Impaired Immune Reconstitution after HLA-Mismatched Transplantation Due to Antigen Specific T-Cell Recognition Restricted by the Disparate Haplotype

Abstract

The applicability of HLA matched hematopoietic stem cell transplantation (SCT) is limited by the lack of HLA matched donors. In contrast, an HLA haploidentical donor can be found for almost all patients. Posttransplantation immunodeficiency leading to high morbidity and mortality from viral infections is a major barrier to the broader application of haploidentical SCT. In HLA mismatched SCT profound T cell depletion is necessary to prevent GVHD, but also leads to slower T-cell reconstitution. Vigorous T-cell depletion, however, does not fully explain the increased immunodeficiency. Despite a gradual normalization of absolute T-cell and total lymphocyte number after haploidentical SCT, the immunodeficiency may persist for years. Additionally, an increase in the number of mismatched HLA alleles between patient and donor leads to more profound post transplantation immunodeficiency. We hypothesized that another explanation for the long lasting immunodeficiency is T-cell antigen recognition via the haplotype disparate between patient and donor. T-cells recognizing viral epitopes in the donor non-shared HLA molecule will attack virus infected hematopoietic cells of donor origin but not virus infected non-hematopoietic cells of patient origin. To investigate the role of T-cell disparate haplotype restriction in posttransplantation immunodeficiency, we characterized the immune responses against CMV in two patients at various time points after haploidentical and mismatched SCT. The first patient was HLA-A2 negative and transplanted with SCT of an HLA-A2 positive haploidentical donor. After the SCT he suffered from life threatening CMV reactivations for almost two years. Using tetramers composed of the HLA-A2 molecule and CMV-pp65-NLV epitope, we determined that in this patient CMV specific T-cells restricted to the donor HLA-A2 were present from 6 months after the SCT and remained present during the two year period of recurrent CMV infections. Since the HLA-A2 allele was not shared between patient and donor, these results indicate that T cells restricted by non-shared donor-HLA were unable to protect against infections. The second patient transplanted with an HLA mismatched SCT, suffered from CMV reactivations only in the first 6 months after SCT. Already 3 months after SCT CMV specific T cells restricted to the shared HLA-B8 allele were present in high concentrations, whereas the CMV specific T-cells restricted to the non-shared donor HLA-A1 allele disappeared in time. Our results suggest that for an effective immune response the T cells need to recognize viral epitopes restricted to the HLA shared between patient and donor and that impaired immune reconstitution after haploidentical SCT is, in part, the result of antigen specific T cell responses restricted to the disparate haplotype.