Influence of co-transplanted mesenchymal stem cell upon immunological recovery after allogeneic hematopoietic cell transplantation in children
Yuliya E. Mareika, Tatiana V. Shman, Yanina I. Isaikina, Nina V. Minakovskaya, Natalia P. Kirsanava, Olga V. Aleynikova
Belarusian Research Center for Pediatric Oncology, Hematology and Immunology, Minsk, Belarus
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.
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.
Allogeneic hematopoietic cell transplantation, immunological recovery, mesenchymal stem cells, children neurometabolic diseases