ISSN 1866-8836
Клеточная терапия и трансплантация
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Case Report

The patient, a five-year-old boy, was first noted to have pancytopenia at 24 months of age. An evaluation (Duke University Medical Center) showed the following hematologic values: hemoglobin concentration, 9.5 g per deciliter; white-cell count, 4.3 x 109 per liter, with 22 percent granulocytes, 62 percent lymphocytes, 3 percent monocytes, 1 percent eosinophils, and 8 percent basophils; platelet count, 62 x 109 per liter; and reticulocyte level, 2.3 percent. The bone marrow was hypocellular. The patient had the classic malformations of Fanconi's anemia, including retarded growth (5th to 10th percentile), a rudimentary extra thumb on the left hand, the absence of a left kidney, and hypospadias. Testing of the patient's cells with diepoxybutane, performed at 24 months (Rockefeller University), confirmed the diagnosis of Fanconi's anemia. The parents were healthy, and there was no consanguinity or past history of blood disorders in the family. The patient had been treated with danazol (300 mg per day for six months), with a progressive decrease in the blood-cell counts. Before admission, he had received three units of filtered and irradiated packed red cells.

The patient's mother became pregnant in June 1987. Cytogenetic analysis of cultured amniotic-fluid cells (Rockefeller University) showed that the values for chromosome breakage before and after the cells were exposed to diepoxybutane were within the normal range [5]. A girl was delivered vaginally without complications in February 1988. Studies of chromosome breakage in umbilical-cord blood cells indicated that the newborn had a normal karyotype and was not affected by Fanconi's anemia (Table 1).

Table 1. Results of Cytogenetic Analysis.*
*DEB denotes diepoxybutane; its final concentration in the culture medium was 0.1 mg per milliliter in each analysis in this table.
†Analysis performed on quinacrine-stained metaphase preparations.
‡Analysis performed on Giemsa-stained metaphase preparations.

Source Of Cells

Percent Donor
Cells In Sample†

Mean Chromosome  
Breaks/Cell‡  

before deb 

after deb  

before deb 

after deb 

Patient's peripheral blood on day 0    

0

0

0.18

10.6

Donor's cord blood on day 0

100

100

0.00

0.02

Patient's bone marrow on day 120

100

100

0.04

0.30

Patient's peripheral blood
Day 50

30

52

0.7

4.0

Day 64

8

32

1.3

5.0

Day 120

12

32

1.9

6.4

Day 204

64

86

0.30

0.49


Prenatal HLA typing of amniotic-fluid cells (Dr. M.S. Pollack, Methodist Hospital and Baylor Medical Center, Houston) had shown that the fetus was HLA identical to the patient: the first haplotype was Al,B8,DR3, and the second haplotype A29,B44,DR3. Mixed lymphocyte cultures of cells from the patient with cells from the cord blood and peripheral blood of the donor were negative. The cord-blood cells were less reactive against a pool of allogeneic cells than were the peripheral-blood cells (incorporation of [3H]thymidine, 15,437 vs. 112,954 cpm). The ABO blood group of the donor was O Rh+, and that of the recipient B Rh+.

The patient was admitted in September 1988, with the following hematologic values: hemoglobin concentration, 6.8 g per deciliter; white-cell count, 3.1 x 109 per liter, with 7 percent granulocytes, 86 percent lymphocytes, and 5 percent monocytes; and platelet count, 18 x 109 per liter. The marrow was hypocellular, with 10 percent of normal cellularity, 24 percent myeloid cells, 2 percent erythroblast cells, 67 percent lymphocytes, and no megakaryocytes. There were no hemorrhagic or infectious complications of the patient's illness. His liver and kidney functions were normal. Serologic tests were positive for cytomegalovirus (on enzyme-linked immunosorbent assay) and negative for human immunodeficiency virus, hepatitis B, and toxoplasmosis.

The patient was isolated in a room with laminar airflow, and treatment with oral broad-spectrum nonabsorbable antibiotics (vancomycin, tobramycin, and colistin [Colimycine]) was started nine days before transplantation (on day -8). Fluconazole (50 mg per day) was administered to prevent fungal infection, and oral acyclovir (100 mg per day) to prevent herpes simplex virus infection. For pretransplantation conditioning, cyclophosphamide (5 mg per kilogram of body weight) was given intravenously for four consecutive days (from day -6 to day -3; total, 380 mg) along with hyperhydration. Irradiation was delivered to the thoracoabdominal region by a linear accelerator on day -1 (mean rate, 10.87 cGy per minute), for a total of 5 Gy over a period of 46 minutes; the abdomen received 500 cGy, and the lungs and the right liver lobe, which were shielded, received 67 cGy.

On the day of transplantation (day 0 – October 6, 1988), cryopreserved umbilical-cord blood was thawed and infused without further processing, according to predetermined optimal conditions12 (the surviving whole red cells that had not been hemolyzed belonged to group O). The patient received 0.4 x 108 nucleated cells per kilogram, of which a total of 4.37 x 105 were CFU-GM (as determined by assay in Paris). Two hours after the infusion, the patient had chills, fever, and hypotension. These symptoms soon resolved, while the patient was receiving the broad-spectrum antibiotics vancomycin and ceftazidime intravenously. For prophylaxis against graft-versus-host disease, cyclosporine was administered intravenously from day – 1 (4.5 mg per kilogram per day), according to a preliminary pharmacokinetic study. All blood products were irradiated (25 Gy).

Ethical and Regulatory Considerations

Written informed consent was obtained from the patient's parents for collecting the umbilical-cord blood and for the transplantation procedure. The treatment plan was reviewed and approved by the institutional review board for clinical investigation of the Duke University Medical Center and by the ethics committee of the Hôpital Saint-Louis. Approval for the receipt, cryopreservation, storage, and release of cord blood was received from the institutional review board of the Indiana University School of Medicine. The Food and Drug Administration considered the procedure equivalent to the storage and transplantation of bone marrow, which are currently not subject to its regulation.

Methods

Cytogenetic Studies

Chromosome-breakage studies were performed as described elsewhere [4]. Diepoxybutane was added to bone marrow cultures when they were begun, and the cultured cells were harvested after 24 hours. Peripheral blood was cultured in the presence of phytohemagglutinin for 72 hours; diepoxybutane was present in the medium during the last 48 hours of culture. The frequency of chromosome breakage before and after the addition of diepoxybutane was analyzed in Giemsa-stained metaphase preparations; the ratio of cells from the patient to cells from the donor (male:female) was determined on quinacrine-stained slides to facilitate the identification of the Y chromosome.

DNA Studies: Restriction-Fragment-Length Polymorphism

DNA samples obtained for Southern blotting were digested with Taq1 (New England Biolabs, Beverly, Mass.), separated by gel electrophoresis, transferred to an Immobilon-N filter (Millipore Corp., Bedford, Mass.), hybridized, and washed as previously described [13]. The probe used was CRI-pS232 (DXS278) (Collaborative Research, Boston), which hybridizes with sequences from the X and Y chromosomes.

Collection, Storage, and Shipment of Neonatal Blood

Immediately after the birth of the patient's sister, blood was obtained from her umbilical cord and the placenta as described elsewhere [12] and transported at ambient temperature by overnight express service to a laboratory for cellular analysis, cryopreservation, and storage (Indiana University School of Medicine). A sample of cord blood was also sent elsewhere for cytogenetic analysis (Rockefeller University). After a small sample (<2 ml) had been set aside for laboratory tests, including the determination of the level of nucleated cells and the enumeration of progenitor cells, the blood was frozen without further treatment in dimethyl sulfoxide at a final concentration of 10 percent (vol/vol) as previously described [12]. Two bags of cord blood and one bag of placental blood were frozen. Samples (about 1 ml each in Nunc tubes) were similarly frozen for testing of cell recovery after thawing and for confirmation of the HLA types. The volume of blood and the numbers of nucleated and progenitor cells collected are shown in Table 2. These values were within the range associated with successful transplantation of HLA–matched allogeneic bone marrow [12]. Testing of thawed cells, including those in one tube sent from Indiana University to Duke University Medical Center (where the HLA types were confirmed), demonstrated recovery of 79 percent to 90 percent of nucleated cells; on day 14, the mean (±1 SEM) rates of recovery were 100 percent ofCFU-GM, 63±18 percent of BFU-E, and 79±15 percent of CFU-GEMM.

Table 2. Hematopoietic Progenitor Cells in Blood from the Umbili­cal Cord and Placenta of the Donor and Bone Marrow from the Recipient.
* The preparation for the assays has been described elsewhere [12]. The assays of the cord blood and the bone marrow on day 120 were performed in Indianapolis, and those of the bone marrow at day 0 and day 30 in Paris.
† Plus-minus values are means ± 1 SEM; ND denotes not done.
‡ The total volume of cord and placental blood collected was 160 ml and contained 1.19 x 109 nucleated cells.
§ Normal range (Indianapolis laboratory) for low-density cells. 10 to 70 for CFU-GM and 15 to 80 for BFU-E-1 and BFU-E-2.
These were mainly microclusters, with less than 20 cells per cluster.

Source of Cells

Progenitor Cells†

all densities  

low density
(<1.077 g/ml)

Donor (cord and placental blood)‡

total cells x 10-5

Agar culture
Day 14 CFU-GM (colonies)

1.52

ND

Day 14 CFU-GM (colonies and clusters)

2.46

ND

Methylcellulose culture (colonies)
Day 14 CFU-GM

1.56

ND

BFU-E-2

3.95

ND

BFU-E-1

3.60

ND

CFU-GEMM

0.39

ND

Recipient (bone marrow)

cells/105 cells plated§

Methylcellulose culture, day 0
Day 14 CFU-GM (colonies)

ND

1

Day 14 CFU-GM (colonies and clusters)  

ND

8

BFU-E-1

ND

0

CFU-GEMM

ND

0

Methylcellulose culture, day 30
Day 14 CFU-GM (colonies)

ND

9

BFU-E-1

ND

0

CFU-GEMM

ND

0

Agar culture, day 120
Day 7 CFU-GM (colonies)

22±2

140±12

Day 7 CFU-GM (colonies and clusters)

118±16

416±20

Day 14 CFU-GM (colonies)

36±4

156±8

Day 14 CFU-GM (colonies and clusters)

152±4

228±12

Methylcellulose culture, day 120
Day 14 CFU-GM (colonies)

324±16

416±25

BFU-E-2

77±2

134±6

BFU-E-1

96±8

132±10

CFU-GEMM

4±1

9±1


The two bags of frozen cord blood and the bag of placental blood were sent with an escort by air (with the approval of the airline) to the Hôpital Saint-Louis from Indiana University two weeks before transplantation. The bags were sent in a Dry Shipper container (CMC-3200 wide mouth with platform; Cryomed, New Baltimore, Mich.) maintained at -175°C, a temperature optimal for cryopreservation.

Hematopoietic Progenitor Cells in Vitro

Assays were prepared as previously described [12]. In the CFU-GM assay, colonies (>40 cells per aggregate) and clusters (3 to 40 cells per aggregate) were scored after 7 days and 14 days of incubation in agar culture medium. Large-sized colonies formed (>1000 cells). Cell counts were expressed also as colonies plus clusters, for a more accurate estimate of the total CFU-GM compartment. In the assays for BFU-E, CFU-GEMM, and CFU-GM, colonies were scored after 14 days of incubation in methylcellulose culture medium. In the BFU-E-1, CFU-GEMM, and CFU-GM assays, colonies were scored from the same plates, which included erythropoietin (1 unit per milliliter), hemin (0.1 mM), and 5637 conditioned medium (10 percent vol/vol). BFU-E-2 cells were cultured as BFU-E-1, but without 5637 conditioned medium. Each BFU-E-2 colony contained at least 50 cells or comprised at least three subcolonies, each of which contained at least 10 cells, but were usually much larger. Colonies derived from BFU-E-1 were much larger than those derived from BFU-E-2.

Thawing and Recovery of Cells

Eighty-two percent of nucleated cells of the thawed blood transfused into the patient were viable. Progenitor-cell assays performed in Paris (which differed slightly in technique from assays performed in Indianapolis) indicated that the rate of cell recovery was equal to or greater than the count of progenitor cells recorded before freezing.

Results

Clinical Findings

The clinical course of the patient was uneventful and without complications. He tolerated the pretransplantation conditioning without evident toxic effects. On day 15, a transient skin rash and fever resolved with methylprednisolone treatment (2 mg per kilogram). A skin biopsy revealed few vacuolar basal epidermal cells with a mild lymphoid infiltrate, indicative of grade I graft-versus-host disease as defined according to the Seattle classification [14]. Liver-function tests showed that the serum levels of aspartate and alanine aminotransferases were twice normal, probably as a result of the graft-versus-host disease; values returned to normal on day 47. Cytomegalovirus was repeatedly isolated from the urine, but the patient never had any signs of active infection, and all tests for viremia were negative. Five months after transplantation the patient was discharged with normal clinical and laboratory findings. The doses of cyclosporine and corticosteroids were progressively reduced, and the drugs were discontinued at six months. At present (nine months after transplantation), the patient has no chronic graft-versus-host disease and leads a normal life.

Hematologic Findings

The blood-cell counts began to return to normal (Table 3).

Table 3. Blood-Cell Counts before and after Transplantation

Day

Hemoglobin

Leukocytes

Granulocytes

Lymphocytes

Platelets

Reticuloytes

g/dl

no. of cells x 10-9 per liter

-20

6.8

3.1

0.25

2.8

18

10

0

9.7

0.8

0.0

0.8

120

0

8

10.9

0.4

0.0

0.4

80

0

15

11.6

0.4

0.0

0.4

39

0

22

7.8

0.9

0.3

0.6

50

5

29

8.5

1.0

0.3

0.5

105

17

36

9.4

1.7

0.6

0.5

55

36

43

11.3

5.1

2.4

1.9

31

90

50

8.9

3.4

1.5

0.7

62

162

57

8.9

5.6

3.2

1.0

174

63

90

11.3

5.1

4.0

1.1

296

50

120

13.0

3.9

2.3

1.1

265

40

160

12.0

3.7

1.4

1.6

293

45

240

12.3

5.2

2.7

1.6

354

50

282

12.2

4.8

2.3

1.2

315

---

The reticulocyte and granulocyte counts had begun to rise by day 22 after transplantation. The patient received eight transfusions of packed red cells (O Rh+) and 48 units of random platelets. Red cells were last transfused on day 54, and platelets on day 43. Bone marrow aspirated on day 17 was aplastic: an evaluation on day 28 showed 20 percent cellularity, with 19 percent myeloid cells, 73 percent erythroid cells, and few megakaryocytes. On day 120, the marrow had normal cellularity, with 40 percent myeloid cells, 44 percent erythroid cells, and a normal level of megakaryocytes.

Hematopoietic Progenitor Cells

Before transplantation, the marrow contained few or no detectable progenitor cells (Table 2). At 30 days after transplantation, CFU-GM cells were detected but not BFU-E or CFU-GEMM; at 120 days, progenitors were apparent at normal to supranormal frequencies (colonies or clusters per number of cells plated).

Reconstitution by Donor Cells

Blood- Type Studies
The patient's red cells (B Rh+) disappeared progressively and became undetectable on day 90 after transplantation; 46 days after the last transfusion, 100 percent of red cells were of the donor's blood type (O Rh+) and were found to have remained so at 240 days after transplantation.

Cytogenetic Studies
Table 1 shows the results of cytogenetic studies of bone marrow aspirated on day 120 and peripheral blood obtained on days 50, 64, 120, and 204. The chromosomal complement of the bone marrow was 46,XX. No cells of the patient (male cells) in metaphase were seen among 50 quinacrine-stained or 100 Giemsa-stained cells analyzed. The chromosomebreakage frequencies were 0.04 and 0.30 breaks per cell in the base-line and diepoxybutane-treated cultures, respectively.

Through day 120 after transplantation, more than half the metaphases seen in cytogenetic preparations of phytohemagglutinin-stimulated peripheral-blood cultures were of host origin, as indicated by the presence of a Y chromosome. These cells, of lymphoid origin, had greatly elevated levels of chromosome breakage at base line and severe radiation damage, manifested by the presence of multiple dicentrics, rings, and chromosomal fragments; they were also hypersensitive to the clastogenic effect of diepoxybutane, showing multiple chromatid breaks and exchanges typical of the cells characterizing Fanconi's anemia. The cells of donor origin (female) did not have elevated levels of chromosome breakage. By day 204 (61/2 months after transplantation), the majority of peripheral-blood lymphocytes were of donor origin.

These findings reflected engraftment with the donor cells and survival of a minor population of radiationdamaged host cells in the blood – an outcome similar to that in reports of bone marrow transplantation by others [15].

DNA Studies
The CRI-pS232 probe recognizes a complex set of fragments at a highly polymorphic locus on the X chromosome, as well as a polymorphic locus on the Y chromosome [16]. In the present case, all the variable bands present in the DNA of the donor were seen in the DNA extracted from the peripheral blood of the recipient after transplantation (Fig. 1). In addition, the X and Y alleles of the recipient were seen as faint bands, indicating some chimerism in the peripheral blood, with primarily donor cells present.

Gluckman-Fig-1.png

Figure 1. Southern Blot Analysis of DNA from the Patient and His Family.

DNA was extracted from the peripheral blood of the father (lane 1), the mother (lane 2), the patient before transplantation (lane 3), the patient's HI.A-identical sister (lane 4), the patient's HA non-identical sister (lane 5), and the patient on post-transplantation day 50 (lane 6), day 64 (lane 7), and day 120 (lane 8).

The DNA obtained from the patient after transplantation was primarily of donor origin. Each DNA sample was digested with the restriction enzyme Taq1 and examined with the probe CRI-pS232, which recognizes a complex set of fragments at a highly polymorphic locus on the X chromosome as well as a locus on the Y chromosome. The thick arrows indicate X-specific bands from the donor, and the thin arrows denote those from the recipient. Y-specific bands are seen at 4.9 and 3.8 kb. A constant band at 3.0 kb is seen in the DNA of all the subjects.


Discussion

Bone marrow and, under certain circumstances, the blood of adults (see references cited by Broxmeyer et al [12]) and the liver of fetuses [17] have been used in the transplantation of hematopoietic cells. The clinical and biologic data presented above show that the umbilical-cord blood of a single newborn is sufficient to induce hematopoietic reconstitution. The virtually complete occupation of the patient's myeloid system by cells from his sibling was indicated by the cytogenetic studies, blood typing, and studies of DNA polymorphisms and by the absence of undue chromosomal fragility. At present, a small percentage of lymphoid cells with chromosome damage remains in the circulation, but there has been a trend toward the elimination of these damaged cells.

There may be several reasons why cellular repopulation was somewhat delayed in our patient as compared with patients who have undergone transplantation with HLA-matched allogeneic (sibling) bone marrow. For instance, cells that have been frozen and thawed may take longer than fresh cells to seed, respond, and differentiate in their respective inducing microenvironments. Also, consistent with the relative paucity of CFU-GM on day 7 as compared with the more immature CFU-GM on day 14 [12], umbilical-cord blood may typically have a profile with immaturity and less differentiation of hematopoietic stem and progenitor cells. The modified conditioning regimen was adequate to permit complete engraftment with 0.4 x 108 total nucleated cord-blood cells per kilogram, as compared with the mean of 3 x 108 total nucleated bone marrow cells per kilogram that is usually given for bone marrow transplantation.

The use of cord blood in the treatment of Fanconi's anemia may be extended to the treatment of other conditions for which bone marrow transplantation is indicated, and demonstrates the potential of cryopreservation for prospective use of autologous blood.

In the latter respect, our success with allogeneic cord blood is particularly important, because studies in animals have shown that fewer reconstituting cells are required to restore hematopoietic function when these are syngeneic rather than allogeneic [18].

Thus, umbilical-cord blood can be considered an efficacious source of sufficient cells for clinical hematopoietic reconstitution.

Acknowledgements

We are indebted to Dr. Bo Dupont (Sloan-Kettering Institute for Cancer Research) for suggesting the clinical application in Fanconi's anemia, to Dr. Marilyn Pollack (Baylor Medical Center) for HLA typing of the amniotic cells, to Dr. Rebecca H. Buckley (Duke University) for the data from the mixed lymphocyte cultures, to Rita Ghosh, Lui Qian, and Drew Olsen (Rockefeller University) for technical help with the cytogenetic studies, to Dr. William Mann and V.S. Venkatraj (Rockeleller University) for DNA analysis, to Françoise Varrin (Paris) for technical assistance in the assessment of hematopoietic progenitors, to Ms. Linda Cheung (Indiana University) for help in preparing the manuscript, and to Collaborative Research for the probe pS232.

Supported in part by grants from the Biocyte Corporation, by grants (CA36464 and CA-36740 to Dr. Broxmeyer and CA-39827 to Dr. Boyse) from the National Cancer Institute, by a grant (HL-32987 to Dr. Auerbach) from the National Institutes of Health, and by a grant from the Pew Memorial Trust to Rockefeller University. Dr. Boyse holds a Research Professorship from the American Cancer Society, and Dr. Kurtzberg is a Special Fellow of the Leukemia Society of America. In accordance with the Journal's policy, the authors have provided the following information: Dr. Broxmeyer, Dr. Douglas, Ms. Bard, and Dr. Boyse are shareholders in Biocyte Corporation (New York), and Dr. Douglas and Dr. Boyse are members of its board of directors.

References

1. Fanconi G. Familial constitutional panmyelocytopathy, Fanconi's anemia (F.A.). L Clinical aspects. Semin Hematol. 1967;4:233-40. pmid: 6074578.

2. Schroeder TM, Tilgen D, Kruger J, Vogel F. Formal genetics of Fanconi's anemia. Hum Genet. 1976;32:257-88. pmid: 939547.

3. Auerbach AD, Rogatko A, Schroeder-Kurth TM. international Fanconi Anemia Registry: relation of clinical symptoms to diepoxybutane sensitivity. Blood. 1989;73:391-6.

4. Auerbach AD, Wolman SR. Susceptibility of Fanconi's anaemia fibroblasts to chromosome damage by carcinogens. Nature. 1976;261:494-6. pmid: 934283.

5. Auerbach AD, Sagi M, Adler B. Fanconi anemia: prenatal diagnosis in 30 fetuses at risk. Pediatrics. 1985;76:794-800. pmid: 4058989.

