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

Abstract

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.

IL‐34 deficiency impairs FOXP3+ Treg function in a model of autoimmune colitis and decreases immune tolerance homeostasis

“…Plasma cells are negative for CSF‐1R; however, the expression of PTPz has not been reported on plasma cells; thus, IL‐34 could potentially impact plasma cells through CD138. These auto‐antibodies include anti‐IFN‐I antibodies that in addition to the role of pro‐inflammatory monocytes/macrophages in the cytokine storm leading to severe acute respiratory distress syndrome and multi‐organ pathology observed in SARS‐CoV‐2, infection could suggest a role for IL‐34 in COVID‐19 patients 22 , 23 and a link between IL‐34 and AIRE in T cell education in the thymus as high titres of IFNα auto‐antibodies are found in APECED patients 14 , 24 and Aire −/− rats 25 which harbour inborn errors in AIRE, which is responsible for thymic expression of ectopic self‐antigens and is thus responsible for negative T cell selection and Treg education in the thymus. The presence of anti‐IFNα and anti‐IL‐22 auto‐antibodies could also be linked to the mild liver injury observed in Il34 −/− rats.…”

Single cell analysis of human CD8+T cells reveals CD45RClow/-TNFR2+CD29lowCD8+Tregs with superior activity

“…This suggests the co-existence of several subsets of Tregs and explain the lack of consensus regarding their identity. This delineation of pro-inflammatory vs pro-regulatory populations is critical for the generation of a new therapeutic strategy as we have done with anti-CD45RC monoclonal antibodies in preclinical models of organ Tx 9 , aGVHD 34 , and APECED 10 . Using the data generated here, pro-inflammatory or pro-regulatory specific targets could be identified for autoimmune diseases or cancer.…”

Differentiation of Pluripotent Stem Cells Into Thymic Epithelial Cells and Generation of Thymic Organoids: Applications for Therapeutic Strategies Against APECED

“…Nonetheless, a crucial limitation is the long lapse of time needed to reprogram iPSc and to differentiate them into functional thymic tissue. Applied to APECED, early diagnosis would be crucial, since this approach cannot cure the damage already caused by autoimmunity, even though promising immunotherapies are emerging to treat autoimmune manifestations ( 156 ). For pathologies causing lymphopenia, early diagnosis would also be vital to limit the risk of potentially lethal infections during the time needed to generate the engineered thymic tissues.…”