHD prophylaxis with sirolimus, mycophenolate mofetil and ATG in Allo-SCT for leukemia patients with high relapse risk: an observational cohort study. Bone Marrow Transplant. 2009;43:717-723.

92. Deeg HJ. How I treat refractory acute GVHD. Blood. 2007;109:4119-4126.

93. Bacigalupo A, van Lint MT, Frassoni F, et al. High dose bolus methylprednisolone for the treatment of acute graft versus host disease. Blut. 1983;46:125-132. pmid: 6337655.

94. van Lint MT, Uderzo C, Locasciulli A, et al. Early treatment of acute graft-versus-host disease with high- or low-dose 6-methylprednisolone: a multicenter randomized trial from the Italian Group for Bone Marrow Transplantation. Blood. 1998;92:2288-2293.

95. Mielcarek M, Storer BE, Boeckh M, et al. Initial therapy of acute graft-versus-host disease with low-dose prednisone does not compromise patient outcomes. Blood. 2009;113:2888-2894.

96. Rhen T, Cidlowski JA. Antiinflammatory action of glucocorticoids--new mechanisms for old drugs. N.Engl.J.Med. 2005;353:1711-1723. pmid: 16236742.

97. Beck JS, Browning MC. Immunosuppression with glucocorticoids--a possible immunological explanation for interpatient variation in sensitivity: discussion paper. J.R.Soc.Med. 1983;76:473-479.

98. Nijhuis EW, Hinloopen B, van Lier RA, Nagelkerken L. Differential sensitivity of human naive and memory CD4+ T cells for dexamethasone. Int.Immunol. 1995;7:591-595. pmid: 7547686.

99. Lim HY, Muller N, Herold MJ, van den Brandt J, Reichardt HM. Glucocorticoids exert opposing effects on macrophage function dependent on their concentration. Immunology. 2007;122:47-53.

100. Fan PT, Yu DT, Clements PJ, et al. Effect of corticosteroids on the human immune response: comparison of one and three daily 1 gm intravenous pulses of methylprednisolone. J.Lab Clin.Med. 1978;91:625-634. pmid: 76667.

101. Koreth J, Antin JH. Current and future approaches for control of graft-versus-host disease. Expert.Rev.Hematol. 2008;1:111.

102. Viard I, Wehrli P, Bullani R, et al. Inhibition of toxic epidermal necrolysis by blockade of CD95 with human intravenous immunoglobulin. Science. 1998;282:490-493. pmid: 9774279.

103. Nimmerjahn F, Ravetch JV. The antiinflammatory activity of IgG: the intravenous IgG paradox. J.Exp.Med. 2007;204:11-15.

104. McDonald GB, Bouvier M, Hockenbery DM, et al. Oral beclomethasone dipropionate for treatment of intestinal graft-versus-host disease: a randomized, controlled trial. Gastroenterology. 1998;115:28-35. pmid: 9649455.

105. Bertz H, Afting M, Kreisel W, et al. Feasibility and response to budesonide as topical corticosteroid therapy for acute intestinal GVHD. Bone Marrow Transplant. 1999;24:1185-1189.

106. MacMillan ML, Weisdorf DJ, Davies SM, et al. Early antithymocyte globulin therapy improves survival in patients with steroid-resistant acute graft-versus-host disease. Biol.Blood Marrow Transplant. 2002;8:40-46.

107. van Lint MT, Milone G, Leotta S, et al. Treatment of acute graft-versus-host disease with prednisolone: significant survival advantage for day +5 responders and no advantage for nonresponders receiving anti-thymocyte globulin. Blood. 2006;107:4177-4181.

108. Knop S, Hebart H, Gratwohl A, et al. Treatment of steroid-resistant acute GVHD with OKT3 and high-dose steroids results in better disease control and lower incidence of infectious complications when compared to high-dose steroids alone: a randomized multicenter trial by the EBMT Chronic Leukemia Working Party. Leukemia. 2007;21:1830-1833. pmid: 17495972.

109. Schnitzler M, Hasskarl J, Egger M, Bertz H, Finke J. Successful treatment of severe acute intestinal graft-versus-host resistant to systemic and topical steroids with alemtuzumab. Biol.Blood Marrow Transplant. 2009;15:910-918.

110. Schub N, Gunther A, Schrauder A, et al. Therapy of steroid-refractory acute GVHD with CD52 antibody alemtuzumab is effective. Bone Marrow Transplant. 2010;46:143-147.

111. Carpenter PA, Appelbaum FR, Corey L, et al. A humanized non-FcR-binding anti-CD3 antibody, visilizumab, for treatment of steroid-refractory acute graft-versus-host disease. Blood. 2002;99:2712-2719.

112. Carpenter PA, Lowder J, Johnston L, et al. A phase II multicenter study of visilizumab, humanized anti-CD3 antibody, to treat steroid-refractory acute graft-versus-host disease. Biol.Blood Marrow Transplant. 2005;11:465-471.

113. Deeg HJ, Blazar BR, Bolwell BJ, et al. Treatment of steroid-refractory acute graft-versus-host disease with anti-CD147 monoclonal antibody ABX-CBL. Blood. 2001;98:2052-2058.

114. MacMillan ML, Couriel D, Weisdorf DJ, et al. A phase 2/3 multicenter randomized clinical trial of ABX-CBL versus ATG as secondary therapy for steroid-resistant acute graft-versus-host disease. Blood. 2007;109:2657-2662.

115. Kobbe G, Schneider P, Rohr U, et al. Treatment of severe steroid refractory acute graft-versus-host disease with infliximab, a chimeric human/mouse antiTNFalpha antibody. Bone Marrow Transplant. 2001;28:47-49.

116. Couriel D, Saliba R, Hicks K, et al. Tumor necrosis factor-alpha blockade for the treatment of acute GVHD. Blood. 2004;104:649-654.

117. Patriarca F, Sperotto A, Damiani D, et al. Infliximab treatment for steroid-refractory acute graft-versus-host disease. Haematologica. 2004;89:1352-1359.

118. Wolff D, Roessler V, Steiner B, et al. Treatment of steroid-resistant acute graft-versus-host disease with daclizumab and etanercept. Bone Marrow Transplant. 2005;35:1003-1010.

119. Uberti JP, Ayash L, Ratanatharathorn V, et al. Pilot trial on the use of etanercept and methylprednisolone as primary treatment for acute graft-versus-host disease. Biol.Blood Marrow Transplant. 2005;11:680-687.

120. Levine JE, Paczesny S, Mineishi S, et al. Etanercept plus methylprednisolone as initial therapy for acute graft-versus-host disease. Blood. 2008;111:2470-2475.

121. Kennedy GA, Butler J, Western R, et al. Combination antithymocyte globulin and soluble TNFalpha inhibitor (etanercept) +/- mycophenolate mofetil for treatment of steroid refractory acute graft-versus-host disease. Bone Marrow Transplant. 2006;37:1143-1147.

122. Herve P, Wijdenes J, Bergerat JP, et al. Treatment of corticosteroid resistant acute graft-versus-host disease by in vivo administration of anti-interleukin-2 receptor monoclonal antibody (B-B10). Blood. 1990;75:1017-1023.

123. Anasetti C, Hansen JA, Waldmann TA, et al. Treatment of acute graft-versus-host disease with humanized anti-Tac: an antibody that binds to the interleukin-2 receptor. Blood. 1994;84:1320-1327.

124. Przepiorka D, Kernan NA, Ippoliti C, et al. Daclizumab, a humanized anti-interleukin-2 receptor alpha chain antibody, for treatment of acute graft-versus-host disease. Blood. 2000;95:83-89.

125. Lee SJ, Zahrieh D, Agura E, et al. Effect of up-front daclizumab when combined with steroids for the treatment of acute graft-versus-host disease: results of a randomized trial. Blood. 2004;104:1559-1564.

126. Shapira MY, Resnick IB, Bitan M, et al. Rapid response to alefacept given to patients with steroid resistant or steroid dependent acute graft-versus-host disease: a preliminary report. Bone Marrow Transplant. 2005;36:1097-1101.

127. Shapira MY, Abdul-Hai A, Resnick IB, et al. Alefacept treatment for refractory chronic extensive GVHD. Bone Marrow Transplant. 2009;43:339-343.

128. Kamble R, Oholendt M, Carrum G. Rituximab responsive refractory acute graft-versus-host disease. Biol.Blood Marrow Transplant. 2006;12:1201-1202.

129. Furlong T, Martin P, Flowers ME, et al. Therapy with mycophenolate mofetil for refractory acute and chronic GVHD. Bone Marrow Transplant. 2009;44:739-748.

130. Hoda D, Pidala J, Salgado-Vila N, et al. Sirolimus for treatment of steroid-refractory acute graft-versus-host disease. Bone Marrow Transplant. 2009;45:1347-1351.

131. Ghez D, Rubio MT, Maillard N, et al. Rapamycin for refractory acute graft-versus-host disease. Transplantation 2009;88:1081-1087. pmid: 19898203.

132. Pidala J, Kim J, Anasetti C. Sirolimus as primary treatment of acute graft-versus-host disease following allogeneic hematopoietic cell transplantation. Biol.Blood Marrow Transplant. 2009;15:881-885.

133. Durakovic N, Radojcic V, Powell J, Luznik L. Rapamycin promotes emergence of IL-10-secreting donor lymphocyte infusion-derived T cells without compromising their graft-versus-leukemia reactivity. Transplantation 2007;83:631-640. pmid: 17353785.

134. Armand P, Gannamaneni S, Kim HT et al. Improved survival in lymphoma patients receiving sirolimus for graft-versus-host disease prophylaxis after allogeneic hematopoietic stem-cell transplantation with reduced-intensity conditioning. J Clin.Oncol. 2008;26:5767-5774. pmid: 19001324.

135. Bolanos-Meade J, Jacobsohn DA, Margolis J, et al. Pentostatin in steroid-refractory acute graft-versus-host disease. J Clin.Oncol. 2005;23:2661-2668.

136. Schmitt T, Luft T, Hegenbart U, et al. Pentostatin for treatment of steroid-refractory acute GVHD: a retrospective single-center analysis. Bone Marrow Transplant. 2010 Jun 21. doi:10.1038/bmt.2010.146.

137. Jacobsohn DA, Chen AR, Zahurak M, et al. Phase II study of pentostatin in patients with corticosteroid-refractory chronic graft-versus-host disease. J Clin.Oncol. 2007;25:4255-4261.

138. Jacobsohn DA, Gilman AL, Rademaker A, et al. Evaluation of pentostatin in corticosteroid-refractory chronic graft-versus-host disease in children: a Pediatric Blood and Marrow Transplant Consortium study. Blood. 2009;114:4354-4360.

139. Vogelsang GB, Farmer ER, Hess AD, et al. Thalidomide for the treatment of chronic graft-versus-host disease. N.Engl.J Med. 1992;326:1055-1058.

140. Koc S, Leisenring W, Flowers ME, et al. Thalidomide for treatment of patients with chronic graft-versus-host disease. Blood. 2000;96:3995-3996.

141. Lioznov M, El-Cheikh J Jr, Hoffmann F, et al. Lenalidomide as salvage therapy after allo-SCT for multiple myeloma is effective and leads to an increase of activated NK (NKp44(+)) and T (HLA-DR(+)) cells. Bone Marrow Transplant. 2010;45:349-353. pmid: 19584825.

142. Sun K, Li M, Sayers TJ, Welniak LA, Murphy WJ. Differential effects of donor T-cell cytokines on outcome with continuous bortezomib administration after allogeneic bone marrow transplantation. Blood. 2008;112:1522-1529

143. Koreth J, Stevenson KE, Kim HT, et al. Bortezomib, tacrolimus, and methotrexate for prophylaxis of graft-versus-host disease after reduced-intensity conditioning allogeneic stem cell transplantation from HLA-mismatched unrelated donors. Blood. 2009;114:3956-3959.

144. Baroni SS, Santillo M, Bevilacqua F, et al. Stimulatory autoantibodies to the PDGF receptor in systemic sclerosis. N.Engl.J Med. 2006;354:2667-2676.

145. Svegliati S, Olivieri A, Campelli N, et al. Stimulatory autoantibodies to PDGF receptor in patients with extensive chronic graft-versus-host disease. Blood. 2007;110:237-241.

146. Magro L, Catteau B, Coiteux V, et al. Efficacy of imatinib mesylate in the treatment of refractory sclerodermatous chronic GVHD. Bone Marrow Transplant. 2008;42:757-760.

147. Olivieri A, Locatelli F, Zecca M, et al. Imatinib for refractory chronic graft-versus-host disease with fibrotic features. Blood. 2009;114:709-718.

148. Majhail NS, Schiffer CA, Weisdorf DJ. Improvement of pulmonary function with imatinib mesylate in bronchiolitis obliterans following allogeneic hematopoietic cell transplantation. Biol.Blood Marrow Transplant. 2006;12:789-791.

149. Hoffmann P, Eder R, Kunz-Schughart LA, Andreesen R, Edinger M. Large-scale in vitro expansion of polyclonal human CD4(+)CD25high regulatory T cells. Blood. 2004;104:895-903.

150. Di Ianni M, Del Papa B, Cecchini D, et al. Immunomagnetic isolation of CD4+CD25+FoxP3+ natural T regulatory lymphocytes for clinical applications. Clin.Exp.Immunol. 2009;156:246-253.

151. Le BK, Frassoni F, Ball L, et al. Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study. Lancet. 2008;371:1579-1586. pmid: 18468541.

152. Deeg HJ. Ultraviolet irradiation in transplantation biology. Manipulation of immunity and immunogenicity. Transplantation 1988;45:845-851. pmid:  3285528.

153. Hymes SR, Morison WL, Farmer ER, et al. Methoxsalen and ultraviolet A radiation in treatment of chronic cutaneous graft-versus-host reaction. J Am.Acad.Dermatol. 1985;12:30-37. pmid: 3980801.

154. Furlong T, Leisenring W, Storb R, et al. Psoralen and ultraviolet A irradiation (PUVA) as therapy for steroid-resistant cutaneous acute graft-versus-host disease. Biol.Blood Marrow Transplant. 2002;8:206-212.

155. Vogelsang GB, Wolff D, Altomonte V, et al. Treatment of chronic graft-versus-host disease with ultraviolet irradiation and psoralen (PUVA). Bone Marrow Transplant. 1996;17:1061-1067. pmid: 8807115.

156. Ghoreschi K, Thomas P, Penovici M, et al. PUVA-bath photochemotherapy and isotretinoin in sclerodermatous graft-versus-host disease. Eur.J.Dermatol. 2008;18:667-670.