6. Auerbach AD, Min Z, Ghosh R, et al. Clastogen-induced chromosomal breakage as a marker for first trimester prenatal diagnosis of Fanconi anemia. Hum Genet. 1986;73:86-8. pmid: 3458668.

7. Callaway C, Falcon C, Grant G, et al. HLA typing used with cultured amniotic and chorionic villus cells for early prenatal diagnosis or parentage testing without one parent's availability. Hum Immunol. 1986;16:200-4. doi:10.1016/0198-8859(86)90048-0.

8. Gluckman E, Devergie A, Dutreix J. Bone marrow transplantation for Fanconi's anemia. In: Schroeder-Kurth TM, Auerbach AD, Obe G, eds. Fanconi anemia: clinical, cytogenetic and experimental aspects. New York: Springer-Verlag. 1989:60-8.

9. Gluckman E, Devergie A, Schaison G, et al. Bone marrow transplantation in Fanconi anemia. Br J Haematol. 1980;45:557-64. pmid: 7000153.

10. Berger R, Bernheim A, Gluckman E, Gisselbrecht C. In vitro effect of cyclophosphamide metabolites on chromosomes of Fanconi anaemia patients. Br J Haematol. 1980;45:565-8. pmid: 7426437.

11. Gluckman E, Devergie A, Dutreix J. Radiosensitivity in Fanconi anaemia: application to the conditioning regimen for bone marrow transplantation. Br J Haematol. 1983;54:431-40. pmid: 6344915.

12. Broxmeyer HE, Douglas GW, Hangoc G, et al. Human umbilical cord blood as a potential source of transplantable hematopoietic stem/progenitor cells. Proc Natl Acad Sci USA. 1989;86:3828-32.

13. Mann W, Venkatraj VS, Auerbach AD. Two hour hybridization using a new transfer membrane. Nucleic Acids Res. 1989;17:5410.

14. Sale GE, Lerner KG, Barker EA, Shulman HM, Thomas ED. The skin biopsy in the diagnosis of acute graft-versus-host disease in man. Am 1 Pathol. 1977;89:621-35.

15. Butturini A, Seeger RC, Gale RP. Recipient immune-competent T lymphocytes can survive intensive conditioning for bone marrow transplantation. Blood. 1986;68:954-6.

16. Knowlton RG, Nelson CA, Brown VA, Page DC, Donis-Keller H. An extremely polymorphic locus on the short arm of the human X chromosome with homology to the long arm of the Y chromosome. Nucleic Acids Res. 1989;17:423-37.

17. Gale RP, Touraine 1-L, Lucarelli G, eds. Fetal liver transplantation: proceedings of an international symposium held in Pesaro, Italy, September 29-October I, 1984. Vol. 193. Progress in clinical and biological research. New York: Alan R. Liss. 1985:327-42.

18. Balner H. Bone marrow transplantation and other treatment after radiation injury. The Hague, Netherlands: Martinus Nijhoff. 197.

© 1989 Massachusetts Medical Society. All rights reserved.
Originally published: N Engl J Med. 1989 Oct 26;321(17):1174-8. PMID: 2571931

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Case Report

The patient, a five-year-old boy, was first noted to have pancytopenia at 24 months of age. An evaluation (Duke University Medical Center) showed the following hematologic values: hemoglobin concentration, 9.5 g per deciliter; white-cell count, 4.3 x 109 per liter, with 22 percent granulocytes, 62 percent lymphocytes, 3 percent monocytes, 1 percent eosinophils, and 8 percent basophils; platelet count, 62 x 109 per liter; and reticulocyte level, 2.3 percent. The bone marrow was hypocellular. The patient had the classic malformations of Fanconi's anemia, including retarded growth (5th to 10th percentile), a rudimentary extra thumb on the left hand, the absence of a left kidney, and hypospadias. Testing of the patient's cells with diepoxybutane, performed at 24 months (Rockefeller University), confirmed the diagnosis of Fanconi's anemia. The parents were healthy, and there was no consanguinity or past history of blood disorders in the family. The patient had been treated with danazol (300 mg per day for six months), with a progressive decrease in the blood-cell counts. Before admission, he had received three units of filtered and irradiated packed red cells.

The patient's mother became pregnant in June 1987. Cytogenetic analysis of cultured amniotic-fluid cells (Rockefeller University) showed that the values for chromosome breakage before and after the cells were exposed to diepoxybutane were within the normal range [5]. A girl was delivered vaginally without complications in February 1988. Studies of chromosome breakage in umbilical-cord blood cells indicated that the newborn had a normal karyotype and was not affected by Fanconi's anemia (Table 1).

Table 1. Results of Cytogenetic Analysis.*
*DEB denotes diepoxybutane; its final concentration in the culture medium was 0.1 mg per milliliter in each analysis in this table.
†Analysis performed on quinacrine-stained metaphase preparations.
‡Analysis performed on Giemsa-stained metaphase preparations.

Source Of Cells

Percent Donor
Cells In Sample†

Mean Chromosome  
Breaks/Cell‡  

before deb 

after deb  

before deb 

after deb 

Patient's peripheral blood on day 0    

0

0

0.18

10.6

Donor's cord blood on day 0

100

100

0.00

0.02

Patient's bone marrow on day 120

100

100

0.04

0.30

Patient's peripheral blood
Day 50

30

52

0.7

4.0

Day 64

8

32

1.3

5.0

Day 120

12

32

1.9

6.4

Day 204

64

86

0.30

0.49


Prenatal HLA typing of amniotic-fluid cells (Dr. M.S. Pollack, Methodist Hospital and Baylor Medical Center, Houston) had shown that the fetus was HLA identical to the patient: the first haplotype was Al,B8,DR3, and the second haplotype A29,B44,DR3. Mixed lymphocyte cultures of cells from the patient with cells from the cord blood and peripheral blood of the donor were negative. The cord-blood cells were less reactive against a pool of allogeneic cells than were the peripheral-blood cells (incorporation of [3H]thymidine, 15,437 vs. 112,954 cpm). The ABO blood group of the donor was O Rh+, and that of the recipient B Rh+.

The patient was admitted in September 1988, with the following hematologic values: hemoglobin concentration, 6.8 g per deciliter; white-cell count, 3.1 x 109 per liter, with 7 percent granulocytes, 86 percent lymphocytes, and 5 percent monocytes; and platelet count, 18 x 109 per liter. The marrow was hypocellular, with 10 percent of normal cellularity, 24 percent myeloid cells, 2 percent erythroblast cells, 67 percent lymphocytes, and no megakaryocytes. There were no hemorrhagic or infectious complications of the patient's illness. His liver and kidney functions were normal. Serologic tests were positive for cytomegalovirus (on enzyme-linked immunosorbent assay) and negative for human immunodeficiency virus, hepatitis B, and toxoplasmosis.

The patient was isolated in a room with laminar airflow, and treatment with oral broad-spectrum nonabsorbable antibiotics (vancomycin, tobramycin, and colistin [Colimycine]) was started nine days before transplantation (on day -8). Fluconazole (50 mg per day) was administered to prevent fungal infection, and oral acyclovir (100 mg per day) to prevent herpes simplex virus infection. For pretransplantation conditioning, cyclophosphamide (5 mg per kilogram of body weight) was given intravenously for four consecutive days (from day -6 to day -3; total, 380 mg) along with hyperhydration. Irradiation was delivered to the thoracoabdominal region by a linear accelerator on day -1 (mean rate, 10.87 cGy per minute), for a total of 5 Gy over a period of 46 minutes; the abdomen received 500 cGy, and the lungs and the right liver lobe, which were shielded, received 67 cGy.

On the day of transplantation (day 0 – October 6, 1988), cryopreserved umbilical-cord blood was thawed and infused without further processing, according to predetermined optimal conditions12 (the surviving whole red cells that had not been hemolyzed belonged to group O). The patient received 0.4 x 108 nucleated cells per kilogram, of which a total of 4.37 x 105 were CFU-GM (as determined by assay in Paris). Two hours after the infusion, the patient had chills, fever, and hypotension. These symptoms soon resolved, while the patient was receiving the broad-spectrum antibiotics vancomycin and ceftazidime intravenously. For prophylaxis against graft-versus-host disease, cyclosporine was administered intravenously from day – 1 (4.5 mg per kilogram per day), according to a preliminary pharmacokinetic study. All blood products were irradiated (25 Gy).

Ethical and Regulatory Considerations

Written informed consent was obtained from the patient's parents for collecting the umbilical-cord blood and for the transplantation procedure. The treatment plan was reviewed and approved by the institutional review board for clinical investigation of the Duke University Medical Center and by the ethics committee of the Hôpital Saint-Louis. Approval for the receipt, cryopreservation, storage, and release of cord blood was received from the institutional review board of the Indiana University School of Medicine. The Food and Drug Administration considered the procedure equivalent to the storage and transplantation of bone marrow, which are currently not subject to its regulation.

Methods

Cytogenetic Studies

Chromosome-breakage studies were performed as described elsewhere [4]. Diepoxybutane was added to bone marrow cultures when they were begun, and the cultured cells were harvested after 24 hours. Peripheral blood was cultured in the presence of phytohemagglutinin for 72 hours; diepoxybutane was present in the medium during the last 48 hours of culture. The frequency of chromosome breakage before and after the addition of diepoxybutane was analyzed in Giemsa-stained metaphase preparations; the ratio of cells from the patient to cells from the donor (male:female) was determined on quinacrine-stained slides to facilitate the identification of the Y chromosome.

DNA Studies: Restriction-Fragment-Length Polymorphism

DNA samples obtained for Southern blotting were digested with Taq1 (New England Biolabs, Beverly, Mass.), separated by gel electrophoresis, transferred to an Immobilon-N filter (Millipore Corp., Bedford, Mass.), hybridized, and washed as previously described [13]. The probe used was CRI-pS232 (DXS278) (Collaborative Research, Boston), which hybridizes with sequences from the X and Y chromosomes.

Collection, Storage, and Shipment of Neonatal Blood

Immediately after the birth of the patient's sister, blood was obtained from her umbilical cord and the placenta as described elsewhere [12] and transported at ambient temperature by overnight express service to a laboratory for cellular analysis, cryopreservation, and storage (Indiana University School of Medicine). A sample of cord blood was also sent elsewhere for cytogenetic analysis (Rockefeller University). After a small sample (<2 ml) had been set aside for laboratory tests, including the determination of the level of nucleated cells and the enumeration of progenitor cells, the blood was frozen without further treatment in dimethyl sulfoxide at a final concentration of 10 percent (vol/vol) as previously described [12]. Two bags of cord blood and one bag of placental blood were frozen. Samples (about 1 ml each in Nunc tubes) were similarly frozen for testing of cell recovery after thawing and for confirmation of the HLA types. The volume of blood and the numbers of nucleated and progenitor cells collected are shown in Table 2. These values were within the range associated with successful transplantation of HLA–matched allogeneic bone marrow [12]. Testing of thawed cells, including those in one tube sent from Indiana University to Duke University Medical Center (where the HLA types were confirmed), demonstrated recovery of 79 percent to 90 percent of nucleated cells; on day 14, the mean (±1 SEM) rates of recovery were 100 percent ofCFU-GM, 63±18 percent of BFU-E, and 79±15 percent of CFU-GEMM.

Table 2. Hematopoietic Progenitor Cells in Blood from the Umbili­cal Cord and Placenta of the Donor and Bone Marrow from the Recipient.
* The preparation for the assays has been described elsewhere [12]. The assays of the cord blood and the bone marrow on day 120 were performed in Indianapolis, and those of the bone marrow at day 0 and day 30 in Paris.
† Plus-minus values are means ± 1 SEM; ND denotes not done.
‡ The total volume of cord and placental blood collected was 160 ml and contained 1.19 x 109 nucleated cells.
§ Normal range (Indianapolis laboratory) for low-density cells. 10 to 70 for CFU-GM and 15 to 80 for BFU-E-1 and BFU-E-2.
These were mainly microclusters, with less than 20 cells per cluster.

Source of Cells

Progenitor Cells†

all densities  

low density
(<1.077 g/ml)

Donor (cord and placental blood)‡

total cells x 10-5

Agar culture
Day 14 CFU-GM (colonies)

1.52

ND

Day 14 CFU-GM (colonies and clusters)

2.46

ND

Methylcellulose culture (colonies)
Day 14 CFU-GM

1.56

ND

BFU-E-2

3.95

ND

BFU-E-1

3.60

ND

CFU-GEMM

0.39

ND

Recipient (bone marrow)

cells/105 cells plated§

Methylcellulose culture, day 0
Day 14 CFU-GM (colonies)

ND

1

Day 14 CFU-GM (colonies and clusters)  

ND

8

BFU-E-1

ND

0

CFU-GEMM

ND

0

Methylcellulose culture, day 30
Day 14 CFU-GM (colonies)

ND

9

BFU-E-1

ND

0

CFU-GEMM

ND

0

Agar culture, day 120
Day 7 CFU-GM (colonies)

22±2

140±12

Day 7 CFU-GM (colonies and clusters)

118±16

416±20

Day 14 CFU-GM (colonies)

36±4

156±8

Day 14 CFU-GM (colonies and clusters)

152±4

228±12

Methylcellulose culture, day 120
Day 14 CFU-GM (colonies)

324±16

416±25

BFU-E-2

77±2

134±6

BFU-E-1

96±8

132±10

CFU-GEMM

4±1

9±1


The two bags of frozen cord blood and the bag of placental blood were sent with an escort by air (with the approval of the airline) to the Hôpital Saint-Louis from Indiana University two weeks before transplantation. The bags were sent in a Dry Shipper container (CMC-3200 wide mouth with platform; Cryomed, New Baltimore, Mich.) maintained at -175°C, a temperature optimal for cryopreservation.

Hematopoietic Progenitor Cells in Vitro

Assays were prepared as previously described [12]. In the CFU-GM assay, colonies (>40 cells per aggregate) and clusters (3 to 40 cells per aggregate) were scored after 7 days and 14 days of incubation in agar culture medium. Large-sized colonies formed (>1000 cells). Cell counts were expressed also as colonies plus clusters, for a more accurate estimate of the total CFU-GM compartment. In the assays for BFU-E, CFU-GEMM, and CFU-GM, colonies were scored after 14 days of incubation in methylcellulose culture medium. In the BFU-E-1, CFU-GEMM, and CFU-GM assays, colonies were scored from the same plates, which included erythropoietin (1 unit per milliliter), hemin (0.1 mM), and 5637 conditioned medium (10 percent vol/vol). BFU-E-2 cells were cultured as BFU-E-1, but without 5637 conditioned medium. Each BFU-E-2 colony contained at least 50 cells or comprised at least three subcolonies, each of which contained at least 10 cells, but were usually much larger. Colonies derived from BFU-E-1 were much larger than those derived from BFU-E-2.

Thawing and Recovery of Cells

Eighty-two percent of nucleated cells of the thawed blood transfused into the patient were viable. Progenitor-cell assays performed in Paris (which differed slightly in technique from assays performed in Indianapolis) indicated that the rate of cell recovery was equal to or greater than the count of progenitor cells recorded before freezing.

Results

Clinical Findings

The clinical course of the patient was uneventful and without complications. He tolerated the pretransplantation conditioning without evident toxic effects. On day 15, a transient skin rash and fever resolved with methylprednisolone treatment (2 mg per kilogram). A skin biopsy revealed few vacuolar basal epidermal cells with a mild lymphoid infiltrate, indicative of grade I graft-versus-host disease as defined according to the Seattle classification [14]. Liver-function tests showed that the serum levels of aspartate and alanine aminotransferases were twice normal, probably as a result of the graft-versus-host disease; values returned to normal on day 47. Cytomegalovirus was repeatedly isolated from the urine, but the patient never had any signs of active infection, and all tests for viremia were negative. Five months after transplantation the patient was discharged with normal clinical and laboratory findings. The doses of cyclosporine and corticosteroids were progressively reduced, and the drugs were discontinued at six months. At present (nine months after transplantation), the patient has no chronic graft-versus-host disease and leads a normal life.

Hematologic Findings

The blood-cell counts began to return to normal (Table 3).

Table 3. Blood-Cell Counts before and after Transplantation

Day

Hemoglobin

Leukocytes

Granulocytes

Lymphocytes

Platelets

Reticuloytes

g/dl

no. of cells x 10-9 per liter

-20

6.8

3.1

0.25

2.8

18

10

0

9.7

0.8

0.0

0.8

120

0

8

10.9

0.4

0.0

0.4

80

0

15

11.6

0.4

0.0

0.4

39

0

22

7.8

0.9

0.3

0.6

50

5

29

8.5

1.0

0.3

0.5

105

17

36

9.4

1.7

0.6

0.5

55

36

43

11.3

5.1

2.4

1.9

31

90

50

8.9

3.4

1.5

0.7

62

162

57

8.9

5.6

3.2

1.0

174

63

90

11.3

5.1

4.0

1.1

296

50

120

13.0

3.9

2.3

1.1

265

40

160

12.0

3.7

1.4

1.6

293

45

240

12.3

5.2

2.7

1.6

354

50

282

12.2

4.8

2.3

1.2

315

---

The reticulocyte and granulocyte counts had begun to rise by day 22 after transplantation. The patient received eight transfusions of packed red cells (O Rh+) and 48 units of random platelets. Red cells were last transfused on day 54, and platelets on day 43. Bone marrow aspirated on day 17 was aplastic: an evaluation on day 28 showed 20 percent cellularity, with 19 percent myeloid cells, 73 percent erythroid cells, and few megakaryocytes. On day 120, the marrow had normal cellularity, with 40 percent myeloid cells, 44 percent erythroid cells, and a normal level of megakaryocytes.

Hematopoietic Progenitor Cells

Before transplantation, the marrow contained few or no detectable progenitor cells (Table 2). At 30 days after transplantation, CFU-GM cells were detected but not BFU-E or CFU-GEMM; at 120 days, progenitors were apparent at normal to supranormal frequencies (colonies or clusters per number of cells plated).

Reconstitution by Donor Cells

Blood- Type Studies
The patient's red cells (B Rh+) disappeared progressively and became undetectable on day 90 after transplantation; 46 days after the last transfusion, 100 percent of red cells were of the donor's blood type (O Rh+) and were found to have remained so at 240 days after transplantation.

Cytogenetic Studies
Table 1 shows the results of cytogenetic studies of bone marrow aspirated on day 120 and peripheral blood obtained on days 50, 64, 120, and 204. The chromosomal complement of the bone marrow was 46,XX. No cells of the patient (male cells) in metaphase were seen among 50 quinacrine-stained or 100 Giemsa-stained cells analyzed. The chromosomebreakage frequencies were 0.04 and 0.30 breaks per cell in the base-line and diepoxybutane-treated cultures, respectively.

Through day 120 after transplantation, more than half the metaphases seen in cytogenetic preparations of phytohemagglutinin-stimulated peripheral-blood cultures were of host origin, as indicated by the presence of a Y chromosome. These cells, of lymphoid origin, had greatly elevated levels of chromosome breakage at base line and severe radiation damage, manifested by the presence of multiple dicentrics, rings, and chromosomal fragments; they were also hypersensitive to the clastogenic effect of diepoxybutane, showing multiple chromatid breaks and exchanges typical of the cells characterizing Fanconi's anemia. The cells of donor origin (female) did not have elevated levels of chromosome breakage. By day 204 (61/2 months after transplantation), the majority of peripheral-blood lymphocytes were of donor origin.

These findings reflected engraftment with the donor cells and survival of a minor population of radiationdamaged host cells in the blood – an outcome similar to that in reports of bone marrow transplantation by others [15].

DNA Studies
The CRI-pS232 probe recognizes a complex set of fragments at a highly polymorphic locus on the X chromosome, as well as a polymorphic locus on the Y chromosome [16]. In the present case, all the variable bands present in the DNA of the donor were seen in the DNA extracted from the peripheral blood of the recipient after transplantation (Fig. 1). In addition, the X and Y alleles of the recipient were seen as faint bands, indicating some chimerism in the peripheral blood, with primarily donor cells present.

Gluckman-Fig-1.png

Figure 1. Southern Blot Analysis of DNA from the Patient and His Family.

DNA was extracted from the peripheral blood of the father (lane 1), the mother (lane 2), the patient before transplantation (lane 3), the patient's HI.A-identical sister (lane 4), the patient's HA non-identical sister (lane 5), and the patient on post-transplantation day 50 (lane 6), day 64 (lane 7), and day 120 (lane 8).

The DNA obtained from the patient after transplantation was primarily of donor origin. Each DNA sample was digested with the restriction enzyme Taq1 and examined with the probe CRI-pS232, which recognizes a complex set of fragments at a highly polymorphic locus on the X chromosome as well as a locus on the Y chromosome. The thick arrows indicate X-specific bands from the donor, and the thin arrows denote those from the recipient. Y-specific bands are seen at 4.9 and 3.8 kb. A constant band at 3.0 kb is seen in the DNA of all the subjects.


Discussion

Bone marrow and, under certain circumstances, the blood of adults (see references cited by Broxmeyer et al [12]) and the liver of fetuses [17] have been used in the transplantation of hematopoietic cells. The clinical and biologic data presented above show that the umbilical-cord blood of a single newborn is sufficient to induce hematopoietic reconstitution. The virtually complete occupation of the patient's myeloid system by cells from his sibling was indicated by the cytogenetic studies, blood typing, and studies of DNA polymorphisms and by the absence of undue chromosomal fragility. At present, a small percentage of lymphoid cells with chromosome damage remains in the circulation, but there has been a trend toward the elimination of these damaged cells.

There may be several reasons why cellular repopulation was somewhat delayed in our patient as compared with patients who have undergone transplantation with HLA-matched allogeneic (sibling) bone marrow. For instance, cells that have been frozen and thawed may take longer than fresh cells to seed, respond, and differentiate in their respective inducing microenvironments. Also, consistent with the relative paucity of CFU-GM on day 7 as compared with the more immature CFU-GM on day 14 [12], umbilical-cord blood may typically have a profile with immaturity and less differentiation of hematopoietic stem and progenitor cells. The modified conditioning regimen was adequate to permit complete engraftment with 0.4 x 108 total nucleated cord-blood cells per kilogram, as compared with the mean of 3 x 108 total nucleated bone marrow cells per kilogram that is usually given for bone marrow transplantation.

