Anti-CD45RC antibody immunotherapy prevents and treats experimental autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome

• Published in: The Journal of clinical investigation Vol. 132; no. 7
• Main Authors: Besnard, Marine, Sérazin, Céline, Ossart, Jason, Moreau, Anne, Vimond, Nadège, Flippe, Léa, Sein, Hanna, Smith, Grace A, Pittaluga, Stefania, Ferré, Elise Mn, Usal, Claire, Anegon, Ignacio, Ranki, Annamari, Lionakis, Michail S, Peterson, Pärt, Guillonneau, Carole
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.04.2022
• Subjects: Animals; Autoantibodies; Autoimmune Diseases; Autoimmunity; Care and treatment; Development and progression; Genetic aspects; Genetic disorders; Health aspects; Human health and pathology; Humans; Immunology; Immunotherapy; Life Sciences; Monoclonal antibodies; Polyendocrinopathies, Autoimmune - genetics; Polyendocrinopathies, Autoimmune - therapy; Rats; T cells; T-Lymphocytes, Regulatory; Testing; Therapeutics; France; Autoimmunity; Tolerance; Autoimmune diseases; Immunotherapy; Therapeutics
• ISSN: 1558-8238; 0021-9738; 1558-8238
• DOI: 10.1172/JCI156507

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 (Tconv) cells (CD45RChi), their precursors, and terminally differentiated T (TEMRA) cells, but not by regulatory T cells (Tregs; CD45RClo/-). We demonstrated efficacy of anti-CD45RC mAb treatment in transplantation, but its potential has not been examined in autoimmune diseases. Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare genetic syndrome caused by loss-of-function mutations of autoimmune regulator (AIRE), a key central tolerance mediator, leading to abnormal autoreactive T cell responses and autoantibody production. Herein, we show that, in a rat model of APECED syndrome, anti-CD45RC mAb was effective for both prevention and treatment of autoimmune manifestations and inhibited autoantibody development. Anti-CD45RC mAb intervention depleted CD45RChi T cells, inhibited CD45RChi B cells, and restored the Treg/Tconv cell ratio and the altered Treg transcriptomic profile. In APECED patients, CD45RC was significantly increased in peripheral blood T cells, and lesioned organs from APECED patients were infiltrated by CD45RChi cells. Our observations highlight the potential role for CD45RChi cells in the pathogenesis of experimental and human APECED syndrome and the potential of anti-CD45RC antibody treatment.