157. Greinix H, Volc-Platzer B, Rabistch W, et al. Successful use of extracorporeal photochemotherapy in the treatment of severe acute and chronic graft-versus-host disease. Blood. 1998;92:3098-3104.

158. Greinix HT, Knobler RM, Worel N, et al. The effect of intensified extracorporeal photochemotherapy on long-term survival in patients with severe acute graft-versus-host disease. Haematologica. 2006;91:405-408.

159. Perfetti P, Carlier P, Strada P, et al. Extracorporeal photopheresis for the treatment of steroid refractory acute GVHD. Bone Marrow Transplant. 2008;42:609-617.

160. Couriel DR, Hosing C, Saliba R, et al. Extracorporeal photochemotherapy for the treatment of steroid-resistant chronic GVHD. Blood. 2006;107:3074-3080.

161. Perotti C, Del Fante C, Tinelli C, et al. Extracorporeal photochemotherapy in graft-versus-host disease: a longitudinal study on factors influencing the response and survival in pediatric patients. Transfusion. 2010;50:1359-1369.

162. Flowers ME, Apperley JF, Van Besien K, et al. A multicenter prospective phase 2 randomized study of extracorporeal photopheresis for treatment of chronic graft-versus-host disease. Blood. 2008;112:2667-2674

163. Gorgun G, Miller KB, Foss FM. Immunologic mechanisms of extracorporeal photochemotherapy in chronic graft-versus-host disease. Blood. 2002;100:941-947.

164. Bladon J, Taylor PC. Early reduction in number of T cells producing proinflammatory cytokines, observed after extracorporeal photopheresis, is not linked to apoptosis induction. Transplant Proc. 2003;35:1328-1332. pmid: 12826151.

165. Gatza E, Rogers CE, Clouthier SG, et al. Extracorporeal photopheresis reverses experimental graft-versus-host disease through regulatory T cells. Blood.2008;112:1515-1521.

166. Di Biaso I, Di Maio L, Bugarin C, et al. Regulatory T cells and extracorporeal photochemotherapy: correlation with clinical response and decreased frequency of proinflammatory T cells. Transplantation. 2009;87:1422-1425.

167. Ford CE, Micklem HS. The thymus and lymph-nodes in radiation chimaeras. Lancet 1963;1:359-362. pmid: 13958695.

168. Zinkernagel RM. Thymus and lymphohemopoietic cells: their role in T cell maturation in selection of T cells' H-2-restriction-specificity and in H-2 linked Ir gene control. Immunol Rev. 1978;42:224-270. pmid: 83701.

169. Krenger W, Hollander GA. The role of the thymus in allogeneic hematopoietic stem cell transplantation. Swiss.Med Wkly. 2010;140:w13051. doi:10.4414/smw.2010.13051.

170. Steffens CM, Al Harthi L, Shott S, Yogev R, Landay A. Evaluation of Thymopoiesis Using T Cell Receptor Excision Circles (TRECs): Differential Correlation between Adult and Pediatric TRECs and Naive Phenotypes. Clin Immunol. 2000;97:95-101. pmid: 11027449.

171. Witherspoon RP, Sullivan KM, Lum LG, et al. Use of thymic grafts or thymic factors to augment immunologic recovery after bone marrow transplantation: brief report with 2 to 12 years' follow-up. Bone Marrow Transplant. 1988;3:425-435. pmid: 3056551.

172. Wils EJ, Cornelissen JJ. Thymopoiesis following allogeneic stem cell transplantation: new possibilities for improvement. Blood Rev. 2005;19:89-98. pmid: 15603912.

173. Seggewiss R, Lore K, Guenaga FJ, et al. Keratinocyte growth factor augments immune reconstitution after autologous hematopoietic progenitor cell transplantation in rhesus macaques. Blood. 2007;110:441-449.

174. Muller-Hermelink HK, Sale GE, Borisch B, Storb R. Pathology of the thymus after allogeneic bone marrow transplantation in man. A histologic immunohistochemical study of 36 patients. Am.J Pathol. 1987;129:242-256.

175. Pullen AM, Kappler JW, Marrack P. Tolerance to self antigens shapes the T-cell repertoire. Immunol Rev. 1989;107:125-139. pmid: 2522084.

176. Zinkernagel RM, Doherty PC. Restriction of in vitro T cell-mediated cytotoxicity in lymphocytic choriomeningitis within a syngeneic or semiallogeneic system. Nature. 1974;248:701-702. pmid:  4133807.

177. Thomas ED, Kasakura S, Cavins JA, Ferrebee JW. Marrow transplants in lethally irradiated dogs: The effect of Methotrexate on survival of the host and the homograft. Transplantation. 1963;1:571-574. pmid: 14071268.

178. Santos GW. Immunosuppression for clinical marrow transplantation. Semin.Hematol. 1974;11:341-351. pmid: 4151847.

179. Luznik L, Jalla S, Engstrom LW, Iannone R, Fuchs EJ. Durable engraftment of major histocompatibility complex-incompatible cells after nonmyeloablative conditioning with fludarabine, low-dose total body irradiation, and posttransplantation cyclophosphamide. Blood. 2001;98:3456-3464.

180. Miller RG, Muraoka S, Claesson MH, Reimann J, Benveniste P. The veto phenomenon in T-cell regulation. Ann N Y Acad Sci. 1988;532:170-6. pmid: 2972242.

181. Reich-Zeliger S, Zhao Y, Krauthgamer R, Bachar-Lustig E, Reisner Y. Anti-third party CD8+ CTLs as potent veto cells: coexpression of CD8 and FasL is a prerequisite. Immunity. 2000;13:507-515.

182. Gabrilovich DI, Nagaraj S. Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev.Immunol 2009;9:162-174. pmid: 19197294.

183. Lan F, Zeng D, Higuchi M, et al. Predominance of NK1.1(+)TCRalphabeta(+) or DX5(+)TCRalphabeta(+) T Cells in Mice Conditioned with Fractionated Lymphoid Irradiation Protects Against Graft-Versus-Host Disease: "Natural Suppressor" Cells. J Immunol. 2001;167:2087-2096.

184. Rabinovich BA, Li J, Shannon J, et al. Activated, but not resting, T cells can be recognized and killed by syngeneic NK cells. J Immunol. 2003;170:3572-3576.

185. Moseman EA, Liang X, Dawson AJ, et al. Human plasmacytoid dendritic cells activated by CpG oligodeoxynucleotides induce the generation of CD4+CD25+ regulatory T cells. J Immunol. 2004;173:4433-4442.

186. Kapp JA, Bucy RP. CD8+ suppressor T cells resurrected. Hum.Immunol 2008;69:715-720. pmid: 18817830.

187. Peccatori J, Clerici D, Forcina A, et al. In vivo T-regs generation by rapamycin-mycophenolate-ATG as a new platform for GVHD prophylaxis in T-cell repleted unmanipulated haploidentical peripheral stem cell transplantation: results in 59 patients [abstract]. EBMT Meeting Vienna. 2010. 2010;S3-S4.

188. Peritt D. Potential mechanisms of photopheresis in hematopoietic stem cell transplantation. Biol.Blood Marrow Transplant. 2006;12:7-12.

189. Weissinger EM, Schiffer E, Hertenstein B, et al. Proteomic patterns predict acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. Blood. 2007;109:5511-5519.

190. Paczesny S, Braun TM, Levine JE et al. Elafin is a biomarker of graft-versus-host disease of the skin. Sci.Transl.Med 2010;2:13ra2. pmid: 20371463.

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Introduction

Allogeneic hematopoietic stem cell transplantation has become one of the most frequent forms of transplantation, with currently more than 6000 transplants being performed annually. Its use is still increasing in the treatment of hematological and other malignancies. In addition there are a large number of patients with debilitating and life threatening hematological dis-eases, thalassemia, sickle cell anemia, and other non-malignant diseases that may benefit from transplantation. However, the major obstacle to the wider use of transplantation is graft-versus-host disease (GVHD); still a serious threat to these patients. However, at the same time graft-versus-host reactions directed at leukemia, lymphoma, myeloma, and other tumors of the host may be beneficial. Therefore it is necessary to understand GVHD in order to ex-ploit the potential advantages without incurring the risks. Allogeneic stem cell transplantation conveys tolerance toward organs of the donor. As a rule, immunosuppressive therapy can be discontinued after several months without the risk of rejection and GVHD. This tolerance with chimerism allows the transplantation of cells and organs of the same donor without life-long immune suppression. The success of immunotherapy with donor cells and of transplantation of solid organs from the stem cell donor depends on whether or not GVHD can be controlled.

Early observations

Mice protected from hematopoietic failure following total body irradiation by bone marrow transplantation succumbed to a “secondary disease” if the bone marrow was taken from a different strain [1]. This disease was related to an immune reaction of donor cells against the host rather than a delayed radiation syndrome: cells of diseased mice induced hepato-splenomegaly when transferred to non-irradiated newborn mice [2]. Further proof was the oc-currence of this secondary disease in F1-hybrid mice transplanted with parental marrow, but not in parental mice transplanted with F1-hybrid marrow [3]. Finally, organs containing more immunologically competent cells such as those from the spleen produced more secondary disease than bone marrow [4]. Eventually, the principle requirements for GVHD were defined by Billingham [5]: 1. the graft must contain immune reactive cells, 2. the recipient must be im-munogenetically different, and 3. the recipient cannot reject the graft. The first patients with acute GVHD were described by Mathé and colleagues [6]. A major step towards successful transplantation was the selection of marrow donors within the family according to major his-tocompatibility antigens (HLA) [7]. HLA had been previously detected in humans with pre-formed antibodies [8, 9]. Most preconditions for allogeneic transplantation in humans have been elaborated in animal experiments, particularly in dogs 10]. 

Therefore the principles for prevention of GVHD are 1. selection of a histocompatible donor, 2. adequate immune suppression for the patient before and after transplantation, and 3. ma-nipulation of the graft. In more recent years much has been learned about the regulation of the T cell response and mechanisms of tolerance, which may guide the way for immune suppression [11].

Animal models

The manifestation of GVHD in every species investigated so far involves skin, gut, and liver; primarily however hematopoietic tissue (Fig.1). Acute GVHD is a syndrome with similar fea-tures in mice, rats, monkeys, and humans; without prevention or treatment it can be rapidly fatal. Therefore pathophysiology, prevention, and treatment of acute GVHD can be studied in animal models. Chronic GVHD cannot be readily studied in animal models; it is not known why certain organs are involved and others are spared. Obviously hematopoietic cells are the primary targets, and the skin, gut, and liver may contain cells of hematopoietic origin such as dendritic cells and macrophages. These cells produce pro-inflammatory cytokines including interferon-gamma (IFN-g), tumor necrosis factor-alpha (TNF-a), interleukin 6 (IL-6), and others that stimulate donor T cells and induce expression of HLA class II antigens in host tissue (Fig.2). Dendritic cells activated by CD4 cells may stimulate CD8 cells to react against HLA class I presented peptides (Fig.3). Recent studies, however, showed that deficient production of IFN-g can increase GVHD in the skin, and failure of IFN-g induction of B7-H1 enhanced TH2 cells can produce idiopathic pneumonia [12]. TH2 cells and TH17 cells were guided to lungs and skin by the expression of chemokine receptors.

Figure 1. Host target tissues affected in the course of graft-versus-host disease

Kolb_Figure1.png

Figure 2. A proposed role of cytokine network and specific receptors of immune cells at initiation of GvHD (for details see text)

Kolb_Figure2.png

Figure 3. Dendritic cells boost CD8+ cells to react against host target tissues

Kolb_Figure3.png

GVH reactions of the graft are directed against histocompatibility antigens of the recipient that are foreign to the donor. These antigens can be defined by the major histocompatibility complex, a highly polymorphic genetic region determining class I and class II antigens. Class I antigens are present in all cells of the organism, and class II normally only in hematopoietic cells. They may be expressed in other cells if these are affected by inflammation or injury. CD4-positive T cells exert GVH reactions against cells expressing class II antigens, and CD8-positive T cells act against class I antigens [13]. Differences in both antigen classes can induce severe and rapidly fatal GVHD. Polymorphic proteins not encoded by the major histo-compatibility complex may also cause severe GVH reactions. Peptides of these proteins can be presented by MHC class I and class II antigens. In general, MHC class I presents peptides of endogenous proteins of the cell, whereas class II antigens present peptides of exogenously acquired proteins [14, 15]. Here, minor histocompatibility (mHA) directed CD8 T cells require help from CD4 T cells for expansion and generation of memory T cells [16]. Therefore, reactions against mHA require a longer phase of immune recognition and activation than reactions against MHC antigens. Class II antigens are mainly expressed in hematopoietic progenitor cells, and in the case of injury and inflammation they may be expressed in non-hematopoietic cells as well. Reactions directed against class II antigens may induce severe marrow aplasia [17].

The mechanism of initiation of acute GVHD is not entirely clear; the preconditions are given before transplantation [18]. Much has been explained and published on cytokines and the cyto-kine storm liberated by intensive conditioning treatment, including high dose radiation and chemotherapy [19]. The role of cytokine release is confirmed by the suppression of acute GVHD using TNF-a antibodies [20]. There is some evidence that the systemic release of IFN-g leads to the secretion of chemokines in organs affected by GVHD and attracts activated T cells. In transgenic mice carrying the T cell receptor for ovalbumin the distribution of T cells was dependent on whether the antigen was given alone or together with lipopolysaccharide (LPS). Intravenous injection of antigens alone homes the T cells to secondary lymphoid tissue where they produce IL2, whereas injection of a combination of antigens and LPS homes the T cells to the lung, liver, gut, and skin where they produce IFN-g [21]. Systematically activated T cells produce interferons and induce chemokines in GVHD target organs [22]. However, the “danger signal” brought about by LPS may not be necessary, since in human patients donor lymphocyte transfusion may produce GVHD without conditioning treatment and infection [23].

The host's antigen presenting cells survive the conditioning treatment for various periods of time, with the most efficient cells being dendritic cells, but B cells, macrophages and other cells present antigens as well. Whereas dendritic cells in the blood of the host are rapidly re-placed by those of the donor, data on chimerism of dendritic cells in tissues are controversial [24]. Cytokine release by the host's activated dendritic cells and the graft's T cells is part of the initiation of GVH reactions (Fig. 2), and may be powerful enough to induce fatal GVHD even in the absence of histoincompatibility [25]. In general however, histocompatibility differences are necessary to induce and maintain GVH reactions. These histocompatibility differences may be of the major histocompatibility complex (MHC) class I or class II involving CD4- or CD8-positive T cells of the graft, and minor histocompatibility differences requiring profes-sional antigen presentation by dendritic cells of the host. GVHD occurring in the skin, liver, and gut requires dendritic cells expressing class I [26]. There is a possibility of cross presenta-tion of host antigens by donor dendritic cells, but their effects are inferior to direct presentation [27].