The use of cord blood in the treatment of Fanconi's anemia may be extended to the treatment of other conditions for which bone marrow transplantation is indicated, and demonstrates the potential of cryopreservation for prospective use of autologous blood.

In the latter respect, our success with allogeneic cord blood is particularly important, because studies in animals have shown that fewer reconstituting cells are required to restore hematopoietic function when these are syngeneic rather than allogeneic [18].

Thus, umbilical-cord blood can be considered an efficacious source of sufficient cells for clinical hematopoietic reconstitution.

Acknowledgements

We are indebted to Dr. Bo Dupont (Sloan-Kettering Institute for Cancer Research) for suggesting the clinical application in Fanconi's anemia, to Dr. Marilyn Pollack (Baylor Medical Center) for HLA typing of the amniotic cells, to Dr. Rebecca H. Buckley (Duke University) for the data from the mixed lymphocyte cultures, to Rita Ghosh, Lui Qian, and Drew Olsen (Rockefeller University) for technical help with the cytogenetic studies, to Dr. William Mann and V.S. Venkatraj (Rockeleller University) for DNA analysis, to Françoise Varrin (Paris) for technical assistance in the assessment of hematopoietic progenitors, to Ms. Linda Cheung (Indiana University) for help in preparing the manuscript, and to Collaborative Research for the probe pS232.

Supported in part by grants from the Biocyte Corporation, by grants (CA36464 and CA-36740 to Dr. Broxmeyer and CA-39827 to Dr. Boyse) from the National Cancer Institute, by a grant (HL-32987 to Dr. Auerbach) from the National Institutes of Health, and by a grant from the Pew Memorial Trust to Rockefeller University. Dr. Boyse holds a Research Professorship from the American Cancer Society, and Dr. Kurtzberg is a Special Fellow of the Leukemia Society of America. In accordance with the Journal's policy, the authors have provided the following information: Dr. Broxmeyer, Dr. Douglas, Ms. Bard, and Dr. Boyse are shareholders in Biocyte Corporation (New York), and Dr. Douglas and Dr. Boyse are members of its board of directors.

References

1. Fanconi G. Familial constitutional panmyelocytopathy, Fanconi's anemia (F.A.). L Clinical aspects. Semin Hematol. 1967;4:233-40. pmid: 6074578.

2. Schroeder TM, Tilgen D, Kruger J, Vogel F. Formal genetics of Fanconi's anemia. Hum Genet. 1976;32:257-88. pmid: 939547.

3. Auerbach AD, Rogatko A, Schroeder-Kurth TM. international Fanconi Anemia Registry: relation of clinical symptoms to diepoxybutane sensitivity. Blood. 1989;73:391-6.

4. Auerbach AD, Wolman SR. Susceptibility of Fanconi's anaemia fibroblasts to chromosome damage by carcinogens. Nature. 1976;261:494-6. pmid: 934283.

5. Auerbach AD, Sagi M, Adler B. Fanconi anemia: prenatal diagnosis in 30 fetuses at risk. Pediatrics. 1985;76:794-800. pmid: 4058989.

6. Auerbach AD, Min Z, Ghosh R, et al. Clastogen-induced chromosomal breakage as a marker for first trimester prenatal diagnosis of Fanconi anemia. Hum Genet. 1986;73:86-8. pmid: 3458668.

7. Callaway C, Falcon C, Grant G, et al. HLA typing used with cultured amniotic and chorionic villus cells for early prenatal diagnosis or parentage testing without one parent's availability. Hum Immunol. 1986;16:200-4. doi:10.1016/0198-8859(86)90048-0.

8. Gluckman E, Devergie A, Dutreix J. Bone marrow transplantation for Fanconi's anemia. In: Schroeder-Kurth TM, Auerbach AD, Obe G, eds. Fanconi anemia: clinical, cytogenetic and experimental aspects. New York: Springer-Verlag. 1989:60-8.

9. Gluckman E, Devergie A, Schaison G, et al. Bone marrow transplantation in Fanconi anemia. Br J Haematol. 1980;45:557-64. pmid: 7000153.

10. Berger R, Bernheim A, Gluckman E, Gisselbrecht C. In vitro effect of cyclophosphamide metabolites on chromosomes of Fanconi anaemia patients. Br J Haematol. 1980;45:565-8. pmid: 7426437.

11. Gluckman E, Devergie A, Dutreix J. Radiosensitivity in Fanconi anaemia: application to the conditioning regimen for bone marrow transplantation. Br J Haematol. 1983;54:431-40. pmid: 6344915.

12. Broxmeyer HE, Douglas GW, Hangoc G, et al. Human umbilical cord blood as a potential source of transplantable hematopoietic stem/progenitor cells. Proc Natl Acad Sci USA. 1989;86:3828-32.

13. Mann W, Venkatraj VS, Auerbach AD. Two hour hybridization using a new transfer membrane. Nucleic Acids Res. 1989;17:5410.

14. Sale GE, Lerner KG, Barker EA, Shulman HM, Thomas ED. The skin biopsy in the diagnosis of acute graft-versus-host disease in man. Am 1 Pathol. 1977;89:621-35.

15. Butturini A, Seeger RC, Gale RP. Recipient immune-competent T lymphocytes can survive intensive conditioning for bone marrow transplantation. Blood. 1986;68:954-6.

16. Knowlton RG, Nelson CA, Brown VA, Page DC, Donis-Keller H. An extremely polymorphic locus on the short arm of the human X chromosome with homology to the long arm of the Y chromosome. Nucleic Acids Res. 1989;17:423-37.

17. Gale RP, Touraine 1-L, Lucarelli G, eds. Fetal liver transplantation: proceedings of an international symposium held in Pesaro, Italy, September 29-October I, 1984. Vol. 193. Progress in clinical and biological research. New York: Alan R. Liss. 1985:327-42.

18. Balner H. Bone marrow transplantation and other treatment after radiation injury. The Hague, Netherlands: Martinus Nijhoff. 197.

© 1989 Massachusetts Medical Society. All rights reserved.
Originally published: N Engl J Med. 1989 Oct 26;321(17):1174-8. PMID: 2571931

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Гиперчувствительность к кластогенным эффектам – разрывам хромосом под действием препаратов, способствующих сшивке цепей ДНК, таких как диэпоксибутан, используется как диагностический признак генотипа анемии Фанкони, как пре- так и постнатально. Пренатальное <br>HLA-типирование даёт возможность установить, является ли плод HLA-идентичным больному сиблингу. <br /><br />Мы описываем здесь восстановление гемопоэза у мальчика с тяжёлой формой анемии Фанкони, которому была введена криоконсервированная пуповинная кровь сестры, не поражённой, по данным пренатального тестирования, данным заболеванием, имевшей нормальный кариотип и HLA-идентичный фенотип. <br /><br />Мы использовали претрансплантационный режим кондиционирования, разработанный специально для таких больных; метод основан на гиперчувствительности аномальных клеток к алкилирующим агентам, вызывающих сшивки цепей ДНК, и воздействию радиации. Метод позволяет использовать  пуповинную кровь и избежать забора клеток костного мозга  у новорожденного сиблинга. Такое применение пуповинной крови вытекало из предположения одного из нас о том, что кровь, взятая из пуповинной вены при рождении и обычно не используемая, может восстанавливать гемопоэз – предположении, основанном на наших предварительных исследованиях, согласующихся с сообщениями о наличии гемопоэтических стволовых и мультипотентных (CFU-GEMM), эритроидных (BFU-E) и гранулоцитарно-макрофагальных (CFU-GM) клеток-предшественников в пуповинной крови человека (см. ссылки в работе Broxmeyer et al.).<br /><br /> <h3>Ключевые слова</h3> <p> анемия, апластическая терапия, консервация крови, анемия Фанкони, женская особь, плодная кровь, HLA антигены, трансплантация гемопоэтических стволовых клеток, тестирование гистосовместимости, человек, мужская особь, беременность, пренатальный диагноз, дети дошкольного возраста </p>" ["ELEMENT_PREVIEW_PICTURE_FILE_TITLE"]=> string(193) "Восстановление гемопоэза у больного анемией Фалькони с помощью пуповинной крови HLA-идентичного сиблинга" 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Фалькони с помощью пуповинной крови HLA-идентичного сиблинга" ["SECTION_PICTURE_FILE_NAME"]=> string(100) "vosstanovlenie-gemopoeza-u-bolnogo-anemiey-falkoni-s-pomoshchyu-pupovinnoy-krovi-hla-identichnogo-si" ["SECTION_DETAIL_PICTURE_FILE_ALT"]=> string(193) "Восстановление гемопоэза у больного анемией Фалькони с помощью пуповинной крови HLA-идентичного сиблинга" ["SECTION_DETAIL_PICTURE_FILE_TITLE"]=> string(193) "Восстановление гемопоэза у больного анемией Фалькони с помощью пуповинной крови HLA-идентичного сиблинга" ["SECTION_DETAIL_PICTURE_FILE_NAME"]=> string(100) "vosstanovlenie-gemopoeza-u-bolnogo-anemiey-falkoni-s-pomoshchyu-pupovinnoy-krovi-hla-identichnogo-si" ["ELEMENT_PREVIEW_PICTURE_FILE_NAME"]=> string(100) "vosstanovlenie-gemopoeza-u-bolnogo-anemiey-falkoni-s-pomoshchyu-pupovinnoy-krovi-hla-identichnogo-si" ["ELEMENT_DETAIL_PICTURE_FILE_NAME"]=> string(100) "vosstanovlenie-gemopoeza-u-bolnogo-anemiey-falkoni-s-pomoshchyu-pupovinnoy-krovi-hla-identichnogo-si" } 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Броксмайер, Арлин Д. Ауэрбах, Генри С. Фридман, Гордон У. Дуглас, Агнес Девержи, Элен Эсперо, Доминик Тьерри, Жерар Соси, Пьер Лен, Скотт Купер, Денис Инглиш, Джоан Кюртцберг, Юдифь Бард, Эдвард А. Бойз</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(404) "

Элиана Глюкман, Хэл Е. Броксмайер, Арлин Д. Ауэрбах, Генри С. Фридман, Гордон У. Дуглас, Агнес Девержи, Элен Эсперо, Доминик Тьерри, Жерар Соси, Пьер Лен, Скотт Купер, Денис Инглиш, Джоан Кюртцберг, Юдифь Бард, Эдвард А. Бойз

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Клинические проявления анемии Фанкони, аутосомной рецессивной болезни, включают прогрессирующую панцитопению, предрасположенность к злокачественным опухолям и развитию аномалий, не связанных с гемопоэзом. Гиперчувствительность к кластогенным эффектам – разрывам хромосом под действием препаратов, способствующих сшивке цепей ДНК, таких как диэпоксибутан, используется как диагностический признак генотипа анемии Фанкони, как пре- так и постнатально. Пренатальное
HLA-типирование даёт возможность установить, является ли плод HLA-идентичным больному сиблингу.

Мы описываем здесь восстановление гемопоэза у мальчика с тяжёлой формой анемии Фанкони, которому была введена криоконсервированная пуповинная кровь сестры, не поражённой, по данным пренатального тестирования, данным заболеванием, имевшей нормальный кариотип и HLA-идентичный фенотип.

Мы использовали претрансплантационный режим кондиционирования, разработанный специально для таких больных; метод основан на гиперчувствительности аномальных клеток к алкилирующим агентам, вызывающих сшивки цепей ДНК, и воздействию радиации. Метод позволяет использовать  пуповинную кровь и избежать забора клеток костного мозга  у новорожденного сиблинга. Такое применение пуповинной крови вытекало из предположения одного из нас о том, что кровь, взятая из пуповинной вены при рождении и обычно не используемая, может восстанавливать гемопоэз – предположении, основанном на наших предварительных исследованиях, согласующихся с сообщениями о наличии гемопоэтических стволовых и мультипотентных (CFU-GEMM), эритроидных (BFU-E) и гранулоцитарно-макрофагальных (CFU-GM) клеток-предшественников в пуповинной крови человека (см. ссылки в работе Broxmeyer et al.).

Ключевые слова

анемия, апластическая терапия, консервация крови, анемия Фанкони, женская особь, плодная кровь, HLA антигены, трансплантация гемопоэтических стволовых клеток, тестирование гистосовместимости, человек, мужская особь, беременность, пренатальный диагноз, дети дошкольного возраста

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Eliane Gluckman1, Hal E. Broxmeyer2, Arleen D. Auerbach3, Henry S. Friedman4, Gordon W. Douglas5, Agnes Devergie1, Helene Esperou1, Dominique Thierry6, Gerard Socie1, Pierre Lehn1, Scott Cooper2, Denis English2, Joanne Kurtzberg4, Judith Bard7, and Edward A. Boyse7

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1Bone Marrow Transplant Unit, Hôpital Saint-Louis, Paris, France; 2Departments of Medicine (Hematology/Oncology), Microbiology and Immunology, Pathology, and the Walther Oncology Center, Indiana University School of Medicine, Indianapolis, USA; 3Laboratory for Investigative Dermatology, Rockefeller University, New York, USA; 4Department of Pediatrics (Hematology/Oncology), Duke University Medical Center, Durham, N.C., USA; 5Department of Obstetrics and Gynecology, New York University Medical Center, New York, USA; 6Central Nuclear Agency, Paris, France; 7Memorial Sloan-Kettering Cancer Center, New York, USA.

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The clinical manifestations of Fanconi's anemia, an autosomal recessive disorder, include progressive pancytopenia, a predisposition to neoplasia, and nonhematopoietic developmental anomalies [1-3]. Hypersensitivity to the clastogenic effect of DNA-cross-linking agents such as diepoxybutane acts as a diagnostic indicator of the genotype of Fanconi's anemia, both prenatally and postnatally [3-6]. Prenatal HLA typing has made it possible to ascertain whether a fetus is HLA-identical to an affected sibling [7].
We report here on hematopoietic reconstitution in a boy with severe Fanconi's anemia who received cryo-preserved umbilical-cord blood from a sister shown by prenatal testing to be unaffected by the disorder, to have a normal karyotype, and to be HLA-identical to the patient. We used a pretransplantation conditioning procedure developed specifically for the treatment of such patients [8]; this technique makes use of the hypersensitivity of the abnormal cells to alkylating agents that cross-link DNA [9, 10] and to irradiation [11] In this case, the availability of cord blood obviated the need for obtaining bone marrow from the infant sibling.
This use of cord blood followed the suggestion of one of us that blood retrieved from umbilical cord at delivery, usually discarded, might restore hematopoiesis – a proposal supported by preparatory studies by some of us [12] and consistent with reports on the presence of hematopoietic stem and multipotential (CFU-GEMM), erythroid (BFU-E), and granulocyte-macrophage (CFU-GM) progenitor cells in human umbilical-cord blood (see the references cited by Broxmeyer et al. [12]).

Keywords

anemia, aplastic therapy, blood preservation, Fanconi anemia, female, fetal blood, HLA antigens, hematopoietic stem cell transplantation, histocompatibility testing, humans, male, pregnancy, prenatal diagnosis, preschool child

© 1989 Massachusetts Medical Society. All rights reserved.
Originally published: N Engl J Med. 1989 Oct 26;321(17):1174-8. pmid: 2571931

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Broxmeyer</strong><sup>2</sup><strong>, Arleen D. Auerbach</strong><sup>3</sup><strong>, Henry S. Friedman</strong><sup>4</sup><strong>, Gordon W. Douglas</strong><sup>5</sup><strong>, Agnes Devergie</strong><sup>1</sup><strong>, Helene Esperou</strong><sup>1</sup><strong>, Dominique Thierry</strong><sup>6</sup><strong>, Gerard Socie<sup>1</sup>, Pierre Lehn</strong><sup>1</sup><strong>, Scott Cooper</strong><sup>2</sup><strong>, Denis English</strong><sup>2</sup><strong>, Joanne Kurtzberg</strong><sup>4</sup><strong>, Judith Bard</strong><sup>7</sup><strong>, and Edward A. Boyse</strong><sup>7</sup></p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(675) "

Eliane Gluckman1, Hal E. Broxmeyer2, Arleen D. Auerbach3, Henry S. Friedman4, Gordon W. Douglas5, Agnes Devergie1, Helene Esperou1, Dominique Thierry6, Gerard Socie1, Pierre Lehn1, Scott Cooper2, Denis English2, Joanne Kurtzberg4, Judith Bard7, and Edward A. Boyse7

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Eliane Gluckman1, Hal E. Broxmeyer2, Arleen D. Auerbach3, Henry S. Friedman4, Gordon W. Douglas5, Agnes Devergie1, Helene Esperou1, Dominique Thierry6, Gerard Socie1, Pierre Lehn1, Scott Cooper2, Denis English2, Joanne Kurtzberg4, Judith Bard7, and Edward A. Boyse7

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The clinical manifestations of Fanconi's anemia, an autosomal recessive disorder, include progressive pancytopenia, a predisposition to neoplasia, and nonhematopoietic developmental anomalies [1-3]. Hypersensitivity to the clastogenic effect of DNA-cross-linking agents such as diepoxybutane acts as a diagnostic indicator of the genotype of Fanconi's anemia, both prenatally and postnatally [3-6]. Prenatal HLA typing has made it possible to ascertain whether a fetus is HLA-identical to an affected sibling [7].
We report here on hematopoietic reconstitution in a boy with severe Fanconi's anemia who received cryo-preserved umbilical-cord blood from a sister shown by prenatal testing to be unaffected by the disorder, to have a normal karyotype, and to be HLA-identical to the patient. We used a pretransplantation conditioning procedure developed specifically for the treatment of such patients [8]; this technique makes use of the hypersensitivity of the abnormal cells to alkylating agents that cross-link DNA [9, 10] and to irradiation [11] In this case, the availability of cord blood obviated the need for obtaining bone marrow from the infant sibling.
This use of cord blood followed the suggestion of one of us that blood retrieved from umbilical cord at delivery, usually discarded, might restore hematopoiesis – a proposal supported by preparatory studies by some of us [12] and consistent with reports on the presence of hematopoietic stem and multipotential (CFU-GEMM), erythroid (BFU-E), and granulocyte-macrophage (CFU-GM) progenitor cells in human umbilical-cord blood (see the references cited by Broxmeyer et al. [12]).

Keywords

anemia, aplastic therapy, blood preservation, Fanconi anemia, female, fetal blood, HLA antigens, hematopoietic stem cell transplantation, histocompatibility testing, humans, male, pregnancy, prenatal diagnosis, preschool child

© 1989 Massachusetts Medical Society. All rights reserved.
Originally published: N Engl J Med. 1989 Oct 26;321(17):1174-8. pmid: 2571931

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The clinical manifestations of Fanconi's anemia, an autosomal recessive disorder, include progressive pancytopenia, a predisposition to neoplasia, and nonhematopoietic developmental anomalies [1-3]. Hypersensitivity to the clastogenic effect of DNA-cross-linking agents such as diepoxybutane acts as a diagnostic indicator of the genotype of Fanconi's anemia, both prenatally and postnatally [3-6]. Prenatal HLA typing has made it possible to ascertain whether a fetus is HLA-identical to an affected sibling [7].
We report here on hematopoietic reconstitution in a boy with severe Fanconi's anemia who received cryo-preserved umbilical-cord blood from a sister shown by prenatal testing to be unaffected by the disorder, to have a normal karyotype, and to be HLA-identical to the patient. We used a pretransplantation conditioning procedure developed specifically for the treatment of such patients [8]; this technique makes use of the hypersensitivity of the abnormal cells to alkylating agents that cross-link DNA [9, 10] and to irradiation [11] In this case, the availability of cord blood obviated the need for obtaining bone marrow from the infant sibling.
This use of cord blood followed the suggestion of one of us that blood retrieved from umbilical cord at delivery, usually discarded, might restore hematopoiesis – a proposal supported by preparatory studies by some of us [12] and consistent with reports on the presence of hematopoietic stem and multipotential (CFU-GEMM), erythroid (BFU-E), and granulocyte-macrophage (CFU-GM) progenitor cells in human umbilical-cord blood (see the references cited by Broxmeyer et al. [12]).

Keywords

anemia, aplastic therapy, blood preservation, Fanconi anemia, female, fetal blood, HLA antigens, hematopoietic stem cell transplantation, histocompatibility testing, humans, male, pregnancy, prenatal diagnosis, preschool child

© 1989 Massachusetts Medical Society. All rights reserved.
Originally published: N Engl J Med. 1989 Oct 26;321(17):1174-8. pmid: 2571931

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1Bone Marrow Transplant Unit, Hôpital Saint-Louis, Paris, France; 2Departments of Medicine (Hematology/Oncology), Microbiology and Immunology, Pathology, and the Walther Oncology Center, Indiana University School of Medicine, Indianapolis, USA; 3Laboratory for Investigative Dermatology, Rockefeller University, New York, USA; 4Department of Pediatrics (Hematology/Oncology), Duke University Medical Center, Durham, N.C., USA; 5Department of Obstetrics and Gynecology, New York University Medical Center, New York, USA; 6Central Nuclear Agency, Paris, France; 7Memorial Sloan-Kettering Cancer Center, New York, USA.

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1Bone Marrow Transplant Unit, Hôpital Saint-Louis, Paris, France; 2Departments of Medicine (Hematology/Oncology), Microbiology and Immunology, Pathology, and the Walther Oncology Center, Indiana University School of Medicine, Indianapolis, USA; 3Laboratory for Investigative Dermatology, Rockefeller University, New York, USA; 4Department of Pediatrics (Hematology/Oncology), Duke University Medical Center, Durham, N.C., USA; 5Department of Obstetrics and Gynecology, New York University Medical Center, New York, USA; 6Central Nuclear Agency, Paris, France; 7Memorial Sloan-Kettering Cancer Center, New York, USA.

