Kidney transplant patients treated with belatacept without depletional induction experience higher rates of acute rejection compared to patients treated with conventional immunosuppression. Costimulation blockade-resistant rejection (CoBRR) is associated with terminally differentiated T cells. Alemtuzumab induction and belatacept/sirolimus immunotherapy effectively prevent CoBRR. We hypothesized that cells in late phases of differentiation would be selectively less capable than more naive phenotypes of repopulating postdepletion, providing a potential mechanism by which lymphocyte depletion and repopulation could reduce the risk of CoBRR. Lymphocytes from 20 recipients undergoing alemtuzumab-induced depletion and belatacept/sirolimus immunosuppression were studied longitudinally for markers of maturation (CCR7, CD45RA, CD57, PD1), recent thymic emigration (CD31), and the IL-7 receptor-α (IL-7Rα). Serum was analyzed for IL-7. Alemtuzumab induction produced profound lymphopenia followed by repopulation, during which naive IL-7Rα+ CD57- PD1- cells progressively became the predominant subset. This did not occur in a comparator group of 10 patients treated with conventional immunosuppression. Serum from depleted patients showed markedly elevated IL-7 levels posttransplantation. Sorted CD57- PD1- cells demonstrated robust proliferation in response to IL-7, whereas more differentiated cells proliferated poorly. These data suggest that differences in IL-7-dependent proliferation is one exploitable mechanism that distinguishes CoB-sensitive and CoB-resistant T cell populations to reduce the risk of CoBRR. (ClinicalTrials.gov - NCT00565773.).
Keywords: basic (laboratory) research/science; clinical research/practice; cytokines/cytokine receptors; immunobiology; immunosuppressant - fusion proteins and monoclonal antibodies: belatacept; immunosuppressant - mechanistic target of rapamycin: sirolimus; immunosuppression/immune modulation; immunosuppressive regimens - induction; kidney transplantation/nephrology; lymphocyte biology: differentiation/maturation.
© 2017 The American Society of Transplantation and the American Society of Transplant Surgeons.