In contrast to cases involving the transplantation of solid organs, immunosuppressive therapy can be discontinued 3–6 months after transplantation in most patients receiving hematopoietic stem cell transplants, although patients who develop chronic GVHD may require therapy for several years. The host’s immune system is continuously suppressed by the graft, and the graft becomes tolerant towards the host. The mechanism of tolerance has been related to the occurrence of non-specific and specific suppressor cells followed by clonal deletion [28-30]. In DLA-identical canine chimeras tolerance could not be abrogated by the transfusion of donor lymphocytes unless the donors were immunized against the recipient [31]. Refractoriness to donor lymphocytes inducing GVHD develops at about two months after T cell depleted transplantation [32]. It may occur earlier in dogs transplanted with marrow depleted of T cells by CD6-antibody sparing NK cells [33]. NK cells can inactivate host dendritic cells and thereby prevent GVHD in mice [34]. Besides depletion of T cells and dendritic cells in the graft and the host, responder cells to antigen stimulation may respectively be eliminated by subsequent chemotherapy with methotrexate or cyclophosphamide. Cyclophosphamide can be given in rather high doses after transplantation without jeopardizing engraftment [35]. Modulation and suppression of GVH reactions has been shown for fractions of marrow cells such as mesenchymal stromal cells [36], NK-T cells (NKT1.1) [37], and regulatory T cells [11].

The results of animal models are highly informative with respect to the principles and me-chanisms of GVHD, but they also have their limitations. Apart from species-specific regulato-ry mechanisms of hematopoiesis and the immune system, animals are mostly young, have grown up in a protected environment, and are free of disease for which clinical transplantation is undertaken. In contrast, human patients are commonly older, have a history of infections and most likely a number of latent viral infections, and are possibly allo-immunized by previous transfusions and pregnancies, as are their donors. Moreover the primary disease and its treatment have a major impact on the transplant course.

The role of the immune repertoire of donor and host is still poorly defined. Female donors produce more GVHD and GVL in male recipients; most likely due to immunization during pregnancies by antigens derived from the fetuses' father [38]. Conversely, central memory T cells produce less GVHD than naïve T cells, indicating that the GVH reaction in most cases is a primary reaction [39]. Presumably central memory T cells cannot be involved in new primary reactions; there is also a risk that central memory T cells may produce vigorous GVHD when they recognize the antigen against which they developed. Alternatively they could be regulated by regulatory T cells.

Genetics

Selecting an HLA-identical sibling as donor was the major step towards successful stem cell transplantation. Selecting the donor within a family by typing for HLA-A, -B and DR-antigens is sufficient for successful transplantation, since antigen typing defines the haplotypes inhe-rited from the parents. Unlike identity by inheritance, selection of an unrelated donor relies on the most accurate typing of as many loci as possible. In general genetic definition of alleles of 10 HLA-loci is required to select a matched donor [40]. Severe GVHD can occur with any form of mismatch, but graft failure is less serious with mismatches for HLA-alleles than for the broader HLA-antigens [41]. In multiple mismatches the impact of various HLA-loci (A, B, C, DR) was similar, with the possible exception of HLA-DQ, which was less important. Notewor-thy is a possible racial difference in the role of HLA-C; in Japanese populations HLA-C has a lesser effect on GVHD than other HLA-loci [42]. In Caucasian populations HLA-C is as impor-tant for GVHD as other HLA-antigens [43]. The linkage disequilibrium, i.e. the occurrence of two antigens together, is more frequent than expected by the antigen frequency, is high for HLA-B and -C as well as for HLA-DRB1 and DQB1; therefore isolated mismatches are infre-quent. The linkage disequilibrium of HLA-DP with HLA-DRB1 is rather low, and differences of HLA-DP do not carry an additional risk for GVHD. They may, however, have an effect on the graft-versus-leukemia activity [44].

Presently little is known about permissible HLA-mismatches that allow for the development of tolerance. There may be racial differences as shown for HLA-C in Japanese as compared to Caucasian populations. In general HLA-mismatches are more permissible in patients with advanced disease than in patients with early disease. An allele mismatch may produce se-vere GVHD in a patient in chronic phase CML, but it may not have an effect in a patient with relapse of leukemia [43]. Cytokine levels and cytokine receptors are coded for by genes of the major histocompatibility complex. Sequence polymorphisms of genes for tumor necrosis fac-tor alpha (TNF-a), IL-6 and interferon-gamma (IFN-g) are different in persons with different racial backgrounds, i.e. Caucasians, Africans, and Cubans [45]. There have been several al-leles defined for both the TNF-a locus and the TNF-a receptor II locus that are associated with an increased risk of GVHD. Contrary to the pro-inflammatory cytokine TNF-a, IL-10 has anti-inflammatory effects. Polymorphisms of the promoter of IL-10 had an impact on GVHD. High levels of IL-10 correlated with a lower risk of GVHD.

Genetic factors outside of the HLA-complex may also be involved in the pathogenesis of GVHD. In the analysis of the gene expression profiles of donor cells, a particular role of transforming growth factor beta for chronic GVHD has been found [45]. In patients transplanted for chronic myelogenous leukemia [46] polymorphic alleles of TNF-receptor in the patient and certain alleles in IL10 and IL1 receptor in donor lymphocytes were associated with an in-creased risk of GVHD and decreased survival. A genetic factor associated with inflammatory bowel disease had an impact on GVHD (NOD/Card1) [47]. However, the effect could be dimi-nished if the gut was microbiologically well decontaminated. Antimicrobial prophylaxis de-creases the risk of GVHD without the GVL effect deteriorating.

There is good evidence that minor histocompatibility antigens play a role in GVHD and GVL reactivity [48, 49]. However, a recent analysis of the role of minor antigens in HLA-matched unrelated transplants by the NMDP did not find an impact of minor HA differences on the out-come of allogeneic stem cell transplantation [50].

Clinical features

Acute GVHD

GVHD was described and classified in the '70s [51, 52], when most patients were conditioned with total body irradiation. Skin is the organ most frequently affected; a maculopapular rash is common. This rash starts frequently in the upper thorax, arms, and face, but it can occur elsewhere and spread over the whole body. Features range from a maculopapular rash to general dermatitis with blisters and epidermal necrolysis. Histological findings are degenera-tion and apoptosis of the basal cells, dyskeratosis and lymphocytic infiltration. Involvement of the gastrointestinal tract is clinically characterized by diarrhea, malaise and vomitus; diarrhea may be severe with several liters of liquid and bloody stools. Histological findings are flatten-ing of the mucosa with debris in crypts (crypt abscesses); the most frequently affected part is the ileum. GVHD of the liver is characterized by jaundice and increases of liver enzymes. Histologically the Glisson triads are infiltrated, and the bile ducts are destroyed by infiltrating lymphocytes. Unfortunately none of the histological signs are diagnostic — viral infections and drug reactions may present similar features. Nevertheless biopsies may be indicated in order to exclude other diagnoses with characteristic signs and to obtain material for microbio-logical studies.

Despite prophylactic treatment with immunosuppressive drugs the prevalence of acute GVHD of all grades of severity is high, with a rate of 40–60% in patients with an HLA-identical sibling donor and 60–90% with a matched unrelated donor. Only at a severity of grade 2 and higher is additional immunosuppressive treatment required: this equates to 40–70% of patients. Another grading system was designed by the International Bone Marrow Transplant Registry IBMTR and validated in two studies [53, 54]. This grading system does not take into account the clinical performance as does the system of H. Glucksberg [51]. No advantage of one system over the other has been shown [54]. In both grading systems microangiopathy has not been scored as a form of acute GVHD; microangiopathy is characterized by red cell fragmentation, high levels of serum lactate dehydrogenase and thrombocytopenia. It is more frequent in patients treated with calcineurin inhibitors [18] or sirolimus, and resembles thrombotic thrombocytopenic purpura, but polymers of von Willebrand factor have not been found [55].

Table I. Acute GVHD. Diagnostic criteria according to H. Glucksberg

Stage

Skin maculopapular rash

Liver bilirubin

Gut diarrhea

+

 < 25% body surface area

2 - 3 mg/dl

> 500 ml

++

25 - 505 BSA

3,1 - 6 mg/dl

> 1000 ml

+++

Generalized erythroderma

6,1 - 15 mg/dl

> 1500 ml

++++

General erythroderma with bulla formation and desquamation

> 15 mg/dl

Severe abdominal pain w/wo ileus

Cell Ther Transplant. 2012;2:e.000089.01. doi:10.3205/ctt-2012-en-000089.01-table1

Table II. Acute GVHD. Diagnostic criteria according to H. Glucksberg

Grade of aGVHD

Skin

Liver:

Gut:

Clinical performance

I

+ - ++

bilirubin < 2,0 mg/dl

No diarrhea

Ok

II

+ - +++

3,1 - 6 mg/dl

Diarrhea > 500 ml

Mild decrease

III

++ - +++

6,1 - 15 mg/dl

> 1000 ml

Marked decrease

IV

++ - ++++

> 6,1 mg/dl

> 1000 ml

Severe decrease

Cell Ther Transplant. 2012;2:e.000089.01. doi:10.3205/ctt-2012-en-000089.01-table2

Chronic GVHD

Acute GVHD may resolve completely with immunosuppressive treatment or it may lead to chronic GVHD. Chronic GVHD may also develop de novo without prior acute GVHD within a year from transplantation. Chronic GVHD involves most frequently the skin with lichenoid and sclerotic changes, the nails with dystrophy, the eyes with keratoconjunctivitis, the mouth with dryness and paradontosis, the vagina with dryness and sclerosis, liver and lungs. The clinical features of chronic GVHD resemble autoimmune diseases like lupus erythematodes, Sjögren syndrome, and biliary cirrhosis in many aspects. Characteristically there is hypogammaglo-bulinemia with loss of IgA, and lymphopenia, but there may also be hypergammaglobulinemia and eosinophilia. Thrombocytopenia is a sign of poor prognosis; another factor of poor prognosis is involvement of the lungs, which may be in the form of late interstitial pneumonitis and fibrosis or obliterating bronchiolitis. As a rule lung involvement is progressive and carries the risk of severe infections. The skeletal system may be involved in form of fasciitis, muscle dystrophy, tendinitis, and contractures. Transplant vasculopathy is a problem of solid organ transplants: in stem cell transplanted patients vasculitic changes in the CNS have been observed and vascular events can be seen in young patients [56] without other risk factors.

Overlapping GVHD

Besides the clinical features, acute and chronic GVHD have been defined by the time of oc-currence: acute GVHD in the first weeks and months, and chronic GVHD after day 100. This definition has been challenged by the introduction of cyclosporine A for immune suppression and conditioning with reduced intensity. Following discontinuation of cyclosporine A, a flare of acute GVHD may occur, and following reduced intensity conditioning, acute GVHD may occur late. Similarly, late onset of acute GVHD has been observed after prophylactic treat-ment with TNF-antibody during conditioning [20]. Obviously the activation of T cells is delayed by reduced intensity conditioning and prophylactic treatment, with TNF-antibodies leading to late acute GVHD.

Prophylaxis of GVHD

Some form of prophylaxis of GVHD is absolutely necessary even in HLA-identical sibling transplants, as hyperacute GVHD was seen in every patient with engraftment [57]. T cells are responsible for GVHD and depletion of T cells from the transplant was very successful in an-imal models [58, 59]. In the clinical setting GVHD could be prevented or suppressed [60, 61] effec-tively. Antithymocyte globulin (ATG) has a broad specificity, recognizing not only T cells, but other mononuclear cells as well. The monoclonal antibody alemtuzumab recognizes CD52, an antigen that is present in many leukocytes including lymphocytes, monocytes, and den-dritic cells; alemtuzumab has broad activities despite its specificity. In humans [62] as in dogs [63] the number of clonable T cells should be below 105/ kg body weight for effective prevention of GVHD. So far more selective depletion of T cells has not improved the overall results of transplantation [64], and depletion of CD8 has been insufficient in preventing GVHD [65]. CD6 has the advantage of sparing most of the NK cells in the transplant [64]. In dogs CD6-depleted marrow suppresses alloresponses [66] and recipients of CD6-depleted marrow tolerate donor lymphocyte transfusions earlier than recipients of marrow treated with absorbed ATG [33].

However, the advantage of ex vivo T cell depletion was offset by a high rate of graft rejection, relapse, infections, and EBV-associated post transplant lymphoproliferative disease (PTLD) [67, 68]. Treatment of the patient prior to transplantation with ATG prevents rejection; T cell anti-bodies persist in the patient for 4–5 weeks and deplete T cells of the graft in vivo. A rando-mized study comparing standard post-grafting immune suppressive treatment with and with-out ATG prior to transplantation showed lower rates of acute and chronic GVHD in the group treated with ATG [69]. A beneficial effect of ATG in the conditioning treatment for chronic GVHD has also been observed in Italian studies [70] and in retrospective analyses of non-randomized studies (own unpublished observations).

Alemtuzumab also persists in the patient for a prolonged period of time, and reconstitution of T cells is delayed for 6–9 months [71]. Severity of GVHD is low in patients treated with alemtu-zumab, but graft failures have been observed [72]. There is also an increased risk of viral infec-tions, particularly cytomegalovirus, and insufficient response of the malignant disease. These deficiencies can be compensated at least partially by the transfusion of donor lymphocytes [73].

In the last decade G-CSF mobilized peripheral blood stem cells (PBSC) have replaced mar-row in most instances. PBSC contain enormous amounts of T cells and depletion of T cells has been largely unsuccessful. Surprisingly, transplantation of PBSC is not associated with an increased risk of acute GVHD, but is instead associated with a more rapid engraftment and an increased risk of chronic GVHD [74]. PBSC may be preferable for patients with advanced disease and elderly patients. Conversely, T cell depletion and marrow transplantation may be the preferred treatment for patients with early disease, non-malignant disease, and patients who are younger.