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Элиана Глюкман, Хэл Е. Броксмайер, Арлин Д. Ауэрбах, Генри С. Фридман, Гордон У. Дуглас, Агнес Девержи, Элен Эсперо, Доминик Тьерри, Жерар Соси, Пьер Лен, Скотт Купер, Денис Инглиш, Джоан Кюртцберг, Юдифь Бард, Эдвард А. Бойз

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Элиана Глюкман, Хэл Е. Броксмайер, Арлин Д. Ауэрбах, Генри С. Фридман, Гордон У. Дуглас, Агнес Девержи, Элен Эсперо, Доминик Тьерри, Жерар Соси, Пьер Лен, Скотт Купер, Денис Инглиш, Джоан Кюртцберг, Юдифь Бард, Эдвард А. Бойз

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Клинические проявления анемии Фанкони, аутосомной рецессивной болезни, включают прогрессирующую панцитопению, предрасположенность к злокачественным опухолям и развитию аномалий, не связанных с гемопоэзом. Гиперчувствительность к кластогенным эффектам – разрывам хромосом под действием препаратов, способствующих сшивке цепей ДНК, таких как диэпоксибутан, используется как диагностический признак генотипа анемии Фанкони, как пре- так и постнатально. Пренатальное
HLA-типирование даёт возможность установить, является ли плод HLA-идентичным больному сиблингу.

Мы описываем здесь восстановление гемопоэза у мальчика с тяжёлой формой анемии Фанкони, которому была введена криоконсервированная пуповинная кровь сестры, не поражённой, по данным пренатального тестирования, данным заболеванием, имевшей нормальный кариотип и HLA-идентичный фенотип.

Мы использовали претрансплантационный режим кондиционирования, разработанный специально для таких больных; метод основан на гиперчувствительности аномальных клеток к алкилирующим агентам, вызывающих сшивки цепей ДНК, и воздействию радиации. Метод позволяет использовать  пуповинную кровь и избежать забора клеток костного мозга  у новорожденного сиблинга. Такое применение пуповинной крови вытекало из предположения одного из нас о том, что кровь, взятая из пуповинной вены при рождении и обычно не используемая, может восстанавливать гемопоэз – предположении, основанном на наших предварительных исследованиях, согласующихся с сообщениями о наличии гемопоэтических стволовых и мультипотентных (CFU-GEMM), эритроидных (BFU-E) и гранулоцитарно-макрофагальных (CFU-GM) клеток-предшественников в пуповинной крови человека (см. ссылки в работе Broxmeyer et al.).

Ключевые слова

анемия, апластическая терапия, консервация крови, анемия Фанкони, женская особь, плодная кровь, HLA антигены, трансплантация гемопоэтических стволовых клеток, тестирование гистосовместимости, человек, мужская особь, беременность, пренатальный диагноз, дети дошкольного возраста

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Клинические проявления анемии Фанкони, аутосомной рецессивной болезни, включают прогрессирующую панцитопению, предрасположенность к злокачественным опухолям и развитию аномалий, не связанных с гемопоэзом. Гиперчувствительность к кластогенным эффектам – разрывам хромосом под действием препаратов, способствующих сшивке цепей ДНК, таких как диэпоксибутан, используется как диагностический признак генотипа анемии Фанкони, как пре- так и постнатально. Пренатальное
HLA-типирование даёт возможность установить, является ли плод HLA-идентичным больному сиблингу.

Мы описываем здесь восстановление гемопоэза у мальчика с тяжёлой формой анемии Фанкони, которому была введена криоконсервированная пуповинная кровь сестры, не поражённой, по данным пренатального тестирования, данным заболеванием, имевшей нормальный кариотип и HLA-идентичный фенотип.

Мы использовали претрансплантационный режим кондиционирования, разработанный специально для таких больных; метод основан на гиперчувствительности аномальных клеток к алкилирующим агентам, вызывающих сшивки цепей ДНК, и воздействию радиации. Метод позволяет использовать  пуповинную кровь и избежать забора клеток костного мозга  у новорожденного сиблинга. Такое применение пуповинной крови вытекало из предположения одного из нас о том, что кровь, взятая из пуповинной вены при рождении и обычно не используемая, может восстанавливать гемопоэз – предположении, основанном на наших предварительных исследованиях, согласующихся с сообщениями о наличии гемопоэтических стволовых и мультипотентных (CFU-GEMM), эритроидных (BFU-E) и гранулоцитарно-макрофагальных (CFU-GM) клеток-предшественников в пуповинной крови человека (см. ссылки в работе Broxmeyer et al.).

Ключевые слова

анемия, апластическая терапия, консервация крови, анемия Фанкони, женская особь, плодная кровь, HLA антигены, трансплантация гемопоэтических стволовых клеток, тестирование гистосовместимости, человек, мужская особь, беременность, пренатальный диагноз, дети дошкольного возраста

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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

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

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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.

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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.

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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.

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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.

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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.

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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.

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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).

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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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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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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

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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.

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["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "4" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "Y" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(13) "EAutocomplete" ["USER_TYPE_SETTINGS"]=> array(9) { ["VIEW"]=> string(1) "E" ["SHOW_ADD"]=> string(1) "Y" ["MAX_WIDTH"]=> int(0) ["MIN_HEIGHT"]=> int(24) ["MAX_HEIGHT"]=> int(1000) ["BAN_SYM"]=> string(2) ",;" ["REP_SYM"]=> string(1) " " ["OTHER_REP_SYM"]=> string(0) "" ["IBLOCK_MESS"]=> string(1) "Y" } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> bool(false) ["VALUE"]=> bool(false) ["DESCRIPTION"]=> bool(false) ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> bool(false) ["~DESCRIPTION"]=> bool(false) ["~NAME"]=> string(27) "Ключевые слова" ["~DEFAULT_VALUE"]=> string(0) "" } ["SUBMITTED"]=> array(36) { ["ID"]=> string(2) "20" ["TIMESTAMP_X"]=> string(19) "2015-09-02 17:21:42" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Дата подачи" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "SUBMITTED" ["DEFAULT_VALUE"]=> NULL ["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) "20" ["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(8) "DateTime" ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "18953" ["VALUE"]=> string(22) "12/08/2009 12:00:00 am" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(22) "12/08/2009 12:00:00 am" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(21) "Дата подачи" ["~DEFAULT_VALUE"]=> NULL } ["ACCEPTED"]=> array(36) { ["ID"]=> string(2) "21" ["TIMESTAMP_X"]=> string(19) "2015-09-02 17:21:42" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(25) "Дата принятия" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(8) "ACCEPTED" ["DEFAULT_VALUE"]=> NULL ["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) "21" ["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(8) "DateTime" ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "18954" ["VALUE"]=> string(22) "01/25/2010 12:00:00 am" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(22) "01/25/2010 12:00:00 am" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(25) "Дата принятия" ["~DEFAULT_VALUE"]=> NULL } ["PUBLISHED"]=> array(36) { ["ID"]=> string(2) "22" ["TIMESTAMP_X"]=> string(19) "2015-09-02 17:21:42" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Дата публикации" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "PUBLISHED" ["DEFAULT_VALUE"]=> NULL ["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) "22" ["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(8) "DateTime" ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "18955" ["VALUE"]=> string(22) "04/29/2010 12:00:00 am" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(22) "04/29/2010 12:00:00 am" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(29) "Дата публикации" ["~DEFAULT_VALUE"]=> NULL } ["CONTACT"]=> array(36) { ["ID"]=> string(2) "23" ["TIMESTAMP_X"]=> string(19) "2015-09-03 14:43:05" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(14) "Контакт" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(7) "CONTACT" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "E" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "23" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "3" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "Y" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(13) "EAutocomplete" ["USER_TYPE_SETTINGS"]=> array(9) { ["VIEW"]=> string(1) "E" ["SHOW_ADD"]=> string(1) "Y" ["MAX_WIDTH"]=> int(0) ["MIN_HEIGHT"]=> int(24) ["MAX_HEIGHT"]=> int(1000) ["BAN_SYM"]=> string(2) ",;" ["REP_SYM"]=> string(1) " " ["OTHER_REP_SYM"]=> string(0) "" ["IBLOCK_MESS"]=> string(1) "N" } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "18956" ["VALUE"]=> string(4) "1426" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(4) "1426" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(14) "Контакт" ["~DEFAULT_VALUE"]=> string(0) "" } ["AUTHORS"]=> array(36) { ["ID"]=> string(2) "24" ["TIMESTAMP_X"]=> string(19) "2015-09-03 10:45:07" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(12) "Авторы" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(7) "AUTHORS" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "E" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "Y" ["XML_ID"]=> string(2) "24" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "3" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "Y" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(13) "EAutocomplete" ["USER_TYPE_SETTINGS"]=> array(9) { ["VIEW"]=> string(1) "E" ["SHOW_ADD"]=> string(1) "Y" ["MAX_WIDTH"]=> int(0) ["MIN_HEIGHT"]=> int(24) ["MAX_HEIGHT"]=> int(1000) ["BAN_SYM"]=> string(2) ",;" ["REP_SYM"]=> string(1) " " ["OTHER_REP_SYM"]=> string(0) "" ["IBLOCK_MESS"]=> string(1) "N" } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> array(2) { [0]=> string(5) "18970" [1]=> string(5) "18971" } ["VALUE"]=> array(2) { [0]=> string(4) "1426" [1]=> string(4) "1427" } ["DESCRIPTION"]=> array(2) { [0]=> string(0) "" [1]=> string(0) "" } ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { [0]=> string(4) "1426" [1]=> string(4) "1427" } ["~DESCRIPTION"]=> array(2) { [0]=> string(0) "" [1]=> string(0) "" } ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> string(0) "" } ["AUTHOR_RU"]=> array(36) { ["ID"]=> string(2) "25" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(12) "Авторы" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "AUTHOR_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) "25" ["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) "18959" ["VALUE"]=> array(2) { ["TEXT"]=> string(99) "<p>Аравинд Рамакришнан, Биверли Дж.Торок-Шторб</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(87) "

Аравинд Рамакришнан, Биверли Дж.Торок-Шторб

" ["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) "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" } } ["DOI"]=> array(36) { ["ID"]=> string(2) "28" ["TIMESTAMP_X"]=> string(19) "2016-04-06 14:11:12" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(3) "DOI" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(3) "DOI" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "80" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "28" ["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"]=> NULL ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "18961" ["VALUE"]=> string(29) "10.3205/ctt-2010-en-000072.01" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(29) "10.3205/ctt-2010-en-000072.01" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(3) "DOI" ["~DEFAULT_VALUE"]=> string(0) "" } ["AUTHOR_EN"]=> array(36) { ["ID"]=> string(2) "37" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(6) "Author" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "AUTHOR_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) "37" ["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) "18965" ["VALUE"]=> array(2) { ["TEXT"]=> string(76) "<p>Aravind Ramakrishnan (MD), Beverly J. Torok-Storb (Ph.D.)</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(64) "

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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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

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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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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. 

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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. 

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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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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

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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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Scott Baker, M.D.<sup>2</sup>, Paul J. Orchard, M.D.<sup>1</sup></p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(122) "

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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["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "23" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "3" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "Y" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(13) "EAutocomplete" ["USER_TYPE_SETTINGS"]=> array(9) { ["VIEW"]=> string(1) "E" ["SHOW_ADD"]=> string(1) "Y" ["MAX_WIDTH"]=> int(0) ["MIN_HEIGHT"]=> int(24) ["MAX_HEIGHT"]=> int(1000) ["BAN_SYM"]=> string(2) ",;" ["REP_SYM"]=> string(1) " " ["OTHER_REP_SYM"]=> string(0) "" ["IBLOCK_MESS"]=> string(1) "N" } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "18993" ["VALUE"]=> string(4) "1429" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(4) "1429" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(14) "Контакт" ["~DEFAULT_VALUE"]=> string(0) "" ["DISPLAY_VALUE"]=> string(55) "Jakub Tolar" ["LINK_ELEMENT_VALUE"]=> bool(false) } ["SUMMARY_RU"]=> array(37) { ["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) "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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General principles of hematopoietic cell transplantation for primary immune deficiency diseases

The primitive hematopoietic stem cell (HSC) has the capability for self-renewal and differentiation, characteristics that allow transplantation of small numbers of HSC sufficient for complete restoration of the hematopoietic system of another individual. Transplanted HSC ultimately will differentiate into multiple lineages, including erythrocyte, monocyte/macrophage, granulocyte, megakaryocyte, and lymphoid cells. Thus hematopoietic cell transplantation (HCT) has the potential to cure disorders resulting from defects in the pluripotent progenitor cells as well as defects in single hematopoietic lineages. Primary immune deficiency syndromes are a group of disorders that primarily affect a single lineage, e.g., lymphoid or myeloid lineage, and can be cured with HCT. The goal of HCT for treatment of most primary immune deficiency disorders is to restore sufficient numbers of normal donor cells in the affected lineage(s); donor reconstitution of an unaffected lineage is not required for cure of the disease.

The barrier to successful allogeneic HCT is determined by differences in major or minor histocompatibility antigens between donor and recipient, resulting in bi-directional immunologically mediated graft-vs.-host (GVH) and host-vs.-graft (HVG) reactions. The barrier to engraftment is further determined by the capacity of host immune cells to generate a response to alloantigens. In addition, it has been postulated that host cell occupancy of a specific hematopoietic cell niche functions as a “space-occupying” barrier to engraftment. The strength of the opposing GVH reaction is determined by the number of alloreactive T cells in the graft. The conventional strategy to overcome this bi-directional barrier has relied upon three elements: first, elimination of host alloreactivity with agents capable of immunoablation and myeloablation; second, infusion of donor HSCs to rescue the patient from lethal myeloablation; and third, control of donor alloreactivity with post-transplant immune suppression or by elimination of T cells from the donor graft.

When these general principles are applied to the treatment of specific primary immune deficiency disorders, several distinct concepts emerge. First, syndromes that cause profound immune deficiency may not require a conditioning regimen, as there is no immunological resistance to engraftment. That said, there appears to be a barrier even in cases of severe combined immune deficiency (SCID), particularly when the MHC barrier is increased, i.e. in the situation of HLA-mismatched or haploidentical grafts. For example, donor B cell chimerism is less likely in γ-chain deficiency (X-SCID), as host cells persistently occupy the B lymphocyte niche, than in syndromes without B cells such as adenosine deaminase (ADA) deficiency. Accordingly, the intensity of the conditioning regimen generally is determined not only by the degree of human leukocyte antigen (HLA) disparity, but also by the magnitude of T cell deficiency and the occupancy of niches thought to be required for engraftment by host cells. Wiskott-Aldrich syndrome (WAS) exemplifies this concept in a different way: a successful allograft must generate normal platelets as well as functional T cells; hence the conditioning regimen must provide some degree of myeloablation. Second, the immune defect may be corrected by partial reconstitution of normal immune cells — in other words full donor chimerism of the affected cell subset may not be required. A natural model is the absence of immune deficiency in most female carriers of X-linked immune deficiencies. This concept may add further justification for limiting the intensity of the conditioning regimen. Third, there is no potential benefit for GVH alloreactivity among patients with an immune deficiency, in contrast to patients with hematological malignancy in whom a graft-vs.-leukemia effect might be advantageous. Thus HCT protocols generally employ intensive post-grafting immune suppression or deplete alloreactive T cells from the graft, so as to minimize the risk of GVH disease (GVHD). The strong preference to avoid GVHD also forms the basis for the general disinclination to transplant peripheral blood stem cells, which contain approximately 10 times the number of T cells in the graft compared to bone marrow. The potential risk for life-threatening GVHD often enters into the determination of whether HCT should be undertaken in a specific patient, and the degree of disparate HLA or minor histocompatibility antigens among available donors must be balanced against the effectiveness of alternative therapies, such as enzyme replacement, intravenous immune globulin, prophylactic antibiotics, and other medical treatments.

Severe combined immune deficiency (SCID)

SCID encompasses a broad range of inherited defects that individually cause a profound immune deficiency of both T and B cell function. The individual genetic defects give rise to various phenotypes in which the lymphocyte subsets may or may not be present, and if present, may or may not be functional, and which may pose a barrier to engraftment (Table 1) [1].

Table 1. Lymphocyte phenotype in the SCID syndromes

Lymphocyte phenotype

Mutation or deficiency

T

B

NK

-

-

-

Adenosine deaminase

-

-

+

RAG1 or RAG2

-

-

+

Artemis

-

+

-

Common γ chain

-

+

-

Jak3

-

+

+/-

CD45 deficiency

-

+

+

IL-7Rα-chain

-

+

+

CD3γ/CD3ε/CD3ζ deficiency


Since the goal of HCT is to restore both T and B cell function, the SCID phenotype must be taken into consideration in addition to the degree of recipient-donor mismatch. As mentioned above, elimination of occupancy of a B cell niche may require conditioning, particularly with haploidentical grafts; alternatively, establishment of “split” mixed chimerism (donor T / host B cells) may be sufficient to ameliorate the T cell dysfunction and allow the X-SCID patient to be supported with IVIG, similar to a patient with agammaglobulinemia. Lui et al recently showed that resistance to B cell engraftment in B+ SCID appears to be at the level of the pro-B cell, thus suggesting a potential role for targeting early B cell progenitors in lieu of high intensity conditioning [2].

Other biological factors associated with the SCID phenotype may influence the barrier to engraftment. NK cells, which are relatively radio resistant and may survive intensive conditioning regimens, have been shown to mediate graft rejection [3, 4]. The Perugia team has shown that donor NK alloreactivity is enhanced in the absence of T cells in the graft. Although this concept has been exploited to engineer donor grafts with enhanced anti-host NK activity, it may have implications for the reciprocal situation where T cells are lacking in the host. Particularly in the situation where the donor lacks inhibitory ligands, NK cells theoretically could pose an additional immune barrier to engraftment into a patient with SCID. This concept is supported by a murine model of Artemis deficiency, wherein NK-mediated graft rejection has been observed [5]. Another potential barrier is the presence of maternal T cells that have “engrafted” in the fetus in utero, often seen in patients with X-SCID. Maternal T cells can be detected using the standard methods for assessing chimerism, such as sex-chromosome specific fluorescent in situ hybridization (FISH) probes or polymerase chain reaction (PCR) detection of maternal-specific genetic polymorphisms, termed variable number tandem repeat (VNTR) sequences [6, 7]. High-levels of maternal T cells have been associated with resistance to engraftment of haploidentical cells when no conditioning is given [8, 9]. Thus, it is reasonable to consider use of a conditioning regimen in SCID patients with NK cells or maternal T cells. In the absence of a conditioning regimen, some reports have suggested that very large dose CD34+-selected peripheral blood stem cell (PBSC) grafts may help overcome graft rejection, although it may not facilitate B cell reconstitution [10].

One of the difficulties in analyzing the outcome of HCT in SCID patients is the relative rarity of the condition, which prohibits conducting large single center studies of a specific modality over a short period of time. Most reports with large numbers of patients represent either retrospective analyses of registry data, or single center studies conducted over a long period of time. Studies confined to a single phenotype or pilot studies of novel approaches generally have too few patients for meaningful assessment. The largest series of analyses has been reported by the European cooperative groups. In 1990 a retrospective study included 183 SCID patients given marrow transplants [11]. Among the 70 patients given grafts from HLA-identical siblings, 65 of whom were not given a preparative regimen, long term survival was 70%, and the majority of patients achieved stable engraftment of T and B lymphocytes. Factors that correlated with improved chances of survival included lack of infection prior to HCT and isolation of the patient in a protective environment. Clinical improvement was observed in all patients, including those with partial donor cell engraftment. In contrast to these results, less than 60% of patients given haploidentical grafts survived. The analysis definitively showed the important role of conditioning in establishing donor engraftment of T-depleted HLA-mismatched haploidentical marrow. Graft failure occurred in 50% of unconditioned patients compared to 14% of conditioned patients, and the rate of engraftment improved proportionately with increased intensity of the regimen. Immunological recovery, including B cell recovery, was also facilitated by the preparative regimen, and the frequency of late deaths related to poor immunological reconstitution was reduced. However, the benefit of a preparative regimen for establishing donor cell engraftment was negated by an increase in regimen-related complications and did not improve overall survival.

Over time, the outcome of HCT for SCID has improved, as novel supportive care and alternative donor sources have been used. Survival for recipients of HLA-identical sibling grafts now approaches 90%, and in the 2003 retrospective study by the European Group for Blood and Marrow Transplantation (EBMT), outcome for recipients of HLA-phenotypically identical grafts was not statistically significantly different from that for genotypically HLA-identical donors [12]. This analysis also showed a significant improvement over time for recipients of T-depleted haploidentical grafts, from approximately 60% to almost 80% survival (p=.0007) by the late 1990s. The most important factor for improved survival after an HLA-identical sibling graft was younger age at time of HCT, with a 2-fold increase in risk for patients aged 6–12 years, and an 8-fold increase in risk for patients >12 years when compared with patients given HCT before 6 years of age. Factors significantly associated with improved survival after haploidentical transplants were B+ SCID phenotype (64% vs. 36%, p=.0007), protected environment (57% vs. 15%, p=.0001), and lack of pulmonary infections before HCT (59% vs. 38%, p=.0001). Use of a conditioning regimen was associated with improved survival for B- SCID patients, although the difference was not statistically significant. More recently, Fischer and colleagues analyzed a large cohort of SCID patients to determine factors that correlated with good clinical outcomes (survival and amelioration of clinical immune deficiency) [13]. Graft source was significant, and risk for poor outcome was 3.7-fold higher for recipients of haploidentical and 4.8-fold higher for phenotypically HLA-identical (related or unrelated) compared to HLA-identical sibling grafts. Establishment of donor myeloid cells correlated with better survival, presumably because donor chimerism of the myeloid lineage correlated with donor origin of lymphocytes. Lack of CD4+ cell reconstitution and persistent need for IVIG were both significantly associated with poor outcome. Finally, the type of SCID appears to affect outcome, as specifically those with Artemis mutations have a 6-fold higher risk for poor outcome. These patients had a higher incidence of chronic papilloma virus infections, malnutrition, and chronic GVHD. Other studies indicate that survival generally is higher among B+ compared to B- SCID patients, particularly after alternative donor HCT [14].

