T cell responses to allogeneic major histocompatibility complex antigens present a formidable path to organ transplantation, necessitating long-term immunosuppression to minimize rejection. Chronic rejection and drug-induced morbidities are major limitations that could be overcome by allograft tolerance induction. Tolerance was first intentionally merged in humans through combined kidney and bone marrow transplantation, but the mechanisms of tolerance in these patients are incompletely understood.
Recently established an assay to identify donor-reactive T cells and test the role of deletion in tolerance after combined kidney and bone marrow transplantation. Using high-throughput sequencing of the T cell receptor B chain CDR3 region, to define a fingerprint of the donor-reactive T cell repertoire before transplantation and track those clones after transplant. After observation in post-transplant reduction in donor-reactive T cell cloned into three tolerant combined kidney and bone marrow transplantation patients, such reductions were not found in a fourth, non-tolerant, combined kidney and bone marrow transplantation patient or in two conventional kidney transplant recipients on standard immunosuppressive regimens.
T cell repertoire turnover due to lymphocyte-depleting conditioning only partially accounted for the observed reductions in tolerant patients in fact, conventional transplant recipients showed expansion of circulating donor-reactive clones, despite extensive repertoire turnover. Moreover, loss of donor-reactive T cell clones more closely associated with tolerance induction than in vitro functional assays. Our analysis supports clonal deletion as a mechanism of allograft tolerance in combined kidney and bone marrow transplantation patients. The validate results are the contribution of donor-reactive T cell clones identified before transplant by our method, supporting further exploration as a potential biomarker of transplant outcomes.