Other approaches to prevent GVHD use specific conditioning regimens [37] or specific cells to induce transplantation tolerance. Low dose total lymphoid irradiation in combination with ATG may spare natural killer T cells in the marrow and regulatory T cells suppressing GVHD, but allow graft-versus-leukemia/lymphoma effects. The addition of regulatory T cells to the graft has suppressed GVHD without inhibiting GVL effects in mice [75] and recently in humans (Martelli F, Plenary session ASH 2009). Another immunosuppressive cell product are me-senchymal stromal cells, which have been successful in the treatment of severe GVHD [76]. Co-transplantation of mesenchymal stromal cells prevented rejection in HLA-haploidentical transplants [77] and GVHD was less severe, but the difference did not reach significance be-cause of low numbers. We have used CD6-depleted PBSC transfused 6 days after trans-plantation of unmodified marrow from HLA-haploidentical donors with a low rate of acute GVHD [78].

Post-graft immunosuppressive treatment with either methotrexate or cyclophosphamide has been used since the early days of stem cell transplantation. Both agents preferably kill proli-ferating cells and should be started early after grafting. These drugs suppress donor cells proliferating in response to host antigens as well as residual host cells responding to the graft. They sustain engraftment and suppress GVHD at the same time. They induce transplantation tolerance by killing the responsive cells, and therefore patients with incomplete responses usually take a disastrous course. A recent application of this principle is the use of large doses of cyclophosphamide 3 and 4 days after HLA-haploidentical transplantation [35, 79].

The introduction of the calcineurin inhibitors cyclosporine A and tacrolimus has also changed the outlook for these patients. Both drugs inhibit the activation and proliferation of T cells by inhibiting dephosphorylation and translocation of the nuclear factor of activated T cells (NFAT). The continuous inhibition is effective in suppressing GVHD and rejection, but the effect is not necessarily maintained after discontinuation of treatment; calcineurin inhibitors are less potent in the induction of transplantation tolerance [80]. Treatment should be started prior to transplantation in order to avoid antigen recognition and T cell activation. Tacrolimus is a somewhat stronger immunosuppressive than cyclosporine A and possibly less neurotoxic. However, in controlled studies comparing tacrolimus and cyclosporine A less severe GVHD was not associated with improved survival [81].

The combination of cyclosporine A and methotrexate is better than either drug alone [82]. It has become the gold standard of GVHD prophylaxis. In recent years mycophenolate mofetil (MMF) has been introduced to replace methotrexate [83]. MMF inhibits the purine synthesis and the de novo pathway of guanosine nucleotide synthesis; it kills not only proliferating T cells, but also T cells in the interphase. MMF produces less mucositis and less marrow toxicity than methotrexate. However the best regimen and timing (2–3 times per day) remains unknown.

Sirolimus binds to the tacrolimus binding protein FKBP12 and forms a complex with mTOR (target of rapamycin) that inhibits several signal transduction pathways including PTEN, PI3kinase and AKT as well as the JANUS kinase pathway. Thereby it produces several ef-fects including immunosuppression of T cells, anti-angiogenesis and inhibition of tumor growth [84]. Its immunosuppressive activity is presumably linked to the suppression of the second signal of T cell activation. This way T cell apoptosis and specific peripheral non-responsiveness may be induced [85]. Th1 cells and their cytokines are more affected by siroli-mus than Th2 cells and regulatory T cells [86, 87]. The sirolimus/mTOR complex inhibits the ac-tivation signals of CD28 and CD40L stimulation and thereby the second signal essential for T cell activation [88], a situation that may lead to transplantation tolerance. The combination of sirolimus and tacrolimus is synergistic and has shown little toxicity [89], but veno-occlusive dis-ease of the liver and thrombotic microangiopathy have been observed [90]. The combination of sirolimus and MMF was promising in a smaller group of patients, where VOD and TMA were not observed [91].

The goal of preventing GVHD is the induction of tolerance in both directions, the host-versus-graft and graft-versus-host direction. Contrary to transplantation of solid organs, stem cell transplantation induces self-sustained tolerance without life-long immunosuppressive therapy. As a rule, a period of 4–6 months of immunosuppressive therapy is sufficient for tolerance to become established. In clinical terms tolerance is evident by persistent chimerism without GVHD and without severe infections more than 30 days after discontinuation of immunosuppression.  

Treatment

Glucocorticoids

Despite prophylactic treatment with immunosuppressive agents, acute GVHD requiring addi-tional treatment occurs in 40–80% of patients within 3–4 weeks of transplantation [92]. Corti-costeroid therapy is the standard of treatment for acute GVHD, but the regimen and the do-sage is still under discussion. Originally, treatment with large doses was favored [93], but there are no controlled studies to support this treatment. Similarly, in organ transplantation, rejection crises are treated with bolus methylprednisolone without prospective randomized trials supporting this. Despite this general use there are only a few studies on the schedule and the dosage rates. A randomized Italian trial comparing 2mg/kg per day with 10mg/kg per day showed no advantage for the higher dose [94], however 50% of patients were switched to a high dose because of insufficient response. Recently, a retrospective study from Seattle indi-cated that even lower doses of corticosteroids (1mg/kg instead of the standard 2 mg/kg) can be given without disadvantage [95]. However the patients of the low dose group had more fa-vorable risk factors and less severe GVHD; in addition oral non-absorbable corticosteroids were given more frequently.

The mechanisms of the actions of glucocorticoids are still not fully understood, lymphopenia is mainly due to sequestration of lymphocytes, and less to lympholysis. However, glucocorti-coids exhibit strong anti-inflammatory effects in several ways including genomic and non-genomic pathways [96]. Glucocorticoids are bound to a receptor from which heat shock protein 70 is released. The glucocorticoid complex activates anti-inflammatory proteins directly and their production genomically. Inhibition of nuclear factor kB is highly sensitive to glucocortico-ids preventing the production of inflammatory proteins. Sensitivity to the treatment with glu-cocorticoids may be determined by the relative levels of glucocorticoid receptor α and ß. This may explain interpatient variation of sensitivity [97]; memory T cells [98] as well as mature den-dritic cells are less sensitive to glucocorticoids. In macrophages low doses of glucocorticoids stimulate the production of proinflammatory cytokines, whereas high doses suppress it [99]. High dose glucocorticoid therapy given for few days has shown little immune suppression in vivo [100].

Commonly treatment is started in patients with clinical grade II–IV severity of GVHD. About 40–50% of patients respond with resolution or improvement of clinical symptoms [92]. The re-mainder are classified as “steroid-refractory”. The time until refractoriness to glucocorticoids is stated may vary from 5 to 14 days [101]. Many centers increase the dose of steroids in re-fractory patients prior to the addition of other agents. We prefer to start with rather high doses of glucocorticoids (1–2mg/kg every 8 hours) and score the response after three days of treatment for refractoriness. This way we initiate secondary treatment early in refractory pa-tients. The decision to start the treatment is made by two physicians. In the case of a pro-gressive and characteristic skin rash the diagnosis is not difficult, but in cases of isolated ga-strointestinal GVHD with diarrhea and nausea or isolated hepatic GVHD the diagnosis may be more difficult. Persistent toxicity of the conditioning treatment, veno-occlusive disease of the liver, drug-induced changes and viral infections are considered as differential diagnosis. In our centre skin biopsies are regularly performed, biopsies of gut and liver are only made in patients that do not respond to the treatment. This way we obtain not only histological con-firmation of the clinical suspicion, but also information about viral infection. Concomitant vi-rostatic treatment is given to patients with biopsies positive for viral infection as well as those that are seropositive for cytomegalovirus. Another option is the use of high doses of iv immu-noglobulins that may inhibit the deleterious effects of FAS by their blockade of FAS-L [102]. Al-though their immune modulating effects are far from understood [103], 20–30% of patients with skin GVHD do respond to the treatment with iv immunoglobulins. In any case early treatment is important as delay of the start of treatment until the results of laboratory investigations are available may jeopardize the response to glucocorticoids.

The effect of systemic glucocorticoids on gastrointestinal GVHD can be improved by local treatment with beclomethasone [104] and budesonide [105].

Antibodies

In many instances the first choice in patients with steroid refractory GVHD has been immu-nosuppressive antibodies. Antithymocyte globulin (ATG) has been used in several uncon-trolled studies with some success [106], but in controlled studies a beneficial effect could not be demonstrated [107]. Similarly, OKT3 is a monoclonal antibody against CD3 on T cells: it dep-letes T cells and stimulates proliferation by its mitogenic activity. Even though many patients have responded to the treatment with OKT3 with complete remission of GVHD, better surviv-al could not be demonstrated in controlled clinical trials [108]. Alemtuzumab has been used mainly for prophylaxis of acute GVHD by treating the patient in vivo or the graft prior to transplantation ex vivo: recently beneficial outcomes of treatment of established GVHD have been reported in two uncontrolled studies [109, 110]. Viral infections may complicate treatment with alemtuzumab; therefore regular control and pre-emptive treatment is necessary. ATG and OKT3 both stimulate proliferation of lymphocytes that are not killed by cytolysis; there-fore the combination of antibody treatment with chemotherapy (methotrexate, Cyclophos-phamide, mycophenolate mofetil, etc.) may be beneficial. A humanized CD3-antibody (visili-zumab) produced good first results [111] which unfortunately were not confirmed in multicenter trials [112]. In those patients the reactivation of EBV and the incidence of post transplant lym-phoproliferative disease (PTLD) increased.

Encouraging results were also reported with ABXCBL, an antibody against CD147 that is ex-pressed in activated T cells [113]. However in a comparative study ABXCBL was not better than ATG, where survival was even inferior [114].

Antibodies against tumor necrosis factor α (TNF-a) and soluble receptors of TNF-a (etaner-cept) have been studied in the prophylaxis of GVHD [20] and the treatment of steroid refractory GVHD [115]. There has been a high rate of complete response to infliximab even in gastrointes-tinal GVHD, but this is complicated by an increased risk of fungal infections [116, 117]. Contrary to infliximab etanercept neutralizes soluble TNF-a without affecting TNF-a in phagocytic cells. Etanercept is associated with a lower risk of fungal infections. The combination of etanercept with an anti-IL2-receptor antibody showed high response rates to acute GVHD, but the long-term survival was rather poor [118]. In comparison, a pilot trial of etanercept in combination with tacrolimus and steroids gave a 75% complete response and a 50% survival rate [119]. When comparing etanercept combined with steroids to steroids alone a significantly better response to the combination was observed [120]. The combination of etanercept with ATG and tacrolimus was compared to ATG and tacrolimus alone [121]; considering the limited number of patients the response and the survival of patients given etanercept was better. Neutralization of TNF-a released by the ATG treatment by etanercept may have been contributing to the better outcome.

Antibodies against IL-2 receptor have been studied early [122] with some transient success. The importance of an early treatment start was stressed. Several studies with humanized anti-IL2-receptor antibodies were encouraging [123, 124], but a randomized study was stopped prematurely because of inferior survival of the antibody (daclizumab) group [125]. There is little doubt that the IL2- receptor antibody is effective in suppressing GVHD of the skin and the gut when started early, but it may have an adverse effect on the generation of regulatory T cells expressing high levels of the IL-2 receptor.

Alefacept is a fusion protein of the CD2-binding domain of LFA-3 and the Fc portion of IgG with specific activities against memory T cells [126]. Promising results in steroid refractory acute GVHD and in chronic GVHD have been reported, but there may be an increased risk of viral and fungal infections [127].

Recently, the role of B cells has been discussed more frequently, although the role of T cells in GVHD is not disputed. However, cytotoxic antibodies may be produced in HLA-mismatched chimeras, and depletion of B cells may prevent EBV-induced B cell lymphoma. Single patients have been reported to show a response to steroid refractory GVHD to the treatment with rituximab [128].

Drugs

As a rule the treatment given for prophylaxis is continued during the treatment of established GVHD, and includes glucocorticoids at a low level. Depending on the prophylactic regimen, cyclosporine A may be substituted by tacrolimus and new drugs may be added. In most Eu-ropean centers a calcineurin inhibitor is combined with methotrexate or mycophenolate mofe-til. In patients not treated prophylactically a trial with mycophenolate mofetil may be justified; a response rate of 47–48% has been reported in steroid refractory GVHD, but the survival at 6 and 12 months was not improved [129]. Methotrexate on a weekly basis in low doses has been helpful in single cases. Mucositis and myelosuppression are limiting factors.

Similarly, sirolimus can be used for patients not treated prophylactically, as response rates of 77% overall and 44–72% complete response have been reported [130, 131]. Again microangiopa-thy has been a problem, but could be controlled by discontinuation of the calcineurin inhibitor (CNH) or both sirolimus and CNH. A small study suggests a good response of acute GVHD to sirolimus without prior treatment with glucocorticoids [132]. Due to its anti-tumor activity siro-limus is preferred to calcineurin inhibitors and glucocorticoids by many investigators [133], par-ticularly in patients with lymphoma [134].

Pentostatin is an inhibitor of the salvage pathway of thymidine kinase that is specific for T cells. Phase I studies have shown efficacy in the treatment of steroid-refractory GVHD [135]. A retrospective analysis has shown activity comparable to other immunosuppressive regimens [136]. However, pentostatin has shown activity in the treatment of chronic GVHD [137, 138]. Pentostatin may have better effects in patients with chronic GVHD.

Thalidomide [139, 140] and more recently lenalidomide [141] have been studied in the treatment of GVHD. The initially positive results of treatment with thalidomide in chronic GVHD [139] were not confirmed in a randomized study [140]. The treatment of recurrent myeloma with lenalido-mide suggested an immune modulatory effect of lenalidomide in producing regulatory T cells [141].

Bortezomib has been tested in mice [142] and patients with HLA-mismatched unrelated donors [143]. The immunomodulatory effect has been related to the suppression of monocyte-derived dendritic cells and modified antigen presentation and release of TNF-a from CD4-positive T cells [142]. It has shown promising activity in the prophylaxis of GVHD [143].

After the description of activating antibodies against the receptor of platelet derived growth factor (PDGF) [144] in patients with systemic sclerosis similar antibodies were found in patients with sclerodermatous chronic GVHD [145] and several groups have treated sclerodermatous chronic GVHD [146, 147], as well as obliterating bronchiolitis with imatinib [148, 145]. In one study more than 70% of patients with sclerotic chronic GVHD responded with partial and complete remissions [147].