Most other centers report comparable results, although in smaller series. The general experience is that genotypically HLA-identical marrow transplantation restores T cell immunity in >90% of unconditioned SCID patients, although B cell reconstitution occurs in only half of these patients [8, 15]. Despite the use of preparative regimens, recipients of T-depleted haploidentical marrow have delayed immune reconstitution, with 3–6 months required for development of antigen responsive T cells, and commonly multiple marrow infusions are needed [16]. B lymphocyte reconstitution is generally suboptimal and most patients require continued immunoglobulin support. The EBMT analysis found long-term functional T cells in about 80% of recipients of HLA-sibling grafts and 90% of B+ SCID recipients of haploidentical grafts; in contrast, functional T cells were observed in only 66% of B- SCID patients (p=.002). Long-term B cell function was less robust in all cohorts: 88% of B+ and 63% of B- SCID recipients of HLA-identical sibling grafts, and 66% of B+ and 44% of B- SCID recipients of haploidentical grafts, respectively. Certain SCID phenotypes may require a preparative regimen, for example patients with reticular dysgenesis given T-depleted grafts appear to have improved outcome if given high intensity conditioning with subsequent reconstitution of normal myeloid cells [17]. B- SCID patients also appear to benefit from conditioning [14].

The role of conditioning for unrelated grafts is the same as for T-depleted haploidentical grafts, in that it may facilitate establishment of donor B lymphocyte chimerism, however, that benefit may be offset by regimen-related toxicities. In 1992 Filipovich and colleagues reported their initial experience with unrelated marrow grafts for 8 SCID patients, of whom 5 were given high intensity conditioning [18]. Graft rejection occurred in 2 of the 3 unconditioned patients, although both survived long term after a second transplant with high intensity conditioning. Among the conditioned patients, 2 died within the first 100 days after HCT, while the others survived long term with improved immune function. Subsequently larger series have shown excellent outcome after high intensity conditioning followed by HLA-matched unrelated grafts, with about 80% survival [19, 20]. Compared to haploidentical recipients, unrelated marrow recipients had significantly lower risk for interstitial pneumonitis, graft failure, acute and chronic GVHD, and abnormal T cell receptor diversity [19]. Thus, immune reconstitution after T-replete unrelated donor transplantation appears to be faster compared to T-depleted haploidentical HCT, and often normal B cell function is achieved.

Outcomes for unrelated umbilical cord blood have been reported in small series and appears equivalent to that of matched unrelated marrow. Bhattacharya et al reported success in establishing well-matched (6/6 or 10/10 HLA match) umbilical cord blood grafts without conditioning [21]. The median time to achieving an absolute T cell count of more than 200 cells/ml among 5 surviving SCID patients was about 60 days, and mixed or full donor B cell engraftment was observed in 4 of these. Diaz reported 11 SCID patients, 9 given high intensity and 2 given reduced intensity conditioning, 7 and 1 of these, respectively, survive long term [22]. High intensity conditioning generally has been employed in recipients of HLA-mismatched cord blood units, with comparable results [20].

The condition of the patient before HCT correlates strongly with the risk of death after HCT irrespective of the graft source. In particular, infections and pulmonary disease are associated with significantly worse outcomes [12, 14, 23]. The most common cause of death in the first 6 months after HCT is infection, thus it is not surprising that pre-existing infection is detrimental to success. Indeed, a pre-existing pulmonary infection confers a 2-to 3-fold increased risk of death following HCT [14]. Therefore, every patient with SCID should have a thorough evaluation for infection and occult pulmonary disease. Liver enzyme elevations may indicate maternal T cell-mediated GVHD or underlying liver dysfunction, the latter is commonly associated with untreated ADA deficiency. Enzyme replacement therapy with polyethylene glycol (PEG) conjugated adenosine deaminase improves T cell function [24]. Since functional T cells pose an immunological barrier to engraftment, the general practice has been to stop PEG-ADA several weeks before HCT in order to “T-deplete” the recipient. However PEG-ADA also prevents or improves the liver injury found in ADA deficiency, thus, early stopping may result in hepatitis and increase the risk for post-transplant liver toxicity during the time required to establish endogenous enzyme production. A reasonable approach is to continue PEG-ADA unless no conditioning is contemplated, in which case pre-transplant discontinuation is warranted. Age of the patient is another important factor associated with survival. The best outcomes are reported for SCID patients given allogeneic transplant within the first year of life [12]. Older patients are more likely to have infections and organ dysfunction that contribute to higher mortality.

The advent of neonatal screening and in utero diagnosis has allowed early detection of SCID and therefore prompt intervention at an early age. Buckley and colleagues reported better survival and the establishment of long-term functional T cells in patients with SCID who received HCT before 28 days of life (overall survival ((OS) 95%) compared to patients who were older (OS 74%) [25]. Survival of 21 SCID infants, given no conditioning and transplanted with haploidentical T cell depleted marrow grafts before 28 days of age (neonatal cohort), was 95% compared to 74% of 96 older infants. Thymopoiesis, as measured by T cell receptor excision circles (TREC), was improved in the neonatal transplant cohort, however, no comparative improvement in B cell function was observed. Acute GVHD grades III–IV developed in only 16% of patients who received grafts mismatched for 2 or 3 HLA antigens. Several factors probably contributed to the improved survival observed in patients less than 28 days old. In particular, younger patients are less likely to have opportunistic infections and subsequent co-morbidities, malnutrition, and failure to thrive, all of which have been associated with increased mortality following HCT, but may also contribute to decreased thymic function. These results show that T cell depleted haploidentical marrow grafts are feasible at a very early age and that there is little benefit in delaying HCT in order to identify a better matched donor.

Once established, donor progenitor cells develop and mature in the vestigial thymus of the SCID patient. Buckley and colleagues demonstrated that T cell receptor (TCR) gene rearrangement occurs in donor T cell precursors resulting in the generation of naïve T cells [25, 26, 27]. Measurements of TCR repertoire show development of a broad diversity within the donor T cell pool, which persists over time. Patel and colleagues reported that thymopoiesis, as measured by TRECs and naïve CD4 cells, declined exponentially over time after HCT. Several studies have suggested that late graft failure or deterioration of thymopoiesis may jeopardize long-term T cell function [28]. In contrast, recent studies have shown that thymic output of T cells and T cell diversity remain normal for decades after HCT in approximately 80% of patients [29, 30]. The degree of early T cell reconstitution appears to be strongly associated with the long-term stability of T cell function, thus, patients at most risk for poor T cell function or loss of T cell grafts are those with low numbers of TRECs and naïve-CD4 cells within the first few years after HCT [13, 31]. Alain Fischer’s team in Paris found that donor chimerism of the myeloid lineage correlated with higher CD4+ T cell counts long term, and that donor myeloid chimerism was limited to patients who received high intensity conditioning. Other factors that may be associated with higher risk for poor long-term T cell reconstitution are SCID phenotypes that lack B cells, presence of NK cells, and possibly young age at time of HCT. As noted above, long term B cell reconstitution is common only among patients given high intensity conditioning regimens [13, 15].

Primary T cell immunodeficiencies other than SCID

Primary T cell immunodeficiency (PTCD) syndromes may be differentiated from SCID by virtue of reduced but not completely absent T cell function, or absent T cell function with the presence of B lymphocyte or NK cell function. Nonetheless, the immune dysfunction leads to progressive decline from opportunistic infections, autoimmune phenomena, and a propensity to develop malignancies, particularly lymphoma. Several of the genetic mutations implicated in SCID also have been found to be present in patients with PTCD, thus termed “leaky SCID”. New genetic mutations also have been characterized, while the genetic causes in many patients remain unrecognized [32, 33, 34]. The more common of these rare disorders are listed in Table 2.

Table 2. Primary T cell immunodeficiency syndromes commonly referred for HCT
Abbreviations:
HIGM, Hyper IgM;
HLA, Human leukocyte antigen;
HSM, hepatosplenomegaly;
IPEX, Immunodeficiency-polyendocrinopathy-enteropathy X-linked;
XLP, X-linked lymphoproliferative

Syndrome

Mutation

Clinical features

Laboratory features

Omenn’s

RAG1 or RAG2

HSM
Rash
Adenopathy

Eosinophilia
Lymphocytosis

ZAP70

ZAP70

CD8+ lymphopenia
High IgE levels

HIGM

CD40L or CD40

X-linked
Pyogenic infection
Sclerosing cholangitis

High IgM & low IgG levels

Common Variable Immunodeficiency

Unknown

Autoimmunity
Allergy

Low IgG

Cartilage Hair Hypoplasia

endoribonuclease RMRP

Dwarfism
Hypoplastic hair growth

Wiskott Aldrich

WASP

Eczema

Thrombocytopenia
Small platelet size

IPEX

FOXP3

X-linked
Diabetes
Diarrhea
Rash

XLP

SH2D1A

X-linked
EBV- lymphoproliferative disease

Hypogammaglobulinemia

Bare Lymphocyte syndrome (Class II HLA deficiency)

RFXANK, RFX5, RFSAP, CIITA

Pulmonary infection
Diarrhea
Hepatitis

Hypogammaglobulinemia
CD4 lymphopenia
Absent antigen-specific T cell responses

Class I HLA deficiency

TAP1 or TAP2

CD8 lymphopenia

DiGeorge syndrome

10p13 or 22q11.2

Hypocalcemia
Cardiac anomolies

CD3 lymphopenia
Elevated IgE


Until gene therapy is perfected, allogeneic marrow transplantation remains the only curative therapy available for these disorders. In general, conventional regimens have included both immunoablative and myeloablative agents to overcome residual immune barriers to engraftment and to ensure multi-lineage chimerism. The combination of busulfan (1 mg/kg x 16 doses) and cyclophosphamide (200 mg/kg total dose), with or without anti-thymocyte globulin is the most commonly used regimen. Our experience indicates that busulfan is metabolized faster in young patients, therefore in order to optimize engraftment it is prudent to adjust the daily doses to achieve steady state concentration (Css) of >200 ng/ml in recipients of HLA-identical sibling grafts and >400 ng/ml in recipients of HLA-matched unrelated grafts [35].

In 2003 the EBMT reported a retrospective analysis of outcome for patients with primary immunodeficiency disease other than SCID [12, 36]. A higher incidence of engraftment was reported in patients who received HLA-identical sibling grafts (99%), compared to those who received haploidentical or unrelated donor grafts (75–80%). In addition, survival at 3 years was better for patients who received HLA-identical sibling grafts (71%) compared to haploidentical grafts [42% (p=.0006)]. Survival after HLA-matched unrelated donor grafts was 59%, which was not statistically significantly different from the HLA-identical sibling cohort. The main cause of death following HCT was infection.

Worse outcomes were seen in patients with PTCD compared to other types of immune deficiencies, regardless of donor. Overall survival was 63% and 35% after HLA-identical sibling grafts or mismatched grafts, respectively [12, 36]. Unfortunately, and in contrast to the results for SCID, the EBMT study found no improvement in survival of the non-SCID cohorts over the two decades included in the analysis, thus highlighting important differences and problems associated with PTCD compared to SCID. Although life-threatening infections may be less common early in life, children with PTCD often develop organ damage from chronic infections, particularly lung disease, prior to HCT. Given that a conditioning regimen is necessary to ensure engraftment, the associated risks for organ toxicity, hemorrhage, and infection are compounded by these co-morbidities. Several studies have associated inferior survival with presence of co-morbidities, including opportunistic infections, Epstein-Barr virus lymphoproliferation, and pulmonary dysfunction [8, 23]. Among boys with X-linked hyper-IgM (XHIM) excessive mortality has been associated with the presence of pulmonary infection or liver disease at time of HCT [37].

In theory, split chimerism (donor T/host B chimerism) or partial donor T cell chimerism should be sufficient to ameliorate the immune dysfunction in most types of PTCD. Accordingly, reducing the intensity of conditioning may be a strategy to reduce regimen-related toxicity without sacrificing immune reconstitution. Specific factors associated with the molecular defect must be taken into consideration, as partial chimerism may not be sufficient for some defects. DiGeorge syndrome and the Bare Lymphocyte syndromes (BLS) pose particular challenges, because the T cell deficiency results from inadequate thymopoiesis, caused by absence of the thymus or absence of HLA molecules on the thymic epithelial cells, respectively. The molecular defects that cause BLS block the transcription of HLA genes; therefore antigen-presenting cells also are defective. Hence, donor chimerism must be established in B cell and dendritic cell lineages. In both disorders, absence of thymic function may prevent formation of naïve donor T cells; therefore full chimerism provides the most likely chance that a broad range of donor antigen-specific memory cells may be established long term.

Molecular deficits that allow T cell proliferation, but preclude intercellular interactions, such as X-linked hyper-IgM (XHIM) syndrome or Immune Dysregulation-Polyendocrinopathy-Enteropathy X-linked (IPEX) syndrome, generally require conditioning in order to prevent T cell mediated graft rejection; however, partial T cell chimerism appears to restore immune function as well as full donor chimerism [38, 39]. The autoimmune manifestations of the IPEX syndrome are caused by absence of CD4+CD25+ FOXP3+ regulatory T cells (Tregs), important for sustaining self-tolerance. Normal numbers of FOXP3 expressing CD4+CD25+ cells have been observed in boys with mixed donor/host chimerism, and several case reports indicate that mixed chimerism is sufficient to ameliorate many of the manifestations of IPEX, including the enteropathy, anemia, failure to thrive, and the susceptibility to infections. Curiously, we and others have observed improvement in diabetes, although in theory autoimmune-mediated islet cell destruction happens well before HCT is carried out [38]. The most common cause of the XHIM syndrome is a mutation in the CD40 ligand gene, which is expressed by T cells and provides a critical signal for B cells to switch antibody production from IgM to IgG subtypes. Theoretically, the introduction of some normal CD40 ligand-expressing T cells should be sufficient to reverse the disease, even if B cells of host origin remain. Amelioration of disease symptoms with mixed chimerism has been observed for some boys treated for XHIM, although no detailed analysis of B cell function was reported [40, 41].

Wiskott-Aldrich Syndrome (WAS). HCT offers significantly improved survival chances for patients with WAS, without which about 50% will die from infection, autoimmune disease, or lymphoproliferative disease by the third decade of life [42]. The WAS mutation affects lymphoid and hematopoietic compartments, both of which are corrected by HCT. Accordingly most patients are conditioned with both immunosuppression and high dose chemotherapy to facilitate multilineage donor cell engraftment. Figure 1 shows cell counts in a patient who was too ill with opportunistic infections to receive high dose conditioning and became a split chimera after reduced intensity conditioning and unrelated marrow transplantation. Following transplantation the T cell immune defect was corrected, but thrombocytopenia persisted as did host CD33+ cells. After the infections resolved, a second graft was given with a high intensity (directed at myeloid cells), but without immunoablative preparative regimen, resulting in amelioration of thrombocytopenia as the CD33+ compartment converted to donor type. The importance of achieving full donor chimerism was shown recently in a retrospective analysis of results in 96 patients, which showed an almost 2-fold reduction in mortality among patients with full chimerism compared to those with mixed or split chimerism [43]. Mixed chimerism also is associated with a significantly higher risk for developing autoimmune manifestations after HCT.

Figure 1. Correction of thrombocytopenia in Wiskott-Aldrich correlates with donor chimerism of CD33+ cell subset
At 30 days after hematopoietic cell transplant, a high proportion of both CD3 (gray line) and CD33 (black line) subsets mark as donor origin. Over time, the proportion of donor CD3 cells remains stable, while the proportion of donor CD33 cells decreases. The platelet count (black dashed line) reaches a normal level when the CD33 donor chimerism is high, and falls proportionately with the fall in donor CD33 chimerism.

Burroughs_et_al_Figure1_72dpi.png

HCT using HLA-identical sibling marrow grafts is highly successful in treating WAS, with approximately 88% event-free survival [43]. The combination of busulfan (1 mg/kg x 16 doses) and cyclophosphamide (200 mg/kg total dose), with or without anti-thymocyte globulin is the most commonly used conditioning regimen. Busulfan is metabolized faster in younger patients, therefore it is prudent to monitor levels and target the dose to achieve a Css of greater than 200 ng/ml to assure engraftment [35]. An EBMT analysis determined that patient age, disease severity, and splenectomy, among other factors, did not affect outcome [43].

Results of alternative donor HCT for treatment of WAS have improved over time, particularly for recipients of unrelated marrow grafts. Most recent studies have shown approximately 70%–78% long-term survival [43, 44]. In a 2001 study facilitated by the International Bone Marrow Transplant Registry (IBMTR), age of 5 years or older was associated with an increased risk of mortality after HCT. Survival for patients younger than 5 years was about the same as for recipients of HLA-identical sibling grafts. In addition, several studies found comparable survival rates among recipients of HLA-matched related and unrelated grafts [44, 45]. The most commonly used regimen was a combination of busulfan, cyclophosphamide, and ATG. In our experience, targeting the dose of busulfan to achieve a C SS above 400 ng/ml facilitates engraftment [35].

Encouraging results have also been reported for umbilical cord blood transplants, but most information comes from case reports or part of smaller series of patients with immune deficiencies. Among 15 patients reported by Ozsahin, et al, event-free survival was approximately 70%, similar to recipients of unrelated marrow grafts [44]. Most patients in these reports were conditioned with the combination of busulfan, cyclophosphamide, and antithymocyte globulin, which the Japanese group found to be an important factor for improved survival when compared to other regimens [44]. Reconstitution of immunity after cord blood approximates that observed with unrelated marrow grafts.

There is more information about haploidentical transplants for WAS, although the historical results are less encouraging. The EBMT study showed a 4–5-fold increase in mortality after haploidentical compared to HLA-identical sibling grafts [43]. Others have reported similar results [36, 44, 46]. These reports show a high incidence of graft failure and poor immune reconstitution following T-depleted haploidentical marrow grafts. The Tubingen team provided a promising case report of “mega-dose” purified CD34+ haploidentical grafts used to overcome the barrier to engraftment without engendering GVHD [47].

Inherited immune defects not primarily affecting T cells

A wide range of rare immune deficiency syndromes result from defects in B lymphocytes, NK cells, or nonlymphocytic subsets including neutrophils (Table 3).

Table 3. Histiocytic and myeloid immune deficiency syndromes commonly referred for HCT
Abbreviations:
FHL, Familial hemophagocytic lymphohistiocytosis;
LCH, Langerhans cell histiocytosis

Syndrome

Mutation

Clinical features

Laboratory features

Histiocytic disorders

FHL

PRF1
UNC13D
STX11

Fever
Hepatosplenomegaly
Lymphadenopathy
Rash
Pulmonary infiltrates
Neurologic deficits

Pancytopenia
Hypertriglyceridemia
Hypofibrinogenemia
Elevated liver function tests

Multifocal LCH

unknown

Bone lesions
Endocrinopathy
Rash
Hepatosplenomegaly

Anemia

Myeloid disorders

Chronic Granulomatous Disease

p91PHOX
CYBA
NCF1

Pneumonia
Cellulitis

Catalase-positive bacteria
Aspergillus

Chediak-Higashi Syndrome

CHS1

Pyogenic infections
Gingivitis
Oculocutaneous albinism
Hemorrhage

Neutropenia
Giant intracellular granules

Leukocyte Adhesion defect

β-2 integrin

Bacterial infections
Stomatitis

Leukocytosis

Kostmann’s neutropenia

GCSF-R

Bacteremia/sepsis

Neutropenia

Shwachman-Diamond Syndrome

Unknown

Pancreatic enzyme deficiency

Neutropenia


The individual immune defects predispose the patients to specific infections, for example with Aspergillus in patients with chronic granulomatous disease (CGD) or staphylococcus aureus in leukocyte adhesion deficiency (LAD)-I, and are associated with distinctive co-morbidities, such as infiltrative pulmonary or central nervous system disease in hemophagocytic lymphohistiocytosis (HLH) or recalcitrant colitis in CGD. As above, the decision to treat with HCT must take into consideration the prognosis of the disorder with available supportive care, the presence of co-morbidities that might increase the risk of mortality following HCT, and the availability of a suitable donor. Unfortunately, because these diseases are rare, meaningful prospective studies reporting on large series of patients with a single disease entity are not available. Within the European retrospective study, survival for specific subsets, 48 patients with phagocytic disorders, and 90 patients with hemophagocytic disorders, was reported to be approximately 70% and 68%, respectively, for recipients of HLA-identical sibling grafts. The small number of patients with phagocytic cell disorders had a similar outcome after transplantation of unrelated marrow, in contrast to patients with hemophagocytic disorders in whom survival was only 28% after unrelated grafts.

Studies that include larger numbers of patients with single diagnoses are limited to a few disorders such as CGD and HLH. The prognosis for CGD patients has improved considerably with more aggressive use of gamma-interferon and antibiotic prophylaxis. HCT is indicated for patients with recurrent life-threatening infections or organ dysfunction caused by refractory granulomatous disease [48]. A series of patients transplanted with HLA-identical sibling marrow (n=10) or unrelated marrow or cord blood (n=10) was reported recently from the United Kingdom [49]. Most patients were conditioned with busulfan and cyclophosphamide, and alemtuzumab was given to recipients of unrelated grafts. Survival was reported to be 90% with a median follow-up of 61 months; one patient in each group died from disseminated infection. Neutrophil oxidative burst was normalized in patients with mixed as well as full donor chimerism. Del Giudice et al published a review of case reports and small series of patients with CGD that included several long-term survivors with stable mixed chimerism, consistent with the notion that a small proportion of normal cells improves disease symptoms [50].

Without HCT, the prognosis for patients with HLH is poor even with intensive supportive care and anti-inflammatory regimens that include etoposide, cyclosporine, and prednisone [51, 52]. The outcome is considerably improved when HCT is performed after control of the initial inflammatory state is gained and infiltrative disease has resolved. The HLH 94 protocol reported 50–60% overall survival for the 113 children entered into the study; overall survival was 65% for the subgroup of 65 children given HCT. The study results suggested that intrathecal chemotherapy plays an important role in gaining disease control [52]. A retrospective analysis of 91 patients in the CIBMTR registry given unrelated marrow grafts found 53% overall survival [53]. Most patients were conditioned with busulfan, cyclophosphamide, and etoposide, with or without ATG. Survival was worse among the small subgroup with active disease at time of HCT, as well as among recipients of HLA-mismatched grafts. Disease manifestations resolved among patients with mixed as well as full donor chimerism. Early mortality (before day 100) was 32%, however, suggesting that a reduced intensity conditioning regimen might be of benefit.

