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

Marine Besnard,Jason Ossart,Carole Guillonneau,Céline Sérazin,Claire Usal,Pärt Peterson,Grace A Smith,Anne Moreau,Hanna Sein,Michail S Lionakis,Stefania Pittaluga,Elise M.N Ferré,Annamari Ranki,Ignacio Anegon,Léa Flippe,Nadège Vimond

doi:10.1172/jci156507

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 (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.

Highlights

Disruption of central tolerance inherently triggers the development of autoimmune diseases with severe or life-threatening symptoms
In the group of Aire–/– rats treated with the anti-CD45RC monoclonal antibody (mAb) (n = 13, 6 independent experiments), none of the animals showed any of the aforementioned visible signs of autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED) (Figure 1B, bottom, and Table 1)
After antiCD45RC mAb immunotherapy, all Aire–/– rat thymi were present with preserved architecture, and the cortex and medulla were distinguishable on H&E staining

Summary

Introduction

Disruption of central tolerance inherently triggers the development of autoimmune diseases with severe or life-threatening symptoms. The autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED) syndrome, known as autoimmune polyglandular syndrome type 1 (APS-1), is one of these diseases [1]. This rare inherited disease (more common among certain populations, such as Finns [1:25,000] and Sardinians [1:14,000]) is caused by a partially defective thymic function due to the loss of autoimmune regulator (AIRE), a critical gene for the negative selection and development of thymocytes

Methods

Results

Conclusion