Cells

Many treatment regimens of GVHD favor the development of regulatory T cells characterized by the expression of CD 4 and CD25 in high density [149]. The suppressive activity is limited to cells of the CD4/CD25 immune phenotype that are positive for FoxP3 mRNA. Typically regulatory T cells should be negative for the IL7 receptor (CD127). Immunomagnetically selected regulatory T cells have been tested in vitro for immunosuppressive effects [149, 150], and preliminary applications for the treatment of refractory GVHD have been promising (M. Edinger, pers. comm.). The first results of preventive application have been reported (Di Ianni et al. ASH 2009); 17 of 20 evaluable patients did not produce GVHD after HLA-haploidentical stem cell transplantation despite admixture of a limited amount of conventional T cells to the CD34-selected graft.

More information is available on the treatment of refractory GVHD with mesenchymal stromal cells [76]. The results were confirmed in a multicenter study of the EBMT involving [151] 55 patients with steroid-refractory GVHD. Twenty-seven patients received one dose, 22 two doses and 6 three doses and more from HLA-mismatched or HLA-matched donors for treatment; 30 patients had a complete response, and an improvement was seen in 9 patients. Responders had a better chance of survival than non-responders. Mesenchymal stem cells have multiple properties including differentiation into bone, cartilage, tendon and muscle cells, repair of damaged tissue and modulation of immune responses [36].

UV light

Ultraviolet light has immunosuppressive properties [152]. UV-A in combination with 8-methoxypsoralen (PUVA) has been used to treat chronic GVHD [153]. UVA may be applied to the skin in combination with oral psoralen or with a bath in psoralen containing water. PUVA treatment was studied in 103 patients with steroid-resistant acute GVHD [154] with good res-ponses in GVHD of the skin and sparing of glucocorticoid doses. The treatment was well to-lerated, but it may induce a flare before lichenoid skin changes respond to the treatment. In chronic GVHD 31 of 40 patients had an improvement following PUVA treatment, but partial and complete responses were limited to the skin [155]. Best responses were seen in the liche-noid phases of chronic GVHD, and less in the sclerodermatous phases.  However, the com-bination of PUVA bath with oral isotretinoin has been effective in a small study of scleroder-matous chronic GVHD: 11 of 14 patients responded, four of these with complete remission [156].

Alternatively PUVA may be applied directly to the blood resp. leukocytes separated by a dis-continuous blood cell separator (extracorporeal photopheresis, ECP). Responses to ECP have been reported for steroid-refractory, acute GVHD [157-159] and chronic GVHD [160]. Complete resolution of acute GVHD of the skin in 82%, liver in 61% and gut in 61% of pa-tients has been reported [158]. Response was associated with better survival. In our own study of 30 patients with acute GVHD, 20 patients responded with CR and PR defined as steroid discontinuation and reduction to 10 mg or less per day respectively (unpublished). Eleven of 20 responders survived as compared to only one non-responder. Steroid treatment was a major risk factor in the treatment of acute GVHD of pediatric patients [161]. In a single centre study on steroid refractory chronic GVHD 22% of patients could discontinue steroid therapy after one year, with response to ECP and absence of thrombocytopenia being the favorable factors for survival [160]. A randomized prospective multicentre study [162] comparing standard treatment with standard treatment plus ECP showed improvement of the skin score and sig-nificant steroid sparing. ECP is a good treatment option in patients with steroid-refractory acute and chronic GVHD with little side effects. The mechanism of the immunosuppression by ECP is not completely understood as only 5–10% of all T cells may be reached by extra-corporeal irradiation. However, a shift of dendritic cells from activating DC1 to down-regulating DC2 and from Th1 to Th2 has been described in the course of ECP [163]. Ex vivo a decrease of T cells producing pro-inflammatory cytokines was described [164]. In a murine model ECP-treated T cells induced regulatory T cells in recipients with established GVHD [165]. An increase in the proportion of regulatory T cells was observed in patients that responded to ECP [166].  Therefore ECP may be one method to induce GVH-tolerance without too many side effects.

Induction of graft-versus-host tolerance

Unlike transplantation of solid organs, transplantation of hematopoietic stem cells induces transplantation tolerance, enabling immunosuppressive therapy to be discontinued. In the form of central tolerance, lymphoid progenitor cells derived from transplanted stem cells tra-vel to the thymus where T cells tolerant to the host’s tissue are produced [167-169]. However, the thymus shows progressive involution in adulthood; central tolerance may be the major form of tolerance in children and young adults. The majority of patients subjected to stem cell transplantation are older, and the thymus has shrunk to a small remnant. Therefore in the majority of our patients a peripheral form of tolerance prevails, but function of the thymus can be recovered even in elderly individuals [170]. Several studies have been performed to speed up recovery of the thymus, mostly without convincing success [171], but new agents may give better results [172, 173, 169]. However, GVHD may affect the thymus [174] and thereby may inhibit the induction of central tolerance in both young and adult patients. Peripheral tolerance is a first step and may be replaced by central tolerance with time. The mechanisms of tolerance may be similar, clonal deletion, clonal anergy, and suppression.

Clonal deletion is a mechanism of self tolerance occurring in the thymus [175]; in the case of allogeneic stem cell transplantation T cells of donor origin derived from lymphoid progenitors may be eliminated by the same mechanism and primed towards host MHC antigens in se-miallogeneic hosts [176]. Deletion in the periphery may be accomplished by the treatment with antimetabolite drugs such as methotrexate, or cycle active drugs like cyclophosphamide; both of which have been shown to induce tolerance in stem cell transplanted patients [177, 178]. The principle of selective depletion of responsive lymphocytes has been applied more recently in HLA-haploidentical transplantation [179]. Unlike these cytotoxic agents calcineurin inhibitors do not kill the responsive cells, but inhibit cytokine production and thereby the progress of the immune response. However they may not favor the induction of tolerance; flares of GVHD have been observed after discontinuation of cyclosporin A, and late rejection of marrow grafts have been reported in single patients with aplastic anemia. Activation induced cell death (AICD) is a natural decrease of the clone size by IFN-g secretion of mature Th1 T cells and death of immature T cells, which may be achieved by the external pathway.  

Clonal anergy may be the result of competitive inhibition by anergic T cells or active sup-pression by a variety of suppressor cells. Formerly, CD8-positive T cells were considered “cytotoxic/suppressor” cells, but the evidence for specific suppression was weak. Instead, several mechanisms of suppression have been described including “veto” cells suppressing the immune reaction against themselves [180]. The veto mechanism, described as the effector cells inhibiting or killing themselves has been primarily ascribed to CD8-positive T cells, but later also to other cells including stem cells. CD8-positive suppressor cells may not only func-tion as veto cells, but they may also suppress third party reactions by the secretion of FAS [181>]. Other cells with suppressor function are myeloid derived suppressor cells [182], NKT cells in the marrow [183], NK cells [184], dendritic cells type 2 [185] and mesenchymal stromal cells [76]; all of them suppress activated T cells more or less specifically. Some of these have already shown clinical effectiveness [183, 76], others are still in a developmental state. In recent years the detection of FoxP3 (forkhead transcription factors) showed suppressive function of CD4, CD25 positive T cells and even CD8 T cells [186]. Naïve CD4, CD25-positive regulatory T cells are able to down regulate allogeneic immune responses without inhibiting graft-versus-leukemia responses [75]. These may be naïve and non-specifically down regulating dendritic cells or adaptive and directed against specific antigen. Recently the Perugia group has reported the use of naïve regulatory T cells suppressing GVHD in patients given HLA-haploidentical transplants including small amounts of conventional T cells (ASH 2009, New Orleans).

Rapamycin exerts differential effects on T cells, inhibiting CD8 positive cells more than CD4 positive cells [86]; CD4 T cells spared by Rapamycin may become regulatory T cells without compromising GVL reactions [133]. Long-term observations of patients treated with Rapamycin and tacrolimus are encouraging with regard to control of acute GVHD and GVL [89]. Chronic GVHD still remains a problem despite tolerogenic effects of Rapamycin. Recently, the Milan group [187] (EBMT 2010) has reported generation of regulatory T cells in patients with HLA-haploidentical transplants. After conditioning with treosulfan, fludarabine, ATG and rituximab, and GVH prophylaxis with Rapamycin and mycophenolate mofetil, immune reconstitution was better than after transplantation of CD34-selected transplants, and regulatory T cells were detected early after transplantation.

Tolerogenic effects have also been described for the treatment with extracorporeal photo-pheresis (ECP) [188]. In acute GVHD ECP was applied with good results [158]. In most patients the effects of ECP are not immediate, but occur after some weeks. ECP has also beneficial effects against chronic GVHD [162] and may be preferable to other treatments for GVHD.

The main goal of prophylactic and therapeutic treatment of GVHD should be the induction of transplantation tolerance. Therefore treatment protocols interfering with tolerance should be avoided in protracted periods in favor of regimens allowing the development of tolerance. Glucocorticoids and calcineurin inhibitors are effective in controlling the acute disease, but they do not support the development of tolerance. Similarly, IL2-R antibodies may be effec-tive in the acute control of GVHD, but may not support the development of tolerance. Toler-ance may be achieved by depletion of mature T cells from the graft, killing of antigen respon-sive T cells with cell cycle active chemotherapy as Cyclophosphamide, methotrexate, or my-cophenolate mofetil, activating CTLA4 receptors by CTLA4-Ig or using drugs like Rapamycin that block the co-stimulatory pathway or ECP producing apoptotic cells that induce tolerance.

Future prospects

The time point to initiate treatment of acute and chronic GVHD is of paramount importance. Therefore, early diagnosis tests, before clinical diagnosis is possible, may improve the out-come significantly. Several proteins have been found in the urine of patients that developed GVHD [189]; a prospective study will help to demonstrate the value of early treatment. Similarly, elafin has been identified as a prognostic marker in the plasma of patients developing skin GVHD [190]. Early diagnosis will allow early treatment and thereby avoid the development of memory T cells or T stem cells with memory that are extremely difficult to suppress.

References

1. Barnes DHW, Loutit JF. Spleen protection: the cellular hypothesis. In: Bacq ZM and Alexander P: Radiobiology Symposium : Proceedings of the Symposium held at Liege, August-September, 1954. London: Butterworths, 1955:134-135.

2. Simonsen M, Jensen E. The graft-versus-host assay in transplantation chimeras. In: Albert F, Lejeune-Ledant G, eds. Biological problems of grafting. Oxford: Blackwell; 1959:214-236.

3. Uphoff, D. E. and Law, P. Genetic factors influencing irradiation protection by bone marrow. II. The histocompatibility 2 (H-2) locus. J Natl Cancer Inst 20, 617-624. 1958. pmid: 13539612.

4. van Bekkum, D. W. The selective elimination of immunologically competent cells from bone marrow and lymphatic cell mixtures. I.Effect of storage at 4°C. Transplantation 2, 393-404. 1964.

5. Billingham, RE. The biology of graft-versus-host reactions. Harvey Lect 1966-1967 62, 21-78. 1967. pmid: 4875305.

6. Mathé G, Amiel JL, Schwartzenberg L, et al. Successful allogeneic bone marrow transplantation in man: Chimerism, induced specific tolerance and possible antileukemic effects. Blood 1965;25:179-96. pmid: 14267694.

7. Epstein RB, Storb R, Ragde H, Thomas ED. Cytotoxic typing antisera for marrow grafting in littermate dogs. Transplantation 1968;6:45-58. pmid: 4866738.

8. Dausset J, Rapaport FT, Colombani J, Feingold N. A leucocyte group and its relationship to tissue histocompatibility in man. Transplantation 1965;3:701-705. pmid: 5324831.

9. van Rood JJ, van Leeuwen A, Eernisse JG, Frederiks E and Bosch LJ. Relationship of Leukocyte groups to tissue transplantation compatibility. Ann.N.Y.Acad.Sci. 1964;120:285-298.

10. Thomas ED, Storb R, Epstein RB, Rudolph RH. Symposium on bone marrow transplantation: experimental aspects in canines. Transplant.Proc. 1969;1:31-33. pmid: 5002661.

11. Hoffmann P, Ermann J, Edinger M, Fathman CG, Strober S. Donor-type CD4(+)CD25(+) regulatory T cells suppress lethal acute graft-versus-host disease after allogeneic bone marrow transplantation. J.Exp.Med. 2002;196:389-399.

12. Yi T, Chen Y, Wang L et al. Reciprocal differentiation and tissue-specific pathogenesis of Th1, Th2, and Th17 cells in graft-versus-host disease. Blood 2009;114:3101-3112. doi: 10.1182/blood-2009-05-219402.

13. Korngold R, Sprent J. Surface markers of T cells causing lethal graft-vs-host disease to class I vs class II H-2 differences. J Immunol. 1985;135:3004-3010. pmid: 3876371.

14. Klein J, Sato A. The HLA system. First of two parts. N Engl J Med. 2000 Sep 7;343(10):702-9 .doi: 10.1056/NEJM200009073431006.

15. Klein J, Sato A. The HLA system. Second of two parts. N Engl J Med. 2000 Sep 14;343(11):782-6. Review. Erratum in: N Engl J Med 2000 Nov 16;343(20):1504. doi: 10.1056/NEJM200009143431106.

16. Robertson, NJ, Chai J-G, Millrain, M, Scott, D, Hashim, F, Maktelov, E, Lemonnier, F, Simpson, E, and Dyson, J. Natural regulation of immunity to minor histocompatibililty antigens. J Immunol 178, 3558-3565. 2007.

17. Sprent J, Surh CD, Agus D et al. Profound atrophy of the bone marrow reflecting mature histocompatibility complex class II restricted destruction of stem cells by CD4+ cells. J.Exp.Med. 1994;180:307-317.

18. Holler E, Kolb HJ, Hiller E et al. Microangiopathy in patients on cyclosporine prophylaxis who developed acute graft-versus-host disease after HLA-identical bone marrow transplantation. Blood 1989;73:2018-2024.

19. Ferrara JLM, Deeg HJ. Graft-versus-host disease. N Engl J Med 1991;324:667-674. doi: 10.1056/NEJM199103073241005.

20. Holler E, Kolb HJ, Mittermüller J et al. Modulation of acute graft-versus-host disease after allogeneic bone marrow transplantation by tumor necrosis factor (TNF) release in the course of pretransplant conditioning: Role of conditioning regimens and prophylactic application of a monoclonal antibody neutralizing human TNF (MAK 195F). Blood 1995;86:890-899.

21. Reinhardt, RL, Khoruts A, Merica R, Zell T, and Jenkins MK. Visualizing the generation of memory CD4 T cells in the whole body. Nature 410, 101-105. 2001. doi: 10.1038/35065111.

22. Wysocki CA, Panoskaltsis-Mortari A, Blazar BR, and Serody JS. Leukocyte migration and graft-versus-host disease. Blood. 2005;105:4191-4199. doi 10.1182/blood-2004-12-4726.

