ena-STUDY-CRTI UMR 1064 ITUN-18-03-2021-11:17:18:244-4
Anti-CD45RC antibody immunotherapy for the treatment of the Auto-immune PolyEndocrinopathy Candidiasis Ectodermal Dystrophy (APECED) syndrome
Monoclonal antibody (mAb) therapy has shown great promises in the treatment of transplant rejection and autoimmune diseases by inducing a more targeted effect than broadly immunosuppressive drugs that are routinely used in these diseases. We recently described the therapeutic advantage of targeting CD45RC, one isoform of the CD45 molecule specifically expressed by CD4+ and CD8+ conventional T cells (Tconv) and their precursors, as well as TEMRA cells, but not CD4+ and CD8+ regulatory T cells (Tregs). We demonstrated the efficacy of a short-term anti-CD45RC mAb treatment to prevent solid organ transplant rejection and graft-versus-host (GvHD) disease, but to date no demonstration of the potential of anti-CD45RC mAbs has been done in autoimmune diseases. The auto-immune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) syndrome is a rare genetic disease caused by loss of expression of the key central tolerance actor, autoimmune regulator (AIRE). Consecutive defect in thymic negative selection leads to an abnormal auto-reactive T cell response associated with autoimmune lesions of peripheral tissues and production of autoantibodies. In this manuscript, we show that in a rat model of APECED syndrome, anti-CD45RC mAb prevents and controls ongoing auto-immune manifestations such as alopecia and vitiligo, preserves organs from autoimmune desctruction and inhibits autoantibody development. Anti-CD45RC mAb treatment depleted CD45RChigh T cells, inhibited CD45RChigh B cells and restored CD45RClow/- CD8+ Tregs transcriptomic profile. Importantly, we demonstrate that CD45RC expression is dysregulated and significantly increased in APECED patients and that organs from APECED patients are infiltrated by CD45RChigh cells, highlighting the potential of the anti-CD45RC mAb immunotherapy to treat the human APECED syndrome.
Monoclonal antibody (mAb) therapy has shown great promises in the treatment of transplant rejection and autoimmune diseases by inducing a more targeted effect than broadly immunosuppressive drugs that are routinely used in these diseases. We recently described the therapeutic advantage of targeting CD45RC, one isoform of the CD45 molecule specifically expressed by CD4+ and CD8+ conventional T cells (Tconv) and their precursors, as well as TEMRA cells, but not CD4+ and CD8+ regulatory T cells (Tregs). We demonstrated the efficacy of a short-term anti-CD45RC mAb treatment to prevent solid organ transplant rejection and graft-versus-host (GvHD) disease, but to date no demonstration of the potential of anti-CD45RC mAbs has been done in autoimmune diseases. The auto-immune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) syndrome is a rare genetic disease caused by loss of expression of the key central tolerance actor, autoimmune regulator (AIRE). Consecutive defect in thymic negative selection leads to an abnormal auto-reactive T cell response associated with autoimmune lesions of peripheral tissues and production of autoantibodies. In this manuscript, we show that in a rat model of APECED syndrome, anti-CD45RC mAb prevents and controls ongoing auto-immune manifestations such as alopecia and vitiligo, preserves organs from autoimmune desctruction and inhibits autoantibody development. Anti-CD45RC mAb treatment depleted CD45RChigh T cells, inhibited CD45RChigh B cells and restored CD45RClow/- CD8+ Tregs transcriptomic profile. Importantly, we demonstrate that CD45RC expression is dysregulated and significantly increased in APECED patients and that organs from APECED patients are infiltrated by CD45RChigh cells, highlighting the potential of the anti-CD45RC mAb immunotherapy to treat the human APECED syndrome.