Влияние аллореактивности естественных киллерных клеток на эффективность аллогенной трансплантации гемопоэтических стволовых клеток с деплецией α/β TCR/CD19+ лимфоцитов у педиатрических пациентов с острыми лейкозами

Abstract

Natural killer (NK) cells constitute the first lymphocyte population to recover after an allogeneic hematopoietic stem cell transplantation (HSCT). It is believed that NK cell alloreactivity is regulated by the difference between activating and inhibitory signals from activating and inhibitory killer cell immunoglobulin-like receptors (KIRs). Human Leukocyte Antigen (HLA) molecules serve as ligands for KIR receptors. NK cell alloreactivity is determined by a KIR-HLA mismatch between donor and patient as well as the presence of specific activating KIR genes. Numerous recent studies show that several factors influence the effectiveness of the graft-versus-leukemia reaction. In particular, these factors include donor’s KIR genotype and the transplant protocol. The aim of the study is to evaluate the influence of KIR genotype of both HLA-haploidentical related donors and HLA-identical unrelated donors on the relapse risk and survival of acute leukemia patients after allogeneic HSCT. The study includes 142 patients (the median age 11) with acute myeloid leukemia (n = 70) and acute lymphoid leukemia (ALL) (n = 72) received first HLA-identical unrelated (n = 64) and HLA-haploidentical (n = 78) with α/βTCR-depleted allogeneic HSCT. All patients were in complete hematologic remission at the moment of HSCT. Peripheral blood mononuclear cells were collected after the administration of granulocyte colony-stimulating factor and used as the source of hematopoietic stem cells. Results of the study are consistent with the conception that potential NK alloreactivity depends on the transplant protocol – conditioning regimen, transplant processing and post-transplant graft-versus-host-disease prophylaxis. The key finding of this study is that more number of activating KIR genes in donor’s KIR genotype is associated with better overall survival of ALL patients (0,67 (95% CI: 0,53–0,81) vs 0,31 (95% CI: 0,07–0,55); р = 0,016). A similar effect was observed for the event-free survival. We failed to find a beneficial effect of NK alloreactivity based on the «ligand-ligand» model in the HLA-haploidentical related HSCT. NK alloreactivity for the same patient group, based on receptor-ligand» model also showed no significant beneficial effect, however there was a tendency for better overall survival for patients transplanted from potentially NK alloreactive donors (0,76 (95% CI: 0,63–0,88) vs 0,56 (95% CI: 0,32–0,81); р = 0,486). In summary, it is recommended to consider donor’s KIR genotype as additional criteria for donor selection prior to allogeneic HSCT for all patients.