23. Kolb HJ, Mittermueller J, Holler E, et al. Treatment of recurrent chronic myelogenous leukemia posttransplant with interferone alpha (INFa) and donor leukocyte transfusions [abstract]. Blut. 1990;61:122.

24. Hessel H, Mittermuller J, Zitzelsberger H, Weier HU, Bauchinger M. Combined immunophenotyping and FISH with sex chromosome-specific DNA probes for the detection of Langerhans cells after sex-mismatched bone marrow transplantation. Histochem Cell Biol. 1996;106:481-485. pmid: 8950606.

25. Teshima T, Ordemann R, Reddy P, et al. Acute graft-versus-host disease does not require alloantigen expression on host epithelium. Nat Med. 2002;8:575-581. doi: 10.1038/nm0602-575.

26. Shlomchik WD, Couzens MS, Tang CB, et al. Prevention of graft versus host disease by inactivation of host antigen-presenting cells. Science 1999;285:412-415. pmid: 10411505. PDF: Free with Registration at http://www.sciencemag.org/content/285/5426/412.long

27. Matte CC, Liu J, Cormier J, et al. Donor APCs are required for maximal GVHD but not for GVL. Nat.Med. 2004;10:987-992. doi: 10.1038/nm1089.

28. Tutschka PJ, Hess AD, Beschorner WE, Santos GW. Suppressor cells in transplantation tolerance. I. Suppressor cells in the mechanism of tolerance in radiation chimeras. Transplantation 1981;32:203-209. pmid: 6456580.

29. Tutschka PJ, Ki PF, Beschorner WE, Hess AD, Santos GW. Suppressor cells in transplantation tolerance. II. maturation of suppressor cells in the bone marrow chimera. Transplantation 1981;32:321-325. pmid: 6460354.

30. Tutschka PJ, Hess AD, Beschorner WE, Santos GW. Suppressor cells in transplantation tolerance. III. The role of antigen in the maintenance of transplantation tolerance. Transplantation 1982;33:510-514. pmid: 6211807.

31. Weiden PL, Storb R, Tsoi M-S, et al. Infusion of donor lymphocytes into stable canine radiation chimeras: Implications for mechanism of transplantation tolerance. J.Immunol. 1976;116:1212-1219. pmid: 774975.

32. Kolb HJ, Günther W, Schumm M, et al. Adoptive immunotherapy in canine chimeras. Transplantation 1997;63:430-436. pmid: 9039935.

33. Zorn J, Herber M, Schwamberger S, et al. Tolerance in DLA-haploidentical canine littermates following CD6-depleted marrow transplantation and donor lymphocyte transfusion. Exp Hematol. 2009;37:998-1006. doi: 10.1016/j.exphem.2009.05.001.

34. Ruggeri L, Capanni M, Urbani E, et al. Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Science. 2002;295:2097-2100. doi: 10.1126/science.1068440.

35. Luznik L, O'Donnell PV, Symons HJ, et al. HLA-haploidentical bone marrow transplantation for hematologic malignancies using nonmyeloablative conditioning and high-dose, posttransplantation cyclophosphamide. Biol.Blood Marrow Transplant 2008;14:641-650. doi: 10.1016/j.bbmt.2008.03.005.

36. Le BK, Ringden O. Mesenchymal stem cells: properties and role in clinical bone marrow transplantation. Curr.Opin.Immunol. 2006;18:586-591. doi: 10.1016/j.coi.2006.07.004 .

37. Lowsky R, Takahashi T, Liu YP, et al. Protective conditioning for acute graft-versus-host disease. N.Engl.J Med. 2005;353:1321-1331. doi: 10.1056/NEJMoa050642.

38. Gratwohl A, Brand R, Apperley J, et al. Graft-versus-host disease and outcome in HLA-identical sibling transplantations for chronic myeloid leukemia. Blood.doi: 10.1182/blood.V100.12.3877 2002;100:3877-3886.

39. Shlomchik WD. Graft-versus-host disease. Nat.Rev.Immunol. 2007;7:340-352. doi: 10.1038/nri2000.

40. Petersdorf EW, Malkki M. Genetics of risk factors for graft-versus-host disease. Semin.Hematol. 2006;43:11-23. doi: 10.1053/j.seminhematol.2005.09.002.

41. Petersdorf EW, Hansen JA, Martin PJ, et al. Major-histocompatibility-complex class I alleles and antigens in hematopoietic-cell transplantation. N.Engl.J Med. 2001;345:1794-1800. doi: 10.1056/NEJMoa011826.

42. Sasazuki T, Juji T, Morishima Y et al. Effect of matching of class I HLA alleles on clinical outcome after transplantation of hematopoietic stem cells from an unrelated donor. Japan Marrow Donor Program [see comments] [published erratum appears in N Engl J Med 1999 Feb 4;340(5):402]. N Engl J Med. 1998;339:1177-1185.

43. Petersdorf EW. Risk assessment in haematopoietic stem cell transplantation: histocompatibility. Best.Pract.Res.Clin.Haematol. 2007;20:155-170. doi: 10.1016/j.beha.2006.09.001.

44. Kawase T, Matsuo K, Kashiwase K et al. HLA mismatch combinations associated with decreased risk of relapse: implications for the molecular mechanism. Blood 2009;113:2851-2858. doi: 10.1182/blood-2008-08-171934.

45. Baron C, Somogyi R, Greller LD, et al. Prediction of graft-versus-host disease in humans by donor gene-expression profiling. PLoS.Med. 2007;4:e23. doi: 10.1371/journal.pmed.0040023.

46. Dickinson AM, Pearce KF, Norden J, et al. Impact of genomic risk factors on outcome after hematopoietic stem cell transplantation for patients with chronic myeloid leukemia. Haematologica. 2010.Jun;95(6):922-7. Epub 2010 Mar 19. doi: 10.3324/haematol.2009.016220.

47. Holler E, Rogler G, Herfarth H, et al. Both donor and recipient NOD2/CARD15 mutations associate with transplant-related mortality and GvHD following allogeneic stem cell transplantation. Blood. 2004;104:889-894. doi: 10.1182/blood-2003-10-3543.

48. Goulmy E. Human minor histocompatibility antigens: New concepts for marrow transplantation and adoptive immunotherapy. Immunol.Rev. 1997;157:125-140.

49. Falkenburg JH, Wafelman AR, Joosten P, et al. Complete remission of accelerated phase chronic myeloid leukemia by treatment with leukemia-reactive cytotoxic T lymphocytes. Blood. 1999;94:1201-1208.

50. Spellman S, Warden MB, Haagenson M, et al. Effects of mismatching for minor histocompatibility antigens on clinical outcomes in HLA-matched, unrelated hematopoietic stem cell transplants. Biol.Blood Marrow Transplant. 2009;15:856-863.

51. Glucksberg H, Storb R, Fefer A, et al. Clinical manifestations of graft-versus-host disease in human recipients of HL-A-matched sibling donors. Transplantation 1974;18:295-304. pmid: 4153799.

52. Kolb H, Sale GE, Lerner KG, Storb R, Thomas ED. Pathology of acute
graft-versus-host disease in the dog. An autopsy study of ninety-five dogs. Am J Pathol. 1979 Aug;96(2):581-94.

53. Rowlings PA, Przepiorka D, Klein JP, et al. IBMTR severity index for grading acute graft-versus-host disease: retrospective comparison with Glucksberg grade. Br J Haematol 1997;97:855-864.

54. Cahn JY, Klein JP, Lee SJ, et al. Prospective evaluation of 2 acute graft-versus-host (GVHD) grading systems: a joint Societe Francaise de Greffe de Moelle et Therapie Cellulaire (SFGM-TC), Dana Farber Cancer Institute (DFCI), and International Bone Marrow Transplant Registry (IBMTR) prospective study. Blood. 2005;106:1495-1500.

55. Salat C, Holler E, Kolb HJ, et al. Endothelial cell markers in bone marrow transplant recipients with and without acute graft-versus-host disease. Bone Marrow Transplant, 1997;19:909-914.

56. Tichelli A, Passweg J, Wojcik D, et al. Late cardiovascular events after allogeneic hematopoietic stem cell transplantation: a retrospective multicenter study of the Late Effects Working Party of the European Group for Blood and Marrow Transplantation. Haematologica. 2008;93:1203-1210.

57. Sullivan KM, Deeg HJ, Sanders J, et al. Hyperacute graft-v-host disease in patients not given immunosuppression after allogeneic marrow transplantation. Blood. 1986;67:1172-1175. pmid: 3513869.

58. Rodt H, Netzel B, Brehm G, Thierfelder S. Production of antibodies specific for human thymus derived lymphocytes purified from antibodies crossreacting with colony-forming cells. Blut. 1974;29:416-422. pmid: 4548852.

59. Kolb HJ, Rieder I, Rodt H, et al. Antilymphocytic antibodies and marrow transplantation. VI. Graft- versus-host tolerance in DLA-incompatible dogs after in vitro treatment of bone marrow with absorbed antithymocyte globulin. Transplantation. 1979;27:242-245. pmid: 35870.

60. Rodt H, Thierfelder S, Bender-Gotze C, et al. Serological inhibition of graft versus host disease: recent results in 28 patients with leukemia. Haematol.Blood Transfus. 1983;28:92-96. pmid: 6345300.

61. Goldman JM, Apperley J, Jones L, et al. Bone marrow transplantation for patients with chronic myeloid leukemia. N Engl J Med 1986;314:202-207. pmid: 6345300.

62. Kernan NA, Collins NJ, Juliano L, et al. Clonable T-lymphocytes in T-depleted bone marrow transplants correlate with development of graft-versus-host disease. Blood. 1986;68:770-773.

63. Schumm M, Günther W, Kolb HJ, et al. Prevention of graft-versus-host disease in DLA-haplotype mismatched dogs and hemopoietic engraftment of CD6-depleted marrow with and without cG-CSF treatment after transplantation. Tissue Antigens 1994;43:170-178. pmid:  7522357.

64. Soiffer RJ, Ritz J. Selective T cell depletion of donor allogeneic marrow with anti-CD6 monoclonal antibody: rationale and results. Bone Marrow Transplant 1993;12 Suppl 3:S7-10. pmid: 8124262.

65. Ho VT, Kim HT, Li S, et al. Partial CD8+ T-cell depletion of allogeneic peripheral blood stem cell transplantation is insufficient to prevent graft-versus-host disease. Bone Marrow Transplant. 2004;34:987-994.

66. Guenther W, Kolb HJ, Schumm M, Thierfelder S, Wilmanns W. Suppressive- and veto-effect of canine bone marrow cells [abstract]. 3rd Int Vet Immun Symp Abstractbook 1992.

67. Goldman JM, Gale RP, Horowitz MM, et al. Bone marrow transplantation for chronic myelogenous leukemia in chronic phase: Increased risk of relapse associated with T-cell depletion. Ann.Intern.Med. 1988;108:806-814. pmid: 3285744.

68. Kolb HJ, Rodt H, Netzel B, et al. In vitro treatment of marrow with ATCG or Campath 1 for prophylaxis of GVHD - Results of the AG-KMT München. Exp Hematol 1985;13:147.

69. Finke J, Bethge WA, Schmoor C, et al. Standard graft-versus-host disease prophylaxis with or without anti-T-cell globulin in haematopoietic cell transplantation from matched unrelated donors: a randomised, open-label, multicentre phase 3 trial. Lancet Oncol. 2009;10:855-864.

70. Bacigalupo A, Lamparelli T, Bruzzi P, et al. Antithymocyte globulin for graft-versus-host disease prophylaxis in transplants from unrelated donors: 2 randomized studies from Gruppo Italiano Trapianti Midollo Osseo (GITMO). Blood. 2001;98:2942-2947.

71. Morris EC, Rebello P, Thomson KJ, et al. Pharmacokinetics of alemtuzumab used for in vivo and in vitro T-cell depletion in allogeneic transplantations: relevance for early adoptive immunotherapy and infectious complications. Blood. 2003;102:404-406.

72. Peggs KS, Sureda A, Qian W, et al. Reduced-intensity conditioning for allogeneic haematopoietic stem cell transplantation in relapsed and refractory Hodgkin lymphoma: impact of alemtuzumab and donor lymphocyte infusions on long-term outcomes. Br.J Haematol. 2007;139:70-80.

73. Peggs KS, Thomson K, Hart DP, et al. Dose-escalated donor lymphocyte infusions following reduced intensity transplantation: toxicity, chimerism, and disease responses. Blood. 2004;103:1548-1556

74. Bensinger WI, Martin PJ, Storer B, et al. Transplantation of bone marrow as compared with peripheral-blood cells from HLA-identical relatives in patients with hematologic cancers. N.Engl.J.Med. 2001;344:175-181.

75. Edinger M, Hoffmann P, Ermann J, et al. CD4+CD25+ regulatory T cells preserve graft-versus-tumor activity while inhibiting graft-versus-host disease after bone marrow transplantation. Nat.Med. 2003;9:1144-1150. pmid: 12925844.

76. Le BK, Rasmusson I, Sundberg B, et al. Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells. Lancet. 2004;363:1439-1441. pmid: 15121408.

77. Ball LM, Bernardo ME, Roelofs H, et al. Cotransplantation of ex vivo expanded mesenchymal stem cells accelerates lymphocyte recovery and may reduce the risk of graft failure in haploidentical hematopoietic stem-cell transplantation. Blood. 2007;110:2764-2767.

78. Kolb HJ, Simoes B, Hoetzl F, et al. CD6-negative mobilized blood cells facilitating HLA-haploidentical marrow transplantation for the treatment of high-risk hematopoietic neoplasia. [abstract]. Blood. 2002;100:637a.

79. O'Donnell PV, Luznik L, Jones RJ, et al. Nonmyeloablative bone marrow transplantation from partially HLA-mismatched related donors using posttransplantation cyclophosphamide. Biol.Blood Marrow Transplant. 2002;8:377-386.

80. White DJ, Lim SM. The induction of tolerance by cyclosporine. Transplantation 1988;46:118S-121S. pmid: 3043793.

81. Nash RA, Antin JH, Karanes C, et al. Phase 3 study comparing methotrexate and tacrolimus with methotrexate and cyclosporine for prophylaxis of acute graft-versus-hiost disease after marrow transplantation from unrelated donors. Blood. 2002;96:2062-2068.

82. Storb R, Deeg HJ, Whitehead J, et al. Methotrexate and cyclosporine compared with  cyclosporine alone for prophylaxis of acute graft-versus-host disease after marrow transplantation for leukemia. N Engl J Med 1986;314:729-735. pmid: 3513012.