Development of reduced toxicity regimens

Conditioning regimens that do not employ agents at doses resulting in long-lasting marrow aplasia are referred to as reduced intensity conditioning (RIC) regimens. Until recently, those regimens have been used routinely for only two conditions: severe aplastic anemia and SCID. Regimens for aplastic anemia have included immunosuppressive agents alone to overcome the allo-immune rejection responses, since these patients are thought to have "unoccupied" marrow space. These reduced intensity regimens have resulted in a markedly lower incidence of both early and late complications [54, 55]. SCID patients have no immune system capable of rejecting the graft, and therefore do not require conditioning except in the instances discussed above [11].

As the power of the graft vs. leukemia (GVL) effect became evident in the late 1970s and early 1980s, subsequent studies found that donor lymphocyte infusions (DLI) could be used to treat leukemic relapse after HCT [56>, 57]. The success of DLI set the stage for the introduction of reduced intensity conditioning for HCT, based on the hypothesis that the graft itself created the needed space through a subclinical GVH reaction directed toward recipient hematopoietic cells. Based on insights from animal models and armed with new potent immunosuppressive agents such as 2-CDA and fludarabine, investigators in Texas, Israel, Seattle, Boston, and Washington, DC pioneered less toxic regimens that facilitated partial or full chimerism in most patients [58, 59, 60, 61, 62, 63, 64].

These studies demonstrated that intensive immunosuppression alone following stem cell infusion was sufficient to establish full or partial donor chimerism and that conditioning was not required for creation of marrow space. The extent of donor cell engraftment following low intensity regimens depends on multiple factors, including the degree of intensity of the preparative regimen, the source of hematopoietic cells (marrow vs. peripheral blood stem cells), the degree of HLA-matching, and the extent of T cell depletion. Most low intensity protocols use PBSC to facilitate engraftment and enhance GVL reactions, as the product may contain 10-fold greater numbers of T cells and 4-fold greater number of hematopoietic stem cells compared to marrow [65].

There are several reasons for the further development of low intensity regimens for the establishment of mixed chimerism in patients with Non-SCID primary immune deficiency disorders. First, the potential risks of high dose conditioning regimens include early treatment related mortality and late effects, such as infertility, hormonal dysfunction, growth failure, and secondary malignancies. These risks may deter patients and families from seeking treatment before co-morbidities arise. Second, as discussed earlier, the risk for regimen-related mortality increases significantly among patients with disseminated infection, pulmonary disease or other organ dysfunction. Third, reversal of disease symptoms with partial chimerism, which may be achievable with low intensity conditioning, has been demonstrated in a number of studies [36, 66].

The main challenge in translating the success of protocols using RIC to patients with primary immune deficiency is the reliance on PBSC grafts, which may be difficult (or impossible) to collect from pediatric donors; also it confers a high risk of GVHD. Some progress has been made using marrow or CD34+ selected PBSC. Some results with HLA-matched related or unrelated marrow using RIC are summarized in Table 4.

Table 4. Intensity conditioning regimens and transplant outcome in immunodeficiency syndromes
Abbreviations:
ATG, anti-thymocyte globulin;
BM, bone marrow;
CB, cord blood;
CGD, chronic granulomatous disease;
DLI, donor lymphocyte infusion;
EBV-LPD, Epstein Barr virus lymphoproliferative disease; Flu, fludarabine;
HCT, hematopoietic cell transplant;
IPEX, Immunodeficiency-polyendocrinopathy-enteropathy X-linked;
Mel, melphalan;
MSD, matched sibling donor;
PBSC, peripheral blood stem cells;
PID, primary immune deficiency (nonSCID);
SCID, severe combined immune deficiency;
SC-M, severe co-morbities;
TBI, total body irradiation

Author

Diagnosis

Regimen

Donor

Rejection (No.)

Survival (No.)

FU (mo)

Reduced Intensity Conditioning

(Rao et al. 2005 [67])

27 PID/ 6 SCID

Flu/ Mel/Campath

BM

0

31

(Amrolia et al. 2000 [68])

6 ID/ 2 SCID

Flu/ Mel/ ATG

0

7

6-18

(Rao et al. 2007 [38])

4 IPEX

Flu/ Mel/Campath

BM

0

4

6-25

(Cohen et al. 2007 [69])

7 PID/ EBV-LPD

Flu/ Mel/Campath

BM or PBSC

0

7

0

Minimal Toxicity (non-myeloablative) Conditioning

(Horwitz et al. 2001 [70])

10 CGD

Flu/ Cy/ ATG
Post-HCT DLI

CD34+ PBSC

1

7

16-26

(Burroughs et al. 2007 [71])

10 PID+SC-M

Flu / 2 Gy TBI

PBSC

1

7

9-96


A high rate of engraftment of marrow grafts has been reported after the combination of fludarabine and melphalan plus, an in vivo T-depleting agent, such as ATG or Campath®, and appears to be associated with low mortality rates [38, 67, 68, 70]. The combination of cyclophosphamide, fludarabine, and ATG has been studied as a low-intensity regimen to facilitate engraftment of CD34+ selected PBSC [70]. In the latter study, the benefit of in vivo and ex vivo T-depletion for reducing GVHD was at least partially abrogated by the use of DLI to improve the level of donor cell chimerism. The Seattle group has studied the combination of fludarabine and low-dose TBI in patients who would be expected to have very poor survival following conventional conditioning for HCT, such as those with disseminated opportunistic infections, mechanical ventilation, or other organ damage. No regimen-related mortality was observed in the first cohort given 2 Gy TBI, however chronic GVHD was observed in 70% of patients, presumably related to the use of PBSC grafts [71]. The substitution of marrow for PBSC in the subsequent cohort appears promising, and early mortality has not been increased despite increasing the dose of TBI to 4 Gy (Figure 2). Taken together, these studies suggest that low-intensity regimens offer the potential for achieving donor cell engraftment with less morbidity than standard regimens, an important consideration for patients who currently may consider the risks of conventional transplants unacceptably high.

Figure 2. Survival of patients with severe infections or pulmonary disease after reduced intensity conditioning HCT is improved with bone marrow as the sole source of allogeneic hematopoietic cells.
The first cohort of patients (dashed line) was conditioned with fludarabine and 2 Gy total body irradiation and most patients received peripheral blood stem cell grafts. The second cohort (solid line) was conditioned with fludarabine and 4 Gy total body irradiation and was given marrow grafts.

Burroughs_et_al_Figure2_72dpi.png

Acknowledgements

This work was supported by National Institute of Health grant NHLBI grant HL36444 and National Cancer Institute grant CA18029.

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59. Giralt S, Estey E, Albitar M, van Besien K, et al. Engraftment of allogeneic hematopoietic progenitor cells with purine analog-containing chemotherapy: harnessing graft-versus-leukemia without myeloablative therapy. Blood. 1997;89:4531-4536.

60. Slavin S, Nagler A, Naparstek E, Kapelushnik Y, et al. Nonmyeloablative stem cell transplantation and cell therapy as an alternative to conventional bone marrow transplantation with lethal cytoreduction for the treatment of malignant and nonmalignant hematologic diseases. Blood. 1998;91:756-763.

61. Khouri IF, Keating M, Körbling M, Przepiorka D, et al. Transplant-lite: induction of graft-versus-malignancy using fludarabine-based nonablative chemotherapy and allogeneic blood progenitor-cell transplantation as treatment for lymphoid malignancies. Journal of Clinical Oncology. 1998;16:2817-2824. pmid: 9704734.

62. Storb R, Yu C, Wagner JL, Deeg HJ, 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.

63. McSweeney PA, Niederwieser D, Shizuru JA, Sandmaier, BM, et al. Hematopoietic cell transplantation in older patients with hematologic malignancies: replacing high-dose cytotoxic therapy with graft-versus-tumor effects. Blood. 2001;97:3390-3400.

64. Sykes M, Preffer F, McAfee S, Saidman SL, et al. Mixed lymphohaemopoietic chimerism and graft-versus-lymphoma effects after non-myeloablative therapy and HLA-mismatched bone-marrow transplantation. Lancet. 1999;353:1755-1759. pmid: 10347989.

65. Bensinger WI, Martin PJ, Storer B, Clift R, et al. Transplantation of bone marrow as compared with peripheral-blood cells from HLA-identical relatives in patients with hematologic cancers. New England Journal of Medicine. 2001;344:175-181.

66. van Leeuwen JE, van Tol MJ, Joosten AM, Schellekens PT, et al. Relationship between patterns of engraftment in peripheral blood and immune reconstitution after allogeneic bone marrow transplantation for (severe) combined immunodeficiency. [Review]. Blood. 1994;84:3936-3947.

67. Rao K, Amrolia PJ, Jones A, Cale CM, et al. Improved survival after unrelated donor bone marrow transplantation in children with primary immunodeficiency using a reduced-intensity conditioning regimen. Blood. 2005;105:879-885.

68. Amrolia P, Gaspar HB, Hassan A, Webb D, et al. Nonmyeloablative stem cell transplantation for congenital immunodeficiencies. Blood. 2000;96:1239-1246.

69. Cohen JM, Sebire NJ, Harvey J, Gaspar HB, et al. Successful treatment of lymphoproliferative disease complicating primary immunodeficiency/immunodysregulatory disorders with reduced-intensity allogeneic stem-cell transplantation. Blood. 2007;110:2209-2214. doi: 10.1182/blood-2006-12-062174.

70. Horwitz ME, Barrett AJ, Brown MR, Carter CS, et al. Treatment of chronic granulomatous disease with nonmyeloablative conditioning and a T-cell-depleted hematopoietic allograft. New England Journal of Medicine. 2001;344:881-888.

71. Burroughs LM, Storb R, Leisenring WM, Pulsipher MA, et al. Intensive postgrafting immune suppression combined with nonmyeloablative conditioning for transplantation of HLA-identical hematopoietic cell grafts: results of a pilot study for treatment of primary immunodeficiency disorders. Bone Marrow Transplantation. 2007;40:633-642. doi: 10.1038/sj.bmt.1705778.

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General principles of hematopoietic cell transplantation for primary immune deficiency diseases

The primitive hematopoietic stem cell (HSC) has the capability for self-renewal and differentiation, characteristics that allow transplantation of small numbers of HSC sufficient for complete restoration of the hematopoietic system of another individual. Transplanted HSC ultimately will differentiate into multiple lineages, including erythrocyte, monocyte/macrophage, granulocyte, megakaryocyte, and lymphoid cells. Thus hematopoietic cell transplantation (HCT) has the potential to cure disorders resulting from defects in the pluripotent progenitor cells as well as defects in single hematopoietic lineages. Primary immune deficiency syndromes are a group of disorders that primarily affect a single lineage, e.g., lymphoid or myeloid lineage, and can be cured with HCT. The goal of HCT for treatment of most primary immune deficiency disorders is to restore sufficient numbers of normal donor cells in the affected lineage(s); donor reconstitution of an unaffected lineage is not required for cure of the disease.

The barrier to successful allogeneic HCT is determined by differences in major or minor histocompatibility antigens between donor and recipient, resulting in bi-directional immunologically mediated graft-vs.-host (GVH) and host-vs.-graft (HVG) reactions. The barrier to engraftment is further determined by the capacity of host immune cells to generate a response to alloantigens. In addition, it has been postulated that host cell occupancy of a specific hematopoietic cell niche functions as a “space-occupying” barrier to engraftment. The strength of the opposing GVH reaction is determined by the number of alloreactive T cells in the graft. The conventional strategy to overcome this bi-directional barrier has relied upon three elements: first, elimination of host alloreactivity with agents capable of immunoablation and myeloablation; second, infusion of donor HSCs to rescue the patient from lethal myeloablation; and third, control of donor alloreactivity with post-transplant immune suppression or by elimination of T cells from the donor graft.

When these general principles are applied to the treatment of specific primary immune deficiency disorders, several distinct concepts emerge. First, syndromes that cause profound immune deficiency may not require a conditioning regimen, as there is no immunological resistance to engraftment. That said, there appears to be a barrier even in cases of severe combined immune deficiency (SCID), particularly when the MHC barrier is increased, i.e. in the situation of HLA-mismatched or haploidentical grafts. For example, donor B cell chimerism is less likely in γ-chain deficiency (X-SCID), as host cells persistently occupy the B lymphocyte niche, than in syndromes without B cells such as adenosine deaminase (ADA) deficiency. Accordingly, the intensity of the conditioning regimen generally is determined not only by the degree of human leukocyte antigen (HLA) disparity, but also by the magnitude of T cell deficiency and the occupancy of niches thought to be required for engraftment by host cells. Wiskott-Aldrich syndrome (WAS) exemplifies this concept in a different way: a successful allograft must generate normal platelets as well as functional T cells; hence the conditioning regimen must provide some degree of myeloablation. Second, the immune defect may be corrected by partial reconstitution of normal immune cells — in other words full donor chimerism of the affected cell subset may not be required. A natural model is the absence of immune deficiency in most female carriers of X-linked immune deficiencies. This concept may add further justification for limiting the intensity of the conditioning regimen. Third, there is no potential benefit for GVH alloreactivity among patients with an immune deficiency, in contrast to patients with hematological malignancy in whom a graft-vs.-leukemia effect might be advantageous. Thus HCT protocols generally employ intensive post-grafting immune suppression or deplete alloreactive T cells from the graft, so as to minimize the risk of GVH disease (GVHD). The strong preference to avoid GVHD also forms the basis for the general disinclination to transplant peripheral blood stem cells, which contain approximately 10 times the number of T cells in the graft compared to bone marrow. The potential risk for life-threatening GVHD often enters into the determination of whether HCT should be undertaken in a specific patient, and the degree of disparate HLA or minor histocompatibility antigens among available donors must be balanced against the effectiveness of alternative therapies, such as enzyme replacement, intravenous immune globulin, prophylactic antibiotics, and other medical treatments.

Severe combined immune deficiency (SCID)

SCID encompasses a broad range of inherited defects that individually cause a profound immune deficiency of both T and B cell function. The individual genetic defects give rise to various phenotypes in which the lymphocyte subsets may or may not be present, and if present, may or may not be functional, and which may pose a barrier to engraftment (Table 1) [1].

Table 1. Lymphocyte phenotype in the SCID syndromes

Lymphocyte phenotype

Mutation or deficiency

T

B

NK

-

-

-

Adenosine deaminase

-

-

+

RAG1 or RAG2

-

-

+

Artemis

-

+

-

Common γ chain

-

+

-

Jak3

-

+

+/-

CD45 deficiency

-

+

+

IL-7Rα-chain

-

+

+

CD3γ/CD3ε/CD3ζ deficiency


Since the goal of HCT is to restore both T and B cell function, the SCID phenotype must be taken into consideration in addition to the degree of recipient-donor mismatch. As mentioned above, elimination of occupancy of a B cell niche may require conditioning, particularly with haploidentical grafts; alternatively, establishment of “split” mixed chimerism (donor T / host B cells) may be sufficient to ameliorate the T cell dysfunction and allow the X-SCID patient to be supported with IVIG, similar to a patient with agammaglobulinemia. Lui et al recently showed that resistance to B cell engraftment in B+ SCID appears to be at the level of the pro-B cell, thus suggesting a potential role for targeting early B cell progenitors in lieu of high intensity conditioning [2].

Other biological factors associated with the SCID phenotype may influence the barrier to engraftment. NK cells, which are relatively radio resistant and may survive intensive conditioning regimens, have been shown to mediate graft rejection [3, 4]. The Perugia team has shown that donor NK alloreactivity is enhanced in the absence of T cells in the graft. Although this concept has been exploited to engineer donor grafts with enhanced anti-host NK activity, it may have implications for the reciprocal situation where T cells are lacking in the host. Particularly in the situation where the donor lacks inhibitory ligands, NK cells theoretically could pose an additional immune barrier to engraftment into a patient with SCID. This concept is supported by a murine model of Artemis deficiency, wherein NK-mediated graft rejection has been observed [5]. Another potential barrier is the presence of maternal T cells that have “engrafted” in the fetus in utero, often seen in patients with X-SCID. Maternal T cells can be detected using the standard methods for assessing chimerism, such as sex-chromosome specific fluorescent in situ hybridization (FISH) probes or polymerase chain reaction (PCR) detection of maternal-specific genetic polymorphisms, termed variable number tandem repeat (VNTR) sequences [6, 7]. High-levels of maternal T cells have been associated with resistance to engraftment of haploidentical cells when no conditioning is given [8, 9]. Thus, it is reasonable to consider use of a conditioning regimen in SCID patients with NK cells or maternal T cells. In the absence of a conditioning regimen, some reports have suggested that very large dose CD34+-selected peripheral blood stem cell (PBSC) grafts may help overcome graft rejection, although it may not facilitate B cell reconstitution [10].

One of the difficulties in analyzing the outcome of HCT in SCID patients is the relative rarity of the condition, which prohibits conducting large single center studies of a specific modality over a short period of time. Most reports with large numbers of patients represent either retrospective analyses of registry data, or single center studies conducted over a long period of time. Studies confined to a single phenotype or pilot studies of novel approaches generally have too few patients for meaningful assessment. The largest series of analyses has been reported by the European cooperative groups. In 1990 a retrospective study included 183 SCID patients given marrow transplants [11]. Among the 70 patients given grafts from HLA-identical siblings, 65 of whom were not given a preparative regimen, long term survival was 70%, and the majority of patients achieved stable engraftment of T and B lymphocytes. Factors that correlated with improved chances of survival included lack of infection prior to HCT and isolation of the patient in a protective environment. Clinical improvement was observed in all patients, including those with partial donor cell engraftment. In contrast to these results, less than 60% of patients given haploidentical grafts survived. The analysis definitively showed the important role of conditioning in establishing donor engraftment of T-depleted HLA-mismatched haploidentical marrow. Graft failure occurred in 50% of unconditioned patients compared to 14% of conditioned patients, and the rate of engraftment improved proportionately with increased intensity of the regimen. Immunological recovery, including B cell recovery, was also facilitated by the preparative regimen, and the frequency of late deaths related to poor immunological reconstitution was reduced. However, the benefit of a preparative regimen for establishing donor cell engraftment was negated by an increase in regimen-related complications and did not improve overall survival.

Over time, the outcome of HCT for SCID has improved, as novel supportive care and alternative donor sources have been used. Survival for recipients of HLA-identical sibling grafts now approaches 90%, and in the 2003 retrospective study by the European Group for Blood and Marrow Transplantation (EBMT), outcome for recipients of HLA-phenotypically identical grafts was not statistically significantly different from that for genotypically HLA-identical donors [12]. This analysis also showed a significant improvement over time for recipients of T-depleted haploidentical grafts, from approximately 60% to almost 80% survival (p=.0007) by the late 1990s. The most important factor for improved survival after an HLA-identical sibling graft was younger age at time of HCT, with a 2-fold increase in risk for patients aged 6–12 years, and an 8-fold increase in risk for patients >12 years when compared with patients given HCT before 6 years of age. Factors significantly associated with improved survival after haploidentical transplants were B+ SCID phenotype (64% vs. 36%, p=.0007), protected environment (57% vs. 15%, p=.0001), and lack of pulmonary infections before HCT (59% vs. 38%, p=.0001). Use of a conditioning regimen was associated with improved survival for B- SCID patients, although the difference was not statistically significant. More recently, Fischer and colleagues analyzed a large cohort of SCID patients to determine factors that correlated with good clinical outcomes (survival and amelioration of clinical immune deficiency) [13]. Graft source was significant, and risk for poor outcome was 3.7-fold higher for recipients of haploidentical and 4.8-fold higher for phenotypically HLA-identical (related or unrelated) compared to HLA-identical sibling grafts. Establishment of donor myeloid cells correlated with better survival, presumably because donor chimerism of the myeloid lineage correlated with donor origin of lymphocytes. Lack of CD4+ cell reconstitution and persistent need for IVIG were both significantly associated with poor outcome. Finally, the type of SCID appears to affect outcome, as specifically those with Artemis mutations have a 6-fold higher risk for poor outcome. These patients had a higher incidence of chronic papilloma virus infections, malnutrition, and chronic GVHD. Other studies indicate that survival generally is higher among B+ compared to B- SCID patients, particularly after alternative donor HCT [14].

Most other centers report comparable results, although in smaller series. The general experience is that genotypically HLA-identical marrow transplantation restores T cell immunity in >90% of unconditioned SCID patients, although B cell reconstitution occurs in only half of these patients [8, 15]. Despite the use of preparative regimens, recipients of T-depleted haploidentical marrow have delayed immune reconstitution, with 3–6 months required for development of antigen responsive T cells, and commonly multiple marrow infusions are needed [16]. B lymphocyte reconstitution is generally suboptimal and most patients require continued immunoglobulin support. The EBMT analysis found long-term functional T cells in about 80% of recipients of HLA-sibling grafts and 90% of B+ SCID recipients of haploidentical grafts; in contrast, functional T cells were observed in only 66% of B- SCID patients (p=.002). Long-term B cell function was less robust in all cohorts: 88% of B+ and 63% of B- SCID recipients of HLA-identical sibling grafts, and 66% of B+ and 44% of B- SCID recipients of haploidentical grafts, respectively. Certain SCID phenotypes may require a preparative regimen, for example patients with reticular dysgenesis given T-depleted grafts appear to have improved outcome if given high intensity conditioning with subsequent reconstitution of normal myeloid cells [17]. B- SCID patients also appear to benefit from conditioning [14].

The role of conditioning for unrelated grafts is the same as for T-depleted haploidentical grafts, in that it may facilitate establishment of donor B lymphocyte chimerism, however, that benefit may be offset by regimen-related toxicities. In 1992 Filipovich and colleagues reported their initial experience with unrelated marrow grafts for 8 SCID patients, of whom 5 were given high intensity conditioning [18]. Graft rejection occurred in 2 of the 3 unconditioned patients, although both survived long term after a second transplant with high intensity conditioning. Among the conditioned patients, 2 died within the first 100 days after HCT, while the others survived long term with improved immune function. Subsequently larger series have shown excellent outcome after high intensity conditioning followed by HLA-matched unrelated grafts, with about 80% survival [19, 20]. Compared to haploidentical recipients, unrelated marrow recipients had significantly lower risk for interstitial pneumonitis, graft failure, acute and chronic GVHD, and abnormal T cell receptor diversity [19]. Thus, immune reconstitution after T-replete unrelated donor transplantation appears to be faster compared to T-depleted haploidentical HCT, and often normal B cell function is achieved.

