W3 - Anti-CD45RC Antibody Immunotherapy Prevents and Treats Experimental Autoimmune Poly Endocrinopathy Candidiasis Ectodermal Dystrophy Syndrome

Targeted monoclonal antibody (mAb) therapies show great promise for the treatment of transplant rejection and autoimmune diseases by inducing more specific immunomodulatory effects than broadly immunosuppressive drugs routinely used. We recently described the therapeutic advantage of targeting CD45RC, expressed at high levels by conventional T cells (Tconv, CD45RC^high), their precursors and terminally differentiated T (TEMRA) cells, but not by regulatory T cells (Tregs, CD45RC^low/-). We demonstrated efficacy of anti-CD45RC mAb treatment in transplantation but its potential has not been examined in autoimmune diseases. APECED is a rare genetic syndrome caused by loss-of-function mutations of the key central tolerance mediator, autoimmune regulator (AIRE) leading to abnormal auto-reactive T cell responses and autoantibodies production. Herein, we showed that, in a rat model of APECED syndrome, anti-CD45RC mAb was effective both as prevention and treatment of autoimmune manifestations and inhibited autoantibody development. Anti-CD45RC mAb intervention depleted CD45RC^high T cells, inhibited CD45RC^high B cells, and restored the Treg/Tconv ratio and the altered Tregs transcriptomic profile. In APECED patients, CD45RC was significantly increased in peripheral blood T cells and lesioned organs from APECED patients were infiltrated by CD45RC^high cells. Our observations highlight the potential role for CD45RC^high cells in the pathogenesis of experimental and human APECED syndrome and the potential of anti-CD45RC antibody treatment.