Influence of co-transplanted mesenchymal stem cell upon immunological recovery after allogeneic hematopoietic cell transplantation in children

Summary

The aim of this study was to evaluate effects of mesenchymal stem cells (MSCs) co-transplantation upon dynamics of immunological reconstitution during post-transplant period after allogeneic hematopoietic cell transplantation (allo-HSCT) in children.

Patients and Methods

Twenty-two patients aged 3 to 18 years were included into the single randomised study. Ten patients comprised a МSC+ group, having been transplanted with HSC and co-transplanted with mesenchymal stem cells (acute lymphoblastic leukemia, 5 children; acute myeloid leukaemia, 2 patients; acquired aplastic anemia, 3 cases). The median number of MSCs infused was 1,56±0,4×106/kg. Twelve patients (acute lymphoblastic leukemia, 5 children; acute myeloid leukaemia, 2; acquired aplastic anemia, 4; severe congenital neutropenia, 1) were transplanted with HSC without MSC cotransplantation (МSC- group). Patients from the both groups were identical by nosological forms of the disease, age, sex, donors type, conditioning regiment, graft-versus-host disease (GVHD) prophylaxis and graft composition. MSCs were derived from donors bone marrow. Immunological recovery was evaluated: В-cells by expression СD19+; natural killers (NK) cells – by CD3-/CD16CD56+, Т-cells - by CD3+, Т helper cells – by CD3+CD4+, cytotoxic T-cells – by CD3+CD8+; activated T-cells – by CD3+HLA-DR+ with flow cytometry. Assessment of immunological parameters in both groups was performed on +30, +60, +100 +180 и +365 days after allogeneic HSCT.

Results

Previously we have shown that the recovery of leukocytes, neutrophils and platelets was significantly faster in the patients co-transplantated with MSCs.The incidence of acute GVHD stage II-IV in the «MSC+»group was 20% (2 patients of 10) versus 58% in the «MSC-»group (7/12). The incidence of chronic GVHD in the «MSC+» group was 30% (3/10), being diagnosed as limited forms only, whereas in the «MSC-» group, 25% (3/12), all of them exhibited extensive chronic GVHD. We have found lower percentages of T-cells in the group of patients co-transplanted with MSCs from day +30 to day +100, as compared with the «MSC» group. The quantity of activated T-cells in the «MSC+» group was also lower at all observation terms. Similarly, a decreased level of cytotoxic T-cells was revealed in the «MSC+» group when compared with «MSC-» group up to day +180. The NK cell quantity was also increased from +30 to +180 days in the «MSC+» group. I.e., the NK absolute counts at +30 day in the «MSC+» group were 0,06 (0,06-0,17)×10⁹/l, whereas in the «MSC-» group, 0,037 (0,02-0,04)×10⁹/l (р=0,03). The group of patients with MSC co-transplantation differs by earlier recovery of B-cells that it got significant up to +100 day. B-cells absolute count at +100 day in the «MSC+» group was 0,1 (0,06-0,2)×10⁹/l, whereas in the «MSC-» group – 0,02 (0,002-0,1)×10⁹/l (р=0,05) due to lower volume immunosuppressive therapy in «MSC+» group. Conclusion. Over the early period after HSCT, the MSCs co-transplantation prevents excessive activation of immune system and leads to lower rates of grade II-IV acute GVHD. At the later post-transplant period, it results into earlier reconstitution of humoral immunity and prevents severe extensive chronic GVHD.

Keywords

Allogeneic hematopoietic cell transplantation, immunological recovery, mesenchymal stem cells, children neurometabolic diseases