Outcomes for unrelated umbilical cord blood have been reported in small series and appears equivalent to that of matched unrelated marrow. Bhattacharya et al reported success in establishing well-matched (6/6 or 10/10 HLA match) umbilical cord blood grafts without conditioning [21]. The median time to achieving an absolute T cell count of more than 200 cells/ml among 5 surviving SCID patients was about 60 days, and mixed or full donor B cell engraftment was observed in 4 of these. Diaz reported 11 SCID patients, 9 given high intensity and 2 given reduced intensity conditioning, 7 and 1 of these, respectively, survive long term [22]. High intensity conditioning generally has been employed in recipients of HLA-mismatched cord blood units, with comparable results [20].

The condition of the patient before HCT correlates strongly with the risk of death after HCT irrespective of the graft source. In particular, infections and pulmonary disease are associated with significantly worse outcomes [12, 14, 23]. The most common cause of death in the first 6 months after HCT is infection, thus it is not surprising that pre-existing infection is detrimental to success. Indeed, a pre-existing pulmonary infection confers a 2-to 3-fold increased risk of death following HCT [14]. Therefore, every patient with SCID should have a thorough evaluation for infection and occult pulmonary disease. Liver enzyme elevations may indicate maternal T cell-mediated GVHD or underlying liver dysfunction, the latter is commonly associated with untreated ADA deficiency. Enzyme replacement therapy with polyethylene glycol (PEG) conjugated adenosine deaminase improves T cell function [24]. Since functional T cells pose an immunological barrier to engraftment, the general practice has been to stop PEG-ADA several weeks before HCT in order to “T-deplete” the recipient. However PEG-ADA also prevents or improves the liver injury found in ADA deficiency, thus, early stopping may result in hepatitis and increase the risk for post-transplant liver toxicity during the time required to establish endogenous enzyme production. A reasonable approach is to continue PEG-ADA unless no conditioning is contemplated, in which case pre-transplant discontinuation is warranted. Age of the patient is another important factor associated with survival. The best outcomes are reported for SCID patients given allogeneic transplant within the first year of life [12]. Older patients are more likely to have infections and organ dysfunction that contribute to higher mortality.

The advent of neonatal screening and in utero diagnosis has allowed early detection of SCID and therefore prompt intervention at an early age. Buckley and colleagues reported better survival and the establishment of long-term functional T cells in patients with SCID who received HCT before 28 days of life (overall survival ((OS) 95%) compared to patients who were older (OS 74%) [25]. Survival of 21 SCID infants, given no conditioning and transplanted with haploidentical T cell depleted marrow grafts before 28 days of age (neonatal cohort), was 95% compared to 74% of 96 older infants. Thymopoiesis, as measured by T cell receptor excision circles (TREC), was improved in the neonatal transplant cohort, however, no comparative improvement in B cell function was observed. Acute GVHD grades III–IV developed in only 16% of patients who received grafts mismatched for 2 or 3 HLA antigens. Several factors probably contributed to the improved survival observed in patients less than 28 days old. In particular, younger patients are less likely to have opportunistic infections and subsequent co-morbidities, malnutrition, and failure to thrive, all of which have been associated with increased mortality following HCT, but may also contribute to decreased thymic function. These results show that T cell depleted haploidentical marrow grafts are feasible at a very early age and that there is little benefit in delaying HCT in order to identify a better matched donor.

Once established, donor progenitor cells develop and mature in the vestigial thymus of the SCID patient. Buckley and colleagues demonstrated that T cell receptor (TCR) gene rearrangement occurs in donor T cell precursors resulting in the generation of naïve T cells [25, 26, 27]. Measurements of TCR repertoire show development of a broad diversity within the donor T cell pool, which persists over time. Patel and colleagues reported that thymopoiesis, as measured by TRECs and naïve CD4 cells, declined exponentially over time after HCT. Several studies have suggested that late graft failure or deterioration of thymopoiesis may jeopardize long-term T cell function [28]. In contrast, recent studies have shown that thymic output of T cells and T cell diversity remain normal for decades after HCT in approximately 80% of patients [29, 30]. The degree of early T cell reconstitution appears to be strongly associated with the long-term stability of T cell function, thus, patients at most risk for poor T cell function or loss of T cell grafts are those with low numbers of TRECs and naïve-CD4 cells within the first few years after HCT [13, 31]. Alain Fischer’s team in Paris found that donor chimerism of the myeloid lineage correlated with higher CD4+ T cell counts long term, and that donor myeloid chimerism was limited to patients who received high intensity conditioning. Other factors that may be associated with higher risk for poor long-term T cell reconstitution are SCID phenotypes that lack B cells, presence of NK cells, and possibly young age at time of HCT. As noted above, long term B cell reconstitution is common only among patients given high intensity conditioning regimens [13, 15].

Primary T cell immunodeficiencies other than SCID

Primary T cell immunodeficiency (PTCD) syndromes may be differentiated from SCID by virtue of reduced but not completely absent T cell function, or absent T cell function with the presence of B lymphocyte or NK cell function. Nonetheless, the immune dysfunction leads to progressive decline from opportunistic infections, autoimmune phenomena, and a propensity to develop malignancies, particularly lymphoma. Several of the genetic mutations implicated in SCID also have been found to be present in patients with PTCD, thus termed “leaky SCID”. New genetic mutations also have been characterized, while the genetic causes in many patients remain unrecognized [32, 33, 34]. The more common of these rare disorders are listed in Table 2.

Table 2. Primary T cell immunodeficiency syndromes commonly referred for HCT
Abbreviations:
HIGM, Hyper IgM;
HLA, Human leukocyte antigen;
HSM, hepatosplenomegaly;
IPEX, Immunodeficiency-polyendocrinopathy-enteropathy X-linked;
XLP, X-linked lymphoproliferative

Syndrome

Mutation

Clinical features

Laboratory features

Omenn’s

RAG1 or RAG2

HSM
Rash
Adenopathy

Eosinophilia
Lymphocytosis

ZAP70

ZAP70

CD8+ lymphopenia
High IgE levels

HIGM

CD40L or CD40

X-linked
Pyogenic infection
Sclerosing cholangitis

High IgM & low IgG levels

Common Variable Immunodeficiency

Unknown

Autoimmunity
Allergy

Low IgG

Cartilage Hair Hypoplasia

endoribonuclease RMRP

Dwarfism
Hypoplastic hair growth

Wiskott Aldrich

WASP

Eczema

Thrombocytopenia
Small platelet size

IPEX

FOXP3

X-linked
Diabetes
Diarrhea
Rash

XLP

SH2D1A

X-linked
EBV- lymphoproliferative disease

Hypogammaglobulinemia

Bare Lymphocyte syndrome (Class II HLA deficiency)

RFXANK, RFX5, RFSAP, CIITA

Pulmonary infection
Diarrhea
Hepatitis

Hypogammaglobulinemia
CD4 lymphopenia
Absent antigen-specific T cell responses

Class I HLA deficiency

TAP1 or TAP2

CD8 lymphopenia

DiGeorge syndrome

10p13 or 22q11.2

Hypocalcemia
Cardiac anomolies

CD3 lymphopenia
Elevated IgE


Until gene therapy is perfected, allogeneic marrow transplantation remains the only curative therapy available for these disorders. In general, conventional regimens have included both immunoablative and myeloablative agents to overcome residual immune barriers to engraftment and to ensure multi-lineage chimerism. The combination of busulfan (1 mg/kg x 16 doses) and cyclophosphamide (200 mg/kg total dose), with or without anti-thymocyte globulin is the most commonly used regimen. Our experience indicates that busulfan is metabolized faster in young patients, therefore in order to optimize engraftment it is prudent to adjust the daily doses to achieve steady state concentration (Css) of >200 ng/ml in recipients of HLA-identical sibling grafts and >400 ng/ml in recipients of HLA-matched unrelated grafts [35].

In 2003 the EBMT reported a retrospective analysis of outcome for patients with primary immunodeficiency disease other than SCID [12, 36]. A higher incidence of engraftment was reported in patients who received HLA-identical sibling grafts (99%), compared to those who received haploidentical or unrelated donor grafts (75–80%). In addition, survival at 3 years was better for patients who received HLA-identical sibling grafts (71%) compared to haploidentical grafts [42% (p=.0006)]. Survival after HLA-matched unrelated donor grafts was 59%, which was not statistically significantly different from the HLA-identical sibling cohort. The main cause of death following HCT was infection.

Worse outcomes were seen in patients with PTCD compared to other types of immune deficiencies, regardless of donor. Overall survival was 63% and 35% after HLA-identical sibling grafts or mismatched grafts, respectively [12, 36]. Unfortunately, and in contrast to the results for SCID, the EBMT study found no improvement in survival of the non-SCID cohorts over the two decades included in the analysis, thus highlighting important differences and problems associated with PTCD compared to SCID. Although life-threatening infections may be less common early in life, children with PTCD often develop organ damage from chronic infections, particularly lung disease, prior to HCT. Given that a conditioning regimen is necessary to ensure engraftment, the associated risks for organ toxicity, hemorrhage, and infection are compounded by these co-morbidities. Several studies have associated inferior survival with presence of co-morbidities, including opportunistic infections, Epstein-Barr virus lymphoproliferation, and pulmonary dysfunction [8, 23]. Among boys with X-linked hyper-IgM (XHIM) excessive mortality has been associated with the presence of pulmonary infection or liver disease at time of HCT [37].

In theory, split chimerism (donor T/host B chimerism) or partial donor T cell chimerism should be sufficient to ameliorate the immune dysfunction in most types of PTCD. Accordingly, reducing the intensity of conditioning may be a strategy to reduce regimen-related toxicity without sacrificing immune reconstitution. Specific factors associated with the molecular defect must be taken into consideration, as partial chimerism may not be sufficient for some defects. DiGeorge syndrome and the Bare Lymphocyte syndromes (BLS) pose particular challenges, because the T cell deficiency results from inadequate thymopoiesis, caused by absence of the thymus or absence of HLA molecules on the thymic epithelial cells, respectively. The molecular defects that cause BLS block the transcription of HLA genes; therefore antigen-presenting cells also are defective. Hence, donor chimerism must be established in B cell and dendritic cell lineages. In both disorders, absence of thymic function may prevent formation of naïve donor T cells; therefore full chimerism provides the most likely chance that a broad range of donor antigen-specific memory cells may be established long term.

Molecular deficits that allow T cell proliferation, but preclude intercellular interactions, such as X-linked hyper-IgM (XHIM) syndrome or Immune Dysregulation-Polyendocrinopathy-Enteropathy X-linked (IPEX) syndrome, generally require conditioning in order to prevent T cell mediated graft rejection; however, partial T cell chimerism appears to restore immune function as well as full donor chimerism [38, 39]. The autoimmune manifestations of the IPEX syndrome are caused by absence of CD4+CD25+ FOXP3+ regulatory T cells (Tregs), important for sustaining self-tolerance. Normal numbers of FOXP3 expressing CD4+CD25+ cells have been observed in boys with mixed donor/host chimerism, and several case reports indicate that mixed chimerism is sufficient to ameliorate many of the manifestations of IPEX, including the enteropathy, anemia, failure to thrive, and the susceptibility to infections. Curiously, we and others have observed improvement in diabetes, although in theory autoimmune-mediated islet cell destruction happens well before HCT is carried out [38]. The most common cause of the XHIM syndrome is a mutation in the CD40 ligand gene, which is expressed by T cells and provides a critical signal for B cells to switch antibody production from IgM to IgG subtypes. Theoretically, the introduction of some normal CD40 ligand-expressing T cells should be sufficient to reverse the disease, even if B cells of host origin remain. Amelioration of disease symptoms with mixed chimerism has been observed for some boys treated for XHIM, although no detailed analysis of B cell function was reported [40, 41].

Wiskott-Aldrich Syndrome (WAS). HCT offers significantly improved survival chances for patients with WAS, without which about 50% will die from infection, autoimmune disease, or lymphoproliferative disease by the third decade of life [42]. The WAS mutation affects lymphoid and hematopoietic compartments, both of which are corrected by HCT. Accordingly most patients are conditioned with both immunosuppression and high dose chemotherapy to facilitate multilineage donor cell engraftment. Figure 1 shows cell counts in a patient who was too ill with opportunistic infections to receive high dose conditioning and became a split chimera after reduced intensity conditioning and unrelated marrow transplantation. Following transplantation the T cell immune defect was corrected, but thrombocytopenia persisted as did host CD33+ cells. After the infections resolved, a second graft was given with a high intensity (directed at myeloid cells), but without immunoablative preparative regimen, resulting in amelioration of thrombocytopenia as the CD33+ compartment converted to donor type. The importance of achieving full donor chimerism was shown recently in a retrospective analysis of results in 96 patients, which showed an almost 2-fold reduction in mortality among patients with full chimerism compared to those with mixed or split chimerism [43]. Mixed chimerism also is associated with a significantly higher risk for developing autoimmune manifestations after HCT.

Figure 1. Correction of thrombocytopenia in Wiskott-Aldrich correlates with donor chimerism of CD33+ cell subset
At 30 days after hematopoietic cell transplant, a high proportion of both CD3 (gray line) and CD33 (black line) subsets mark as donor origin. Over time, the proportion of donor CD3 cells remains stable, while the proportion of donor CD33 cells decreases. The platelet count (black dashed line) reaches a normal level when the CD33 donor chimerism is high, and falls proportionately with the fall in donor CD33 chimerism.

Burroughs_et_al_Figure1_72dpi.png

HCT using HLA-identical sibling marrow grafts is highly successful in treating WAS, with approximately 88% event-free survival [43]. The combination of busulfan (1 mg/kg x 16 doses) and cyclophosphamide (200 mg/kg total dose), with or without anti-thymocyte globulin is the most commonly used conditioning regimen. Busulfan is metabolized faster in younger patients, therefore it is prudent to monitor levels and target the dose to achieve a Css of greater than 200 ng/ml to assure engraftment [35]. An EBMT analysis determined that patient age, disease severity, and splenectomy, among other factors, did not affect outcome [43].

Results of alternative donor HCT for treatment of WAS have improved over time, particularly for recipients of unrelated marrow grafts. Most recent studies have shown approximately 70%–78% long-term survival [43, 44]. In a 2001 study facilitated by the International Bone Marrow Transplant Registry (IBMTR), age of 5 years or older was associated with an increased risk of mortality after HCT. Survival for patients younger than 5 years was about the same as for recipients of HLA-identical sibling grafts. In addition, several studies found comparable survival rates among recipients of HLA-matched related and unrelated grafts [44, 45]. The most commonly used regimen was a combination of busulfan, cyclophosphamide, and ATG. In our experience, targeting the dose of busulfan to achieve a C SS above 400 ng/ml facilitates engraftment [35].

Encouraging results have also been reported for umbilical cord blood transplants, but most information comes from case reports or part of smaller series of patients with immune deficiencies. Among 15 patients reported by Ozsahin, et al, event-free survival was approximately 70%, similar to recipients of unrelated marrow grafts [44]. Most patients in these reports were conditioned with the combination of busulfan, cyclophosphamide, and antithymocyte globulin, which the Japanese group found to be an important factor for improved survival when compared to other regimens [44]. Reconstitution of immunity after cord blood approximates that observed with unrelated marrow grafts.

There is more information about haploidentical transplants for WAS, although the historical results are less encouraging. The EBMT study showed a 4–5-fold increase in mortality after haploidentical compared to HLA-identical sibling grafts [43]. Others have reported similar results [36, 44, 46]. These reports show a high incidence of graft failure and poor immune reconstitution following T-depleted haploidentical marrow grafts. The Tubingen team provided a promising case report of “mega-dose” purified CD34+ haploidentical grafts used to overcome the barrier to engraftment without engendering GVHD [47].

Inherited immune defects not primarily affecting T cells

A wide range of rare immune deficiency syndromes result from defects in B lymphocytes, NK cells, or nonlymphocytic subsets including neutrophils (Table 3).

Table 3. Histiocytic and myeloid immune deficiency syndromes commonly referred for HCT
Abbreviations:
FHL, Familial hemophagocytic lymphohistiocytosis;
LCH, Langerhans cell histiocytosis

Syndrome

Mutation

Clinical features

Laboratory features

Histiocytic disorders

FHL

PRF1
UNC13D
STX11

Fever
Hepatosplenomegaly
Lymphadenopathy
Rash
Pulmonary infiltrates
Neurologic deficits

Pancytopenia
Hypertriglyceridemia
Hypofibrinogenemia
Elevated liver function tests

Multifocal LCH

unknown

Bone lesions
Endocrinopathy
Rash
Hepatosplenomegaly

Anemia

Myeloid disorders

Chronic Granulomatous Disease

p91PHOX
CYBA
NCF1

Pneumonia
Cellulitis

Catalase-positive bacteria
Aspergillus

Chediak-Higashi Syndrome

CHS1

Pyogenic infections
Gingivitis
Oculocutaneous albinism
Hemorrhage

Neutropenia
Giant intracellular granules

Leukocyte Adhesion defect

β-2 integrin

Bacterial infections
Stomatitis

Leukocytosis

Kostmann’s neutropenia

GCSF-R

Bacteremia/sepsis

Neutropenia

Shwachman-Diamond Syndrome

Unknown

Pancreatic enzyme deficiency

Neutropenia


The individual immune defects predispose the patients to specific infections, for example with Aspergillus in patients with chronic granulomatous disease (CGD) or staphylococcus aureus in leukocyte adhesion deficiency (LAD)-I, and are associated with distinctive co-morbidities, such as infiltrative pulmonary or central nervous system disease in hemophagocytic lymphohistiocytosis (HLH) or recalcitrant colitis in CGD. As above, the decision to treat with HCT must take into consideration the prognosis of the disorder with available supportive care, the presence of co-morbidities that might increase the risk of mortality following HCT, and the availability of a suitable donor. Unfortunately, because these diseases are rare, meaningful prospective studies reporting on large series of patients with a single disease entity are not available. Within the European retrospective study, survival for specific subsets, 48 patients with phagocytic disorders, and 90 patients with hemophagocytic disorders, was reported to be approximately 70% and 68%, respectively, for recipients of HLA-identical sibling grafts. The small number of patients with phagocytic cell disorders had a similar outcome after transplantation of unrelated marrow, in contrast to patients with hemophagocytic disorders in whom survival was only 28% after unrelated grafts.

Studies that include larger numbers of patients with single diagnoses are limited to a few disorders such as CGD and HLH. The prognosis for CGD patients has improved considerably with more aggressive use of gamma-interferon and antibiotic prophylaxis. HCT is indicated for patients with recurrent life-threatening infections or organ dysfunction caused by refractory granulomatous disease [48]. A series of patients transplanted with HLA-identical sibling marrow (n=10) or unrelated marrow or cord blood (n=10) was reported recently from the United Kingdom [49]. Most patients were conditioned with busulfan and cyclophosphamide, and alemtuzumab was given to recipients of unrelated grafts. Survival was reported to be 90% with a median follow-up of 61 months; one patient in each group died from disseminated infection. Neutrophil oxidative burst was normalized in patients with mixed as well as full donor chimerism. Del Giudice et al published a review of case reports and small series of patients with CGD that included several long-term survivors with stable mixed chimerism, consistent with the notion that a small proportion of normal cells improves disease symptoms [50].

Without HCT, the prognosis for patients with HLH is poor even with intensive supportive care and anti-inflammatory regimens that include etoposide, cyclosporine, and prednisone [51, 52]. The outcome is considerably improved when HCT is performed after control of the initial inflammatory state is gained and infiltrative disease has resolved. The HLH 94 protocol reported 50–60% overall survival for the 113 children entered into the study; overall survival was 65% for the subgroup of 65 children given HCT. The study results suggested that intrathecal chemotherapy plays an important role in gaining disease control [52]. A retrospective analysis of 91 patients in the CIBMTR registry given unrelated marrow grafts found 53% overall survival [53]. Most patients were conditioned with busulfan, cyclophosphamide, and etoposide, with or without ATG. Survival was worse among the small subgroup with active disease at time of HCT, as well as among recipients of HLA-mismatched grafts. Disease manifestations resolved among patients with mixed as well as full donor chimerism. Early mortality (before day 100) was 32%, however, suggesting that a reduced intensity conditioning regimen might be of benefit.

Development of reduced toxicity regimens

Conditioning regimens that do not employ agents at doses resulting in long-lasting marrow aplasia are referred to as reduced intensity conditioning (RIC) regimens. Until recently, those regimens have been used routinely for only two conditions: severe aplastic anemia and SCID. Regimens for aplastic anemia have included immunosuppressive agents alone to overcome the allo-immune rejection responses, since these patients are thought to have "unoccupied" marrow space. These reduced intensity regimens have resulted in a markedly lower incidence of both early and late complications [54, 55]. SCID patients have no immune system capable of rejecting the graft, and therefore do not require conditioning except in the instances discussed above [11].

As the power of the graft vs. leukemia (GVL) effect became evident in the late 1970s and early 1980s, subsequent studies found that donor lymphocyte infusions (DLI) could be used to treat leukemic relapse after HCT [56>, 57]. The success of DLI set the stage for the introduction of reduced intensity conditioning for HCT, based on the hypothesis that the graft itself created the needed space through a subclinical GVH reaction directed toward recipient hematopoietic cells. Based on insights from animal models and armed with new potent immunosuppressive agents such as 2-CDA and fludarabine, investigators in Texas, Israel, Seattle, Boston, and Washington, DC pioneered less toxic regimens that facilitated partial or full chimerism in most patients [58, 59, 60, 61, 62, 63, 64].

These studies demonstrated that intensive immunosuppression alone following stem cell infusion was sufficient to establish full or partial donor chimerism and that conditioning was not required for creation of marrow space. The extent of donor cell engraftment following low intensity regimens depends on multiple factors, including the degree of intensity of the preparative regimen, the source of hematopoietic cells (marrow vs. peripheral blood stem cells), the degree of HLA-matching, and the extent of T cell depletion. Most low intensity protocols use PBSC to facilitate engraftment and enhance GVL reactions, as the product may contain 10-fold greater numbers of T cells and 4-fold greater number of hematopoietic stem cells compared to marrow [65].