83. Bolwell B, Sobecks R, Pohlman B, et al. A prospective randomized trial comparing cyclosporine and short course methotrexate with cyclosporine and mycophenolate mofetil for GVHD prophylaxis in myeloablative allogeneic bone marrow transplantation. Bone Marrow Transplant. 2004;34:621-625.

84. Seghal SN. Sirolimus: its discovery, biological properties, and mechanism of action. Transplant Proc 2003;35:7S-14S. pmid: 12742462.

85. Wells AD, Li XC, Li Y, et al. Requirement for T-cell apoptosis in the induction of peripheral transplantation tolerance. Nat Med 1999;5:1303-1307. pmid: 10545998.

86. Blazar BR, Taylor PA, Panoskaltsis-Mortani A, Vallera DA. Rapamycin inhibits the generation of graft-versus-host disease- and graft-versus-leukemia-causing T cells by interfering with the production of Th1 or Th1 cytotoxic cytokines. J Immunol 1998;160:5355-5365.

87. Battaglia M, Stabilini A, Roncarolo MG. Rapamycin selectively expands CD4+CD25+?FoxP3+ regulatory T cells. Blood. 2005;105:4743-4748.

88. Yu X, Carpenter P, Anasetti C. Advances in transplantation tolerance. Lancet 2001;357:1959-1963. pmid: 11425437.

89. Cutler C, Li S, Ho VT, et al. Extended follow-up of methotrexate-free immunosuppression using sirolimus and tacrolimus in related and unrelated donor peripheral blood stem cell transplantation. Blood. 2007;109:3108-3114.

90. Rodriguez R, Nakamura R, Palmer JM, et al. A phase II pilot study of tacrolimus/sirolimus GVHD prophylaxis for sibling donor hematopoietic stem cell transplantation using 3 conditioning regimens. Blood. 2010;115:1098-1105.

91. Schleuning M, Judith D, Jedlickova Z, et al. Calcineurin inhibitor-free GVHD prophylaxis with sirolimus, mycophenolate mofetil and ATG in Allo-SCT for leukemia patients with high relapse risk: an observational cohort study. Bone Marrow Transplant. 2009;43:717-723.

92. Deeg HJ. How I treat refractory acute GVHD. Blood. 2007;109:4119-4126.

93. Bacigalupo A, van Lint MT, Frassoni F, et al. High dose bolus methylprednisolone for the treatment of acute graft versus host disease. Blut. 1983;46:125-132. pmid: 6337655.

94. van Lint MT, Uderzo C, Locasciulli A, et al. Early treatment of acute graft-versus-host disease with high- or low-dose 6-methylprednisolone: a multicenter randomized trial from the Italian Group for Bone Marrow Transplantation. Blood. 1998;92:2288-2293.

95. Mielcarek M, Storer BE, Boeckh M, et al. Initial therapy of acute graft-versus-host disease with low-dose prednisone does not compromise patient outcomes. Blood. 2009;113:2888-2894.

96. Rhen T, Cidlowski JA. Antiinflammatory action of glucocorticoids--new mechanisms for old drugs. N.Engl.J.Med. 2005;353:1711-1723. pmid: 16236742.

97. Beck JS, Browning MC. Immunosuppression with glucocorticoids--a possible immunological explanation for interpatient variation in sensitivity: discussion paper. J.R.Soc.Med. 1983;76:473-479.

98. Nijhuis EW, Hinloopen B, van Lier RA, Nagelkerken L. Differential sensitivity of human naive and memory CD4+ T cells for dexamethasone. Int.Immunol. 1995;7:591-595. pmid: 7547686.

99. Lim HY, Muller N, Herold MJ, van den Brandt J, Reichardt HM. Glucocorticoids exert opposing effects on macrophage function dependent on their concentration. Immunology. 2007;122:47-53.

100. Fan PT, Yu DT, Clements PJ, et al. Effect of corticosteroids on the human immune response: comparison of one and three daily 1 gm intravenous pulses of methylprednisolone. J.Lab Clin.Med. 1978;91:625-634. pmid: 76667.

101. Koreth J, Antin JH. Current and future approaches for control of graft-versus-host disease. Expert.Rev.Hematol. 2008;1:111.

102. Viard I, Wehrli P, Bullani R, et al. Inhibition of toxic epidermal necrolysis by blockade of CD95 with human intravenous immunoglobulin. Science. 1998;282:490-493. pmid: 9774279.

103. Nimmerjahn F, Ravetch JV. The antiinflammatory activity of IgG: the intravenous IgG paradox. J.Exp.Med. 2007;204:11-15.

104. McDonald GB, Bouvier M, Hockenbery DM, et al. Oral beclomethasone dipropionate for treatment of intestinal graft-versus-host disease: a randomized, controlled trial. Gastroenterology. 1998;115:28-35. pmid: 9649455.

105. Bertz H, Afting M, Kreisel W, et al. Feasibility and response to budesonide as topical corticosteroid therapy for acute intestinal GVHD. Bone Marrow Transplant. 1999;24:1185-1189.

106. MacMillan ML, Weisdorf DJ, Davies SM, et al. Early antithymocyte globulin therapy improves survival in patients with steroid-resistant acute graft-versus-host disease. Biol.Blood Marrow Transplant. 2002;8:40-46.

107. van Lint MT, Milone G, Leotta S, et al. Treatment of acute graft-versus-host disease with prednisolone: significant survival advantage for day +5 responders and no advantage for nonresponders receiving anti-thymocyte globulin. Blood. 2006;107:4177-4181.

108. Knop S, Hebart H, Gratwohl A, et al. Treatment of steroid-resistant acute GVHD with OKT3 and high-dose steroids results in better disease control and lower incidence of infectious complications when compared to high-dose steroids alone: a randomized multicenter trial by the EBMT Chronic Leukemia Working Party. Leukemia. 2007;21:1830-1833. pmid: 17495972.

109. Schnitzler M, Hasskarl J, Egger M, Bertz H, Finke J. Successful treatment of severe acute intestinal graft-versus-host resistant to systemic and topical steroids with alemtuzumab. Biol.Blood Marrow Transplant. 2009;15:910-918.

110. Schub N, Gunther A, Schrauder A, et al. Therapy of steroid-refractory acute GVHD with CD52 antibody alemtuzumab is effective. Bone Marrow Transplant. 2010;46:143-147.

111. Carpenter PA, Appelbaum FR, Corey L, et al. A humanized non-FcR-binding anti-CD3 antibody, visilizumab, for treatment of steroid-refractory acute graft-versus-host disease. Blood. 2002;99:2712-2719.

112. Carpenter PA, Lowder J, Johnston L, et al. A phase II multicenter study of visilizumab, humanized anti-CD3 antibody, to treat steroid-refractory acute graft-versus-host disease. Biol.Blood Marrow Transplant. 2005;11:465-471.

113. Deeg HJ, Blazar BR, Bolwell BJ, et al. Treatment of steroid-refractory acute graft-versus-host disease with anti-CD147 monoclonal antibody ABX-CBL. Blood. 2001;98:2052-2058.

114. MacMillan ML, Couriel D, Weisdorf DJ, et al. A phase 2/3 multicenter randomized clinical trial of ABX-CBL versus ATG as secondary therapy for steroid-resistant acute graft-versus-host disease. Blood. 2007;109:2657-2662.

115. Kobbe G, Schneider P, Rohr U, et al. Treatment of severe steroid refractory acute graft-versus-host disease with infliximab, a chimeric human/mouse antiTNFalpha antibody. Bone Marrow Transplant. 2001;28:47-49.

116. Couriel D, Saliba R, Hicks K, et al. Tumor necrosis factor-alpha blockade for the treatment of acute GVHD. Blood. 2004;104:649-654.

117. Patriarca F, Sperotto A, Damiani D, et al. Infliximab treatment for steroid-refractory acute graft-versus-host disease. Haematologica. 2004;89:1352-1359.

118. Wolff D, Roessler V, Steiner B, et al. Treatment of steroid-resistant acute graft-versus-host disease with daclizumab and etanercept. Bone Marrow Transplant. 2005;35:1003-1010.

119. Uberti JP, Ayash L, Ratanatharathorn V, et al. Pilot trial on the use of etanercept and methylprednisolone as primary treatment for acute graft-versus-host disease. Biol.Blood Marrow Transplant. 2005;11:680-687.

120. Levine JE, Paczesny S, Mineishi S, et al. Etanercept plus methylprednisolone as initial therapy for acute graft-versus-host disease. Blood. 2008;111:2470-2475.

121. Kennedy GA, Butler J, Western R, et al. Combination antithymocyte globulin and soluble TNFalpha inhibitor (etanercept) +/- mycophenolate mofetil for treatment of steroid refractory acute graft-versus-host disease. Bone Marrow Transplant. 2006;37:1143-1147.

122. Herve P, Wijdenes J, Bergerat JP, et al. Treatment of corticosteroid resistant acute graft-versus-host disease by in vivo administration of anti-interleukin-2 receptor monoclonal antibody (B-B10). Blood. 1990;75:1017-1023.

123. Anasetti C, Hansen JA, Waldmann TA, et al. Treatment of acute graft-versus-host disease with humanized anti-Tac: an antibody that binds to the interleukin-2 receptor. Blood. 1994;84:1320-1327.

124. Przepiorka D, Kernan NA, Ippoliti C, et al. Daclizumab, a humanized anti-interleukin-2 receptor alpha chain antibody, for treatment of acute graft-versus-host disease. Blood. 2000;95:83-89.

125. Lee SJ, Zahrieh D, Agura E, et al. Effect of up-front daclizumab when combined with steroids for the treatment of acute graft-versus-host disease: results of a randomized trial. Blood. 2004;104:1559-1564.

126. Shapira MY, Resnick IB, Bitan M, et al. Rapid response to alefacept given to patients with steroid resistant or steroid dependent acute graft-versus-host disease: a preliminary report. Bone Marrow Transplant. 2005;36:1097-1101.

127. Shapira MY, Abdul-Hai A, Resnick IB, et al. Alefacept treatment for refractory chronic extensive GVHD. Bone Marrow Transplant. 2009;43:339-343.

128. Kamble R, Oholendt M, Carrum G. Rituximab responsive refractory acute graft-versus-host disease. Biol.Blood Marrow Transplant. 2006;12:1201-1202.

129. Furlong T, Martin P, Flowers ME, et al. Therapy with mycophenolate mofetil for refractory acute and chronic GVHD. Bone Marrow Transplant. 2009;44:739-748.

130. Hoda D, Pidala J, Salgado-Vila N, et al. Sirolimus for treatment of steroid-refractory acute graft-versus-host disease. Bone Marrow Transplant. 2009;45:1347-1351.

131. Ghez D, Rubio MT, Maillard N, et al. Rapamycin for refractory acute graft-versus-host disease. Transplantation 2009;88:1081-1087. pmid: 19898203.

132. Pidala J, Kim J, Anasetti C. Sirolimus as primary treatment of acute graft-versus-host disease following allogeneic hematopoietic cell transplantation. Biol.Blood Marrow Transplant. 2009;15:881-885.

133. Durakovic N, Radojcic V, Powell J, Luznik L. Rapamycin promotes emergence of IL-10-secreting donor lymphocyte infusion-derived T cells without compromising their graft-versus-leukemia reactivity. Transplantation 2007;83:631-640. pmid: 17353785.

134. Armand P, Gannamaneni S, Kim HT et al. Improved survival in lymphoma patients receiving sirolimus for graft-versus-host disease prophylaxis after allogeneic hematopoietic stem-cell transplantation with reduced-intensity conditioning. J Clin.Oncol. 2008;26:5767-5774. pmid: 19001324.

135. Bolanos-Meade J, Jacobsohn DA, Margolis J, et al. Pentostatin in steroid-refractory acute graft-versus-host disease. J Clin.Oncol. 2005;23:2661-2668.

136. Schmitt T, Luft T, Hegenbart U, et al. Pentostatin for treatment of steroid-refractory acute GVHD: a retrospective single-center analysis. Bone Marrow Transplant. 2010 Jun 21. doi:10.1038/bmt.2010.146.

137. Jacobsohn DA, Chen AR, Zahurak M, et al. Phase II study of pentostatin in patients with corticosteroid-refractory chronic graft-versus-host disease. J Clin.Oncol. 2007;25:4255-4261.

138. Jacobsohn DA, Gilman AL, Rademaker A, et al. Evaluation of pentostatin in corticosteroid-refractory chronic graft-versus-host disease in children: a Pediatric Blood and Marrow Transplant Consortium study. Blood. 2009;114:4354-4360.

139. Vogelsang GB, Farmer ER, Hess AD, et al. Thalidomide for the treatment of chronic graft-versus-host disease. N.Engl.J Med. 1992;326:1055-1058.

140. Koc S, Leisenring W, Flowers ME, et al. Thalidomide for treatment of patients with chronic graft-versus-host disease. Blood. 2000;96:3995-3996.

141. Lioznov M, El-Cheikh J Jr, Hoffmann F, et al. Lenalidomide as salvage therapy after allo-SCT for multiple myeloma is effective and leads to an increase of activated NK (NKp44(+)) and T (HLA-DR(+)) cells. Bone Marrow Transplant. 2010;45:349-353. pmid: 19584825.

142. Sun K, Li M, Sayers TJ, Welniak LA, Murphy WJ. Differential effects of donor T-cell cytokines on outcome with continuous bortezomib administration after allogeneic bone marrow transplantation. Blood. 2008;112:1522-1529

143. Koreth J, Stevenson KE, Kim HT, et al. Bortezomib, tacrolimus, and methotrexate for prophylaxis of graft-versus-host disease after reduced-intensity conditioning allogeneic stem cell transplantation from HLA-mismatched unrelated donors. Blood. 2009;114:3956-3959.

144. Baroni SS, Santillo M, Bevilacqua F, et al. Stimulatory autoantibodies to the PDGF receptor in systemic sclerosis. N.Engl.J Med. 2006;354:2667-2676.

145. Svegliati S, Olivieri A, Campelli N, et al. Stimulatory autoantibodies to PDGF receptor in patients with extensive chronic graft-versus-host disease. Blood. 2007;110:237-241.

146. Magro L, Catteau B, Coiteux V, et al. Efficacy of imatinib mesylate in the treatment of refractory sclerodermatous chronic GVHD. Bone Marrow Transplant. 2008;42:757-760.

147. Olivieri A, Locatelli F, Zecca M, et al. Imatinib for refractory chronic graft-versus-host disease with fibrotic features. Blood. 2009;114:709-718.