There are several reasons for the further development of low intensity regimens for the establishment of mixed chimerism in patients with Non-SCID primary immune deficiency disorders. First, the potential risks of high dose conditioning regimens include early treatment related mortality and late effects, such as infertility, hormonal dysfunction, growth failure, and secondary malignancies. These risks may deter patients and families from seeking treatment before co-morbidities arise. Second, as discussed earlier, the risk for regimen-related mortality increases significantly among patients with disseminated infection, pulmonary disease or other organ dysfunction. Third, reversal of disease symptoms with partial chimerism, which may be achievable with low intensity conditioning, has been demonstrated in a number of studies [36, 66].

The main challenge in translating the success of protocols using RIC to patients with primary immune deficiency is the reliance on PBSC grafts, which may be difficult (or impossible) to collect from pediatric donors; also it confers a high risk of GVHD. Some progress has been made using marrow or CD34+ selected PBSC. Some results with HLA-matched related or unrelated marrow using RIC are summarized in Table 4.

Table 4. Intensity conditioning regimens and transplant outcome in immunodeficiency syndromes
Abbreviations:
ATG, anti-thymocyte globulin;
BM, bone marrow;
CB, cord blood;
CGD, chronic granulomatous disease;
DLI, donor lymphocyte infusion;
EBV-LPD, Epstein Barr virus lymphoproliferative disease; Flu, fludarabine;
HCT, hematopoietic cell transplant;
IPEX, Immunodeficiency-polyendocrinopathy-enteropathy X-linked;
Mel, melphalan;
MSD, matched sibling donor;
PBSC, peripheral blood stem cells;
PID, primary immune deficiency (nonSCID);
SCID, severe combined immune deficiency;
SC-M, severe co-morbities;
TBI, total body irradiation

Author

Diagnosis

Regimen

Donor

Rejection (No.)

Survival (No.)

FU (mo)

Reduced Intensity Conditioning

(Rao et al. 2005 [67])

27 PID/ 6 SCID

Flu/ Mel/Campath

BM

0

31

(Amrolia et al. 2000 [68])

6 ID/ 2 SCID

Flu/ Mel/ ATG

0

7

6-18

(Rao et al. 2007 [38])

4 IPEX

Flu/ Mel/Campath

BM

0

4

6-25

(Cohen et al. 2007 [69])

7 PID/ EBV-LPD

Flu/ Mel/Campath

BM or PBSC

0

7

0

Minimal Toxicity (non-myeloablative) Conditioning

(Horwitz et al. 2001 [70])

10 CGD

Flu/ Cy/ ATG
Post-HCT DLI

CD34+ PBSC

1

7

16-26

(Burroughs et al. 2007 [71])

10 PID+SC-M

Flu / 2 Gy TBI

PBSC

1

7

9-96


A high rate of engraftment of marrow grafts has been reported after the combination of fludarabine and melphalan plus, an in vivo T-depleting agent, such as ATG or Campath®, and appears to be associated with low mortality rates [38, 67, 68, 70]. The combination of cyclophosphamide, fludarabine, and ATG has been studied as a low-intensity regimen to facilitate engraftment of CD34+ selected PBSC [70]. In the latter study, the benefit of in vivo and ex vivo T-depletion for reducing GVHD was at least partially abrogated by the use of DLI to improve the level of donor cell chimerism. The Seattle group has studied the combination of fludarabine and low-dose TBI in patients who would be expected to have very poor survival following conventional conditioning for HCT, such as those with disseminated opportunistic infections, mechanical ventilation, or other organ damage. No regimen-related mortality was observed in the first cohort given 2 Gy TBI, however chronic GVHD was observed in 70% of patients, presumably related to the use of PBSC grafts [71]. The substitution of marrow for PBSC in the subsequent cohort appears promising, and early mortality has not been increased despite increasing the dose of TBI to 4 Gy (Figure 2). Taken together, these studies suggest that low-intensity regimens offer the potential for achieving donor cell engraftment with less morbidity than standard regimens, an important consideration for patients who currently may consider the risks of conventional transplants unacceptably high.

Figure 2. Survival of patients with severe infections or pulmonary disease after reduced intensity conditioning HCT is improved with bone marrow as the sole source of allogeneic hematopoietic cells.
The first cohort of patients (dashed line) was conditioned with fludarabine and 2 Gy total body irradiation and most patients received peripheral blood stem cell grafts. The second cohort (solid line) was conditioned with fludarabine and 4 Gy total body irradiation and was given marrow grafts.

Burroughs_et_al_Figure2_72dpi.png

Acknowledgements

This work was supported by National Institute of Health grant NHLBI grant HL36444 and National Cancer Institute grant CA18029.

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Недавние исследования показали, что наиболее важным фактором лучшего приживления после HLA-идентичной пересадки от сибса является более юный возраст в момент ТГСК. Факторами, существенно связанными с лучшим выживанием, после гаплоидентичных трансплантаций были: B+ фенотип больных ТКИД, защищенная (асептическая) среда обитания, и отсутствие легочных инфекций до ТГСК. </p> <p class="bodytext">Внедрение неонатального скрининга и диагностика in utero позволили рано выявлять ТКИД и, тем самым, способствуют лечению в раннем возрасте. </p> <p class="bodytext">Синдромы с первичным Т-клеточным иммунодефицитомс (ПТКИД) могут быть дифференцированы от ТКИД по снижению, но не полному отсутствию Т-клеточной функции, или же по отсутствию Т-клеточной активности при наличии функций В-лимфоцитов или НК-клеток. Аллогенная пересадка костного мозга остается единственным исцеляющим методом лечения, доступным для таких заболеваний. 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Барроуз, Э. Вулфри</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(43) "

Л. Барроуз, Э. Вулфри

" ["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"]=> string(5) "19095" ["VALUE"]=> array(2) { ["TEXT"]=> string(168) "<p>Центр раковых исследований Фреда Хатчинсона и Университет Вашингтона, Сиэтл, США</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(156) "

Центр раковых исследований Фреда Хатчинсона и Университет Вашингтона, Сиэтл, США

" ["TYPE"]=> string(4) "HTML" } ["~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) "19096" ["VALUE"]=> array(2) { ["TEXT"]=> string(7407) "<p class="bodytext">Трансплантация гемопоэтических клеток (ТГСК) является средством лечения первичных синдромов иммунодефицита (ПСИД), представляющих собой группу заболеваний, первично нарушающих один из ростков, например, лимфоидный или миелоидный. В целом, применение различных кондиционирующих режимов ТГСК зависит от типа ПСИД. Некоторые синдромы, вызывающие глубокий иммунодефицит, могут и не требовать кондиционирования. Возможно, однако, что существует иммунный барьер даже в случаях тяжелого комбинированного иммунодефицита (ТКИД), особенно в ситуации с расхождением по HLA или при гаплоидентичной ТГСК. Например, донорский В-клеточный химеризм менее вероятен при дефиците γ-цепей (X-сцепленный ТКИД), поскольку клетки больного занимают нишу В-клеток, нежели при синдромах без В-клеток (например при дефиците аденозиндезаминазы. Иммунный дефект может быть исправлен путем частичного восстановления нормальных иммунных клеток, другими словами – может и не требоваться полный донорский химеризм поврежденной клеточной субпопуляции. Эта концепция может служить дальнейшим доводом в пользу ограничения интенсивности кондиционирующего режима. </p> <p class="bodytext">ТКИД включает в себя широкий круг врожденных дефктов, которые в каждом случае приводят к глубокому иммунодефициту как Т-, так и В-клеточной функции. Индивидуальные генетические дефекты ведут к развитию разнообразных фенотипов, и, поскольку цель ТГСК состоит в восстановлении как Т-, так и В-клеточных функций, то фенотип ТКИД должен приниматься в расчет, наряду со степенью различий донора и реципиента. Другие биологические факторы, ассоциированные с фенотипом ТКИД могут влиять на барьер приживления, такие, как НК-клетки больного, которые могут выжмивать после интенсивных кондиционирующих режимов. </p> <p class="bodytext">Одной из проблем в анализе исходов ТГСК у больных ТКИД является относительная редкость этого заболевания, что требует больших многоцентровых программ. Недавние исследования показали, что наиболее важным фактором лучшего приживления после HLA-идентичной пересадки от сибса является более юный возраст в момент ТГСК. Факторами, существенно связанными с лучшим выживанием, после гаплоидентичных трансплантаций были: B+ фенотип больных ТКИД, защищенная (асептическая) среда обитания, и отсутствие легочных инфекций до ТГСК. </p> <p class="bodytext">Внедрение неонатального скрининга и диагностика in utero позволили рано выявлять ТКИД и, тем самым, способствуют лечению в раннем возрасте. </p> <p class="bodytext">Синдромы с первичным Т-клеточным иммунодефицитомс (ПТКИД) могут быть дифференцированы от ТКИД по снижению, но не полному отсутствию Т-клеточной функции, или же по отсутствию Т-клеточной активности при наличии функций В-лимфоцитов или НК-клеток. Аллогенная пересадка костного мозга остается единственным исцеляющим методом лечения, доступным для таких заболеваний. Независимо от донорских факторов, у больных с ПТКИД наблюдаются худшие клинические исходы, по сравнению с другими типами ИДС. Хотя опасные для жизни инфекции могут быть в раннем возрасте менее частыми, у детей с ПТКИД часто развивается органная патология из-за хронических инфекций, в особенности болезни легких до проведения ТГСК. </p> <p class="bodytext">ТГСК при синдроме Вискотт-Олдрича дает больным значительные шансы на выживание. Показано, что достижение полного донорского химеризма является здесь благоприятным фактором. В целом, однако, многочисленные исследования при ИДС показывают, что кондиционирование низкой интенсивности создает условия для приживления донорских клеток при меньшей заболеваемости по сравнению со стандартными режимами, что является важным фактором для больных, у которых может быть неприемлемо высоким риск от проведения обычных трансплантаций. </p> <h3>Ключевые слова</h3> <p> первичные иммунодефициты, тяжелый комбинированный иммунодефицит (ТКИД), первичные Т-клеточные дефициты, трансплантация гемопоэтических стволовых клеток (ТГСК), кондиционирующие режимы, клинические исходы </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(7251) "

Трансплантация гемопоэтических клеток (ТГСК) является средством лечения первичных синдромов иммунодефицита (ПСИД), представляющих собой группу заболеваний, первично нарушающих один из ростков, например, лимфоидный или миелоидный. В целом, применение различных кондиционирующих режимов ТГСК зависит от типа ПСИД. Некоторые синдромы, вызывающие глубокий иммунодефицит, могут и не требовать кондиционирования. Возможно, однако, что существует иммунный барьер даже в случаях тяжелого комбинированного иммунодефицита (ТКИД), особенно в ситуации с расхождением по HLA или при гаплоидентичной ТГСК. Например, донорский В-клеточный химеризм менее вероятен при дефиците γ-цепей (X-сцепленный ТКИД), поскольку клетки больного занимают нишу В-клеток, нежели при синдромах без В-клеток (например при дефиците аденозиндезаминазы. Иммунный дефект может быть исправлен путем частичного восстановления нормальных иммунных клеток, другими словами – может и не требоваться полный донорский химеризм поврежденной клеточной субпопуляции. Эта концепция может служить дальнейшим доводом в пользу ограничения интенсивности кондиционирующего режима.

ТКИД включает в себя широкий круг врожденных дефктов, которые в каждом случае приводят к глубокому иммунодефициту как Т-, так и В-клеточной функции. Индивидуальные генетические дефекты ведут к развитию разнообразных фенотипов, и, поскольку цель ТГСК состоит в восстановлении как Т-, так и В-клеточных функций, то фенотип ТКИД должен приниматься в расчет, наряду со степенью различий донора и реципиента. Другие биологические факторы, ассоциированные с фенотипом ТКИД могут влиять на барьер приживления, такие, как НК-клетки больного, которые могут выжмивать после интенсивных кондиционирующих режимов.

Одной из проблем в анализе исходов ТГСК у больных ТКИД является относительная редкость этого заболевания, что требует больших многоцентровых программ. Недавние исследования показали, что наиболее важным фактором лучшего приживления после HLA-идентичной пересадки от сибса является более юный возраст в момент ТГСК. Факторами, существенно связанными с лучшим выживанием, после гаплоидентичных трансплантаций были: B+ фенотип больных ТКИД, защищенная (асептическая) среда обитания, и отсутствие легочных инфекций до ТГСК.

Внедрение неонатального скрининга и диагностика in utero позволили рано выявлять ТКИД и, тем самым, способствуют лечению в раннем возрасте.

Синдромы с первичным Т-клеточным иммунодефицитомс (ПТКИД) могут быть дифференцированы от ТКИД по снижению, но не полному отсутствию Т-клеточной функции, или же по отсутствию Т-клеточной активности при наличии функций В-лимфоцитов или НК-клеток. Аллогенная пересадка костного мозга остается единственным исцеляющим методом лечения, доступным для таких заболеваний. Независимо от донорских факторов, у больных с ПТКИД наблюдаются худшие клинические исходы, по сравнению с другими типами ИДС. Хотя опасные для жизни инфекции могут быть в раннем возрасте менее частыми, у детей с ПТКИД часто развивается органная патология из-за хронических инфекций, в особенности болезни легких до проведения ТГСК.

ТГСК при синдроме Вискотт-Олдрича дает больным значительные шансы на выживание. Показано, что достижение полного донорского химеризма является здесь благоприятным фактором. В целом, однако, многочисленные исследования при ИДС показывают, что кондиционирование низкой интенсивности создает условия для приживления донорских клеток при меньшей заболеваемости по сравнению со стандартными режимами, что является важным фактором для больных, у которых может быть неприемлемо высоким риск от проведения обычных трансплантаций.

Ключевые слова

первичные иммунодефициты, тяжелый комбинированный иммунодефицит (ТКИД), первичные Т-клеточные дефициты, трансплантация гемопоэтических стволовых клеток (ТГСК), кондиционирующие режимы, клинические исходы

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Lauri Burroughs (MD), Ann Woolfrey (MD)

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Fred Hutchinson Cancer Research Center and University of Washington, Seattle, WA

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Hematopoietic cell transplantation (HCT) has the potential to cure primary immune deficiency syndromes (PIDS) that are a group of disorders primarily affecting a single lineage, e.g., lymphoid or myeloid lineage. Generally, implementation of various conditioning regimens depends the type of IDS. Some syndromes that cause profound immune deficiency may not require a conditioning regimen. There appears to be a barrier even in cases of severe combined immune deficiency (SCID), particularly in the situation of HLA mismatched or haploidentical grafts. For example, donor B cell chimerism is less likely in γ-chain deficiency (X-SCID), as host cells persistently occupy the B lymphocyte niche, than in syndromes without B cells such as adenosine deaminase (ADA) deficiency. The immune defect may be corrected by partial reconstitution of normal immune cells, in other words full donor chimerism of the affected cell subset may not be required. This concept may add further rationale to limiting the intensity of the conditioning regimen.

SCID encompasses a broad range of inherited defects that individually cause a profound immune deficiency of both T and B cell function. The individual genetic defects give rise to various phenotypes, and, since the goal of HCT is to restore both T and B cell function, the SCID phenotype must be taken into consideration in addition to the degree of recipient-donor mismatch. Other biologic factors associated with the SCID phenotype may influence the barrier to engraftment, such as host NK cells, which may survive intensive conditioning regimens. One of the difficulties in analyzing outcome of HCT in SCID patients is the relative rarity of the condition, thus needing large multicentric studies. Recent studies show that the most important factor for improved survival after an HLA-identical sibling graft was younger age at time of HCT. Factors significantly associated with improved survival after haploidentical transplants were B+ SCID phenotype, protected environment, and lack of pulmonary infections before HCT. The advent of neonatal screening and in utero diagnosis has allowed early detection of SCID and therefore prompt intervention at an early age.

Primary T cell immunodeficiency (PTCD) syndromes may be differentiated from SCID by virtue of reduced but not completely absent T cell function, or absent T cell function with the presence of B lymphocyte or NK cell function. Allogeneic marrow transplantation remains the only curative therapy available for these disorders. Worse outcomes were seen in patients with PTCD compared to other types of immune deficiencies, regardless of donor. Although life-threatening infections may be less common early in life, children with PTCD often develop organ damage from chronic infections, particularly lung disease, prior to HCT.

In Wiskott-Aldrich syndrome, HCT offers significantly improved survival chances for patients. Achieving full donor chimerism was shown to be a favorable factor. In general, however, the studies suggest that low intensity regimens offer the potential for achieving donor cell engraftment with less morbidity than standard regimens, an important consideration for patients who currently may consider the risks of conventional transplants unacceptably high.

Keywords

Primary immune deficiencies, SCID, primary T cell deficiencies, hematopoietic stem cell transplantation, conditioning regimens, outcomes

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Lauri Burroughs (MD), Ann Woolfrey (MD)

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Lauri Burroughs (MD), Ann Woolfrey (MD)

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Hematopoietic cell transplantation (HCT) has the potential to cure primary immune deficiency syndromes (PIDS) that are a group of disorders primarily affecting a single lineage, e.g., lymphoid or myeloid lineage. Generally, implementation of various conditioning regimens depends the type of IDS. Some syndromes that cause profound immune deficiency may not require a conditioning regimen. There appears to be a barrier even in cases of severe combined immune deficiency (SCID), particularly in the situation of HLA mismatched or haploidentical grafts. For example, donor B cell chimerism is less likely in γ-chain deficiency (X-SCID), as host cells persistently occupy the B lymphocyte niche, than in syndromes without B cells such as adenosine deaminase (ADA) deficiency. The immune defect may be corrected by partial reconstitution of normal immune cells, in other words full donor chimerism of the affected cell subset may not be required. This concept may add further rationale to limiting the intensity of the conditioning regimen.

SCID encompasses a broad range of inherited defects that individually cause a profound immune deficiency of both T and B cell function. The individual genetic defects give rise to various phenotypes, and, since the goal of HCT is to restore both T and B cell function, the SCID phenotype must be taken into consideration in addition to the degree of recipient-donor mismatch. Other biologic factors associated with the SCID phenotype may influence the barrier to engraftment, such as host NK cells, which may survive intensive conditioning regimens. One of the difficulties in analyzing outcome of HCT in SCID patients is the relative rarity of the condition, thus needing large multicentric studies. Recent studies show that the most important factor for improved survival after an HLA-identical sibling graft was younger age at time of HCT. Factors significantly associated with improved survival after haploidentical transplants were B+ SCID phenotype, protected environment, and lack of pulmonary infections before HCT. The advent of neonatal screening and in utero diagnosis has allowed early detection of SCID and therefore prompt intervention at an early age.

Primary T cell immunodeficiency (PTCD) syndromes may be differentiated from SCID by virtue of reduced but not completely absent T cell function, or absent T cell function with the presence of B lymphocyte or NK cell function. Allogeneic marrow transplantation remains the only curative therapy available for these disorders. Worse outcomes were seen in patients with PTCD compared to other types of immune deficiencies, regardless of donor. Although life-threatening infections may be less common early in life, children with PTCD often develop organ damage from chronic infections, particularly lung disease, prior to HCT.

In Wiskott-Aldrich syndrome, HCT offers significantly improved survival chances for patients. Achieving full donor chimerism was shown to be a favorable factor. In general, however, the studies suggest that low intensity regimens offer the potential for achieving donor cell engraftment with less morbidity than standard regimens, an important consideration for patients who currently may consider the risks of conventional transplants unacceptably high.

Keywords

Primary immune deficiencies, SCID, primary T cell deficiencies, hematopoietic stem cell transplantation, conditioning regimens, outcomes

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Hematopoietic cell transplantation (HCT) has the potential to cure primary immune deficiency syndromes (PIDS) that are a group of disorders primarily affecting a single lineage, e.g., lymphoid or myeloid lineage. Generally, implementation of various conditioning regimens depends the type of IDS. Some syndromes that cause profound immune deficiency may not require a conditioning regimen. There appears to be a barrier even in cases of severe combined immune deficiency (SCID), particularly in the situation of HLA mismatched or haploidentical grafts. For example, donor B cell chimerism is less likely in γ-chain deficiency (X-SCID), as host cells persistently occupy the B lymphocyte niche, than in syndromes without B cells such as adenosine deaminase (ADA) deficiency. The immune defect may be corrected by partial reconstitution of normal immune cells, in other words full donor chimerism of the affected cell subset may not be required. This concept may add further rationale to limiting the intensity of the conditioning regimen.

SCID encompasses a broad range of inherited defects that individually cause a profound immune deficiency of both T and B cell function. The individual genetic defects give rise to various phenotypes, and, since the goal of HCT is to restore both T and B cell function, the SCID phenotype must be taken into consideration in addition to the degree of recipient-donor mismatch. Other biologic factors associated with the SCID phenotype may influence the barrier to engraftment, such as host NK cells, which may survive intensive conditioning regimens. One of the difficulties in analyzing outcome of HCT in SCID patients is the relative rarity of the condition, thus needing large multicentric studies. Recent studies show that the most important factor for improved survival after an HLA-identical sibling graft was younger age at time of HCT. Factors significantly associated with improved survival after haploidentical transplants were B+ SCID phenotype, protected environment, and lack of pulmonary infections before HCT. The advent of neonatal screening and in utero diagnosis has allowed early detection of SCID and therefore prompt intervention at an early age.

Primary T cell immunodeficiency (PTCD) syndromes may be differentiated from SCID by virtue of reduced but not completely absent T cell function, or absent T cell function with the presence of B lymphocyte or NK cell function. Allogeneic marrow transplantation remains the only curative therapy available for these disorders. Worse outcomes were seen in patients with PTCD compared to other types of immune deficiencies, regardless of donor. Although life-threatening infections may be less common early in life, children with PTCD often develop organ damage from chronic infections, particularly lung disease, prior to HCT.

In Wiskott-Aldrich syndrome, HCT offers significantly improved survival chances for patients. Achieving full donor chimerism was shown to be a favorable factor. In general, however, the studies suggest that low intensity regimens offer the potential for achieving donor cell engraftment with less morbidity than standard regimens, an important consideration for patients who currently may consider the risks of conventional transplants unacceptably high.

Keywords

Primary immune deficiencies, SCID, primary T cell deficiencies, hematopoietic stem cell transplantation, conditioning regimens, outcomes

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