148. Majhail NS, Schiffer CA, Weisdorf DJ. Improvement of pulmonary function with imatinib mesylate in bronchiolitis obliterans following allogeneic hematopoietic cell transplantation. Biol.Blood Marrow Transplant. 2006;12:789-791.

149. Hoffmann P, Eder R, Kunz-Schughart LA, Andreesen R, Edinger M. Large-scale in vitro expansion of polyclonal human CD4(+)CD25high regulatory T cells. Blood. 2004;104:895-903.

150. Di Ianni M, Del Papa B, Cecchini D, et al. Immunomagnetic isolation of CD4+CD25+FoxP3+ natural T regulatory lymphocytes for clinical applications. Clin.Exp.Immunol. 2009;156:246-253.

151. Le BK, Frassoni F, Ball L, et al. Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study. Lancet. 2008;371:1579-1586. pmid: 18468541.

152. Deeg HJ. Ultraviolet irradiation in transplantation biology. Manipulation of immunity and immunogenicity. Transplantation 1988;45:845-851. pmid:  3285528.

153. Hymes SR, Morison WL, Farmer ER, et al. Methoxsalen and ultraviolet A radiation in treatment of chronic cutaneous graft-versus-host reaction. J Am.Acad.Dermatol. 1985;12:30-37. pmid: 3980801.

154. Furlong T, Leisenring W, Storb R, et al. Psoralen and ultraviolet A irradiation (PUVA) as therapy for steroid-resistant cutaneous acute graft-versus-host disease. Biol.Blood Marrow Transplant. 2002;8:206-212.

155. Vogelsang GB, Wolff D, Altomonte V, et al. Treatment of chronic graft-versus-host disease with ultraviolet irradiation and psoralen (PUVA). Bone Marrow Transplant. 1996;17:1061-1067. pmid: 8807115.

156. Ghoreschi K, Thomas P, Penovici M, et al. PUVA-bath photochemotherapy and isotretinoin in sclerodermatous graft-versus-host disease. Eur.J.Dermatol. 2008;18:667-670.

157. Greinix H, Volc-Platzer B, Rabistch W, et al. Successful use of extracorporeal photochemotherapy in the treatment of severe acute and chronic graft-versus-host disease. Blood. 1998;92:3098-3104.

158. Greinix HT, Knobler RM, Worel N, et al. The effect of intensified extracorporeal photochemotherapy on long-term survival in patients with severe acute graft-versus-host disease. Haematologica. 2006;91:405-408.

159. Perfetti P, Carlier P, Strada P, et al. Extracorporeal photopheresis for the treatment of steroid refractory acute GVHD. Bone Marrow Transplant. 2008;42:609-617.

160. Couriel DR, Hosing C, Saliba R, et al. Extracorporeal photochemotherapy for the treatment of steroid-resistant chronic GVHD. Blood. 2006;107:3074-3080.

161. Perotti C, Del Fante C, Tinelli C, et al. Extracorporeal photochemotherapy in graft-versus-host disease: a longitudinal study on factors influencing the response and survival in pediatric patients. Transfusion. 2010;50:1359-1369.

162. Flowers ME, Apperley JF, Van Besien K, et al. A multicenter prospective phase 2 randomized study of extracorporeal photopheresis for treatment of chronic graft-versus-host disease. Blood. 2008;112:2667-2674

163. Gorgun G, Miller KB, Foss FM. Immunologic mechanisms of extracorporeal photochemotherapy in chronic graft-versus-host disease. Blood. 2002;100:941-947.

164. Bladon J, Taylor PC. Early reduction in number of T cells producing proinflammatory cytokines, observed after extracorporeal photopheresis, is not linked to apoptosis induction. Transplant Proc. 2003;35:1328-1332. pmid: 12826151.

165. Gatza E, Rogers CE, Clouthier SG, et al. Extracorporeal photopheresis reverses experimental graft-versus-host disease through regulatory T cells. Blood.2008;112:1515-1521.

166. Di Biaso I, Di Maio L, Bugarin C, et al. Regulatory T cells and extracorporeal photochemotherapy: correlation with clinical response and decreased frequency of proinflammatory T cells. Transplantation. 2009;87:1422-1425.

167. Ford CE, Micklem HS. The thymus and lymph-nodes in radiation chimaeras. Lancet 1963;1:359-362. pmid: 13958695.

168. Zinkernagel RM. Thymus and lymphohemopoietic cells: their role in T cell maturation in selection of T cells' H-2-restriction-specificity and in H-2 linked Ir gene control. Immunol Rev. 1978;42:224-270. pmid: 83701.

169. Krenger W, Hollander GA. The role of the thymus in allogeneic hematopoietic stem cell transplantation. Swiss.Med Wkly. 2010;140:w13051. doi:10.4414/smw.2010.13051.

170. Steffens CM, Al Harthi L, Shott S, Yogev R, Landay A. Evaluation of Thymopoiesis Using T Cell Receptor Excision Circles (TRECs): Differential Correlation between Adult and Pediatric TRECs and Naive Phenotypes. Clin Immunol. 2000;97:95-101. pmid: 11027449.

171. Witherspoon RP, Sullivan KM, Lum LG, et al. Use of thymic grafts or thymic factors to augment immunologic recovery after bone marrow transplantation: brief report with 2 to 12 years' follow-up. Bone Marrow Transplant. 1988;3:425-435. pmid: 3056551.

172. Wils EJ, Cornelissen JJ. Thymopoiesis following allogeneic stem cell transplantation: new possibilities for improvement. Blood Rev. 2005;19:89-98. pmid: 15603912.

173. Seggewiss R, Lore K, Guenaga FJ, et al. Keratinocyte growth factor augments immune reconstitution after autologous hematopoietic progenitor cell transplantation in rhesus macaques. Blood. 2007;110:441-449.

174. Muller-Hermelink HK, Sale GE, Borisch B, Storb R. Pathology of the thymus after allogeneic bone marrow transplantation in man. A histologic immunohistochemical study of 36 patients. Am.J Pathol. 1987;129:242-256.

175. Pullen AM, Kappler JW, Marrack P. Tolerance to self antigens shapes the T-cell repertoire. Immunol Rev. 1989;107:125-139. pmid: 2522084.

176. Zinkernagel RM, Doherty PC. Restriction of in vitro T cell-mediated cytotoxicity in lymphocytic choriomeningitis within a syngeneic or semiallogeneic system. Nature. 1974;248:701-702. pmid:  4133807.

177. Thomas ED, Kasakura S, Cavins JA, Ferrebee JW. Marrow transplants in lethally irradiated dogs: The effect of Methotrexate on survival of the host and the homograft. Transplantation. 1963;1:571-574. pmid: 14071268.

178. Santos GW. Immunosuppression for clinical marrow transplantation. Semin.Hematol. 1974;11:341-351. pmid: 4151847.

179. Luznik L, Jalla S, Engstrom LW, Iannone R, Fuchs EJ. Durable engraftment of major histocompatibility complex-incompatible cells after nonmyeloablative conditioning with fludarabine, low-dose total body irradiation, and posttransplantation cyclophosphamide. Blood. 2001;98:3456-3464.

180. Miller RG, Muraoka S, Claesson MH, Reimann J, Benveniste P. The veto phenomenon in T-cell regulation. Ann N Y Acad Sci. 1988;532:170-6. pmid: 2972242.

181. Reich-Zeliger S, Zhao Y, Krauthgamer R, Bachar-Lustig E, Reisner Y. Anti-third party CD8+ CTLs as potent veto cells: coexpression of CD8 and FasL is a prerequisite. Immunity. 2000;13:507-515.

182. Gabrilovich DI, Nagaraj S. Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev.Immunol 2009;9:162-174. pmid: 19197294.

183. Lan F, Zeng D, Higuchi M, et al. Predominance of NK1.1(+)TCRalphabeta(+) or DX5(+)TCRalphabeta(+) T Cells in Mice Conditioned with Fractionated Lymphoid Irradiation Protects Against Graft-Versus-Host Disease: "Natural Suppressor" Cells. J Immunol. 2001;167:2087-2096.

184. Rabinovich BA, Li J, Shannon J, et al. Activated, but not resting, T cells can be recognized and killed by syngeneic NK cells. J Immunol. 2003;170:3572-3576.

185. Moseman EA, Liang X, Dawson AJ, et al. Human plasmacytoid dendritic cells activated by CpG oligodeoxynucleotides induce the generation of CD4+CD25+ regulatory T cells. J Immunol. 2004;173:4433-4442.

186. Kapp JA, Bucy RP. CD8+ suppressor T cells resurrected. Hum.Immunol 2008;69:715-720. pmid: 18817830.

187. Peccatori J, Clerici D, Forcina A, et al. In vivo T-regs generation by rapamycin-mycophenolate-ATG as a new platform for GVHD prophylaxis in T-cell repleted unmanipulated haploidentical peripheral stem cell transplantation: results in 59 patients [abstract]. EBMT Meeting Vienna. 2010. 2010;S3-S4.

188. Peritt D. Potential mechanisms of photopheresis in hematopoietic stem cell transplantation. Biol.Blood Marrow Transplant. 2006;12:7-12.

189. Weissinger EM, Schiffer E, Hertenstein B, et al. Proteomic patterns predict acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. Blood. 2007;109:5511-5519.

190. Paczesny S, Braun TM, Levine JE et al. Elafin is a biomarker of graft-versus-host disease of the skin. Sci.Transl.Med 2010;2:13ra2. pmid: 20371463.

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Многие исследований показали, что первичными мишенями являются гемопоэтические клетки, а также кожа, кишечник и печень, содержащие клетки макрофагального происхождения. Последние продуцируют провоспалительные цитокины, которые стимулируют донорские Т-клетки и индуцируют HLA-антигены II класса в тканях реципиента. Дендритные клетки (ДК) стимулируют CD 8 лимфоциты к реакции на пептиды HLA класса I. Таким образом, РТПХ направлена против антигенов гистосовместимости реципиента, которые чужеродны по отношению к донору. Полиморфные белки (не-HLA) могут также вызвать тяжелые реакции РТПХ. Реакции против минорных антигенов гистосовместимости требуют более длительных сроков для активации, нежели реакции против MHC-антигенов.  <br /><br />Предпосылки к РТПХ возникают до трансплантации (так наз. «цитокиновая буря», которая вызывается интенсивной кондиционирующей терапией и возможными инфекциями). Однако, в клинике показано, что переливание донорских лимфоцитов может вызвать РТПХ и без кондиционирующего лечения. В целом, иммунная система реципиента постоянно подавляется трансплантатом: трансплантат при этом становится толерантным по отношению к реципиенту. Механизм этой толерантности связан  с появлением неспецифических и специфических клеток-супрессоров и последующей клональной делецией, а также при посредстве мезенхимных стволовых клеток, NK-Т-клеток и регуляторных Т-клеток. Выбор HLA-идентичного донора является залогом успешной ТГСК (на практике требуется определить до 10 локусов HLA). Несколько аллелей генов TNF-a и его рецептора II ассоциированы с повышенным риском РТПХ. Описываются также хорошо известные клинические особенности оРТПХ, включая поражения кожи, печени и кишечника. Рассматриваются также вопросы диагностики хронической РТПХ. Ее клинические и гистологические признаки во многом напоминают симптоматику аутоиммунных заболеваний. <br /><br />Профилактика РТПХ хорошо разработана и ее следует применять в любой клинической ситуации. Особое внимание уделяется удалению Т-клеток из трансплантата современным методам иммуносупрессии после трансплантации. Рассматриваются некоторые вопросы, касающиеся удаления Т-клеток при трансплантации периферических ТГСК. Обсуждаются текущие схемы лечения ОТПХ, в том числе ингибиторов кальцинейрина, ряда новых супрессивных препаратов. Роль различных режимов терапии рассматривается в аспекте развития популяции Т-регуляторных клеток, а также мезенхимальных клеток и УФА-облучения для контроля РТПХ. </p> <p class="bodytext">Особое внимание уделено индукции толерантности к РТПХ у больных после ТГСК. В большинстве случаев преобладает периферическая (тимус-независимая) форма толерантности. 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" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["ORGANIZATION_RU"]=> array(36) { ["ID"]=> string(2) "26" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(22) "Организации" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "26" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> NULL ["VALUE"]=> string(0) "" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(0) "" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(22) "Организации" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_RU"]=> array(36) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "19114" ["VALUE"]=> array(2) { ["TEXT"]=> string(5938) "<p class="bodytext">Проблемы патофизиологии, профилактики и лечения острой РТПХ (оРТПХ), возникающей чаще всего после аллогенной трансплантации гемопоэтических стволовых клеток (алло-ТГСК), необходимо изучить, чтобы использовать ее потенциальную выгоду без увеличения рисков. Многие исследований показали, что первичными мишенями являются гемопоэтические клетки, а также кожа, кишечник и печень, содержащие клетки макрофагального происхождения. Последние продуцируют провоспалительные цитокины, которые стимулируют донорские Т-клетки и индуцируют HLA-антигены II класса в тканях реципиента. Дендритные клетки (ДК) стимулируют CD 8 лимфоциты к реакции на пептиды HLA класса I. Таким образом, РТПХ направлена против антигенов гистосовместимости реципиента, которые чужеродны по отношению к донору. Полиморфные белки (не-HLA) могут также вызвать тяжелые реакции РТПХ. Реакции против минорных антигенов гистосовместимости требуют более длительных сроков для активации, нежели реакции против MHC-антигенов.  <br /><br />Предпосылки к РТПХ возникают до трансплантации (так наз. «цитокиновая буря», которая вызывается интенсивной кондиционирующей терапией и возможными инфекциями). Однако, в клинике показано, что переливание донорских лимфоцитов может вызвать РТПХ и без кондиционирующего лечения. В целом, иммунная система реципиента постоянно подавляется трансплантатом: трансплантат при этом становится толерантным по отношению к реципиенту. Механизм этой толерантности связан  с появлением неспецифических и специфических клеток-супрессоров и последующей клональной делецией, а также при посредстве мезенхимных стволовых клеток, NK-Т-клеток и регуляторных Т-клеток. Выбор HLA-идентичного донора является залогом успешной ТГСК (на практике требуется определить до 10 локусов HLA). Несколько аллелей генов TNF-a и его рецептора II ассоциированы с повышенным риском РТПХ. Описываются также хорошо известные клинические особенности оРТПХ, включая поражения кожи, печени и кишечника. Рассматриваются также вопросы диагностики хронической РТПХ. Ее клинические и