CAR-Tregs as a Strategy for Inducing Graft Tolerance
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IMMUNOLOGY (R FAIRCHILD, SECTION EDITOR)
CAR-Tregs as a Strategy for Inducing Graft Tolerance Johanna C. Wagner 1,2 & Qizhi Tang 1,3
# Springer Nature Switzerland AG 2020
Abstract Purpose of Review The adoptive transfer of alloantigen-specific regulatory T cells (Tregs) following organ transplantation is an emerging treatment paradigm that may induce tolerance and reduce the risk for graft rejection. In particular, redirecting Treg specificity via expression of synthetic chimeric antigen receptors (CARs) has demonstrated therapeutic promise in several preclinical studies. In this review, we highlight recent progress and remaining barriers to the clinical translation of CAR-Treg therapies. Recent Findings CAR Tregs targeting human leukocyte antigen (HLA)-A2 showed antigen-specific in vitro activation and superior in vivo protective function relative to polyclonal Tregs. Adoptively transferred anti-HLA-A2 CAR Tregs prolonged the survival of HLA-A2-positive grafts in humanized mouse models. Summary Donor HLA molecules are attractive candidate antigens to target with CAR Tregs in transplantation due to mismatched HLA only expressed on the transplanted organ. The feasibility of this approach has been demonstrated by several independent groups in recent years. However, substantial challenges in CAR design and preclinical modeling must be more extensively addressed prior to clinical application. Keywords Tregs . CAR . Tolerance . Transplantation . HLA
Introduction Solid organ transplantation remains an important therapy for patients with end-stage organ dysfunction but comes with the need for life-long immunosuppression to prevent allograft rejection. Immunosuppression increases risks for infections and cancer development and has direct toxicity for various organs. Thus, promoting immune tolerance to prevent allograft rejection while minimizing or stopping generalized immunosuppression has been an important topic of research in recent years. This article is part of the Topical Collection on Immunology * Qizhi Tang [email protected] 1
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Department of Surgery, Division of Transplantation, University of California San Francisco, 513 Parnassus Ave, San Francisco, CA 94143, USA
Regulatory T cells (Tregs) are a key player in controlling immune responses. Extensive preclinical research has shown that Treg therapy can induce tolerance in transplantation models [1•] and alloantigen-reactive Tregs are more potent than polyclonal Tregs [2, 3, 4•, 5, 6]. One way of achieving alloantigenspecificity is the use of a synthetic chimeric antigen receptor (CAR) targeted toward donor alloantigen. In theory, the human leukocyte antigens (HLA) that are present on allografts and absent in recipients can be used as CAR targets for directing Treg specificity for organ transplantation. Indeed, preclinical and translational efforts are ongoing to develop anti-HLA CAR Tregs for clinical applications. Here we summarize current efforts in developing CAR Treg therapy for organ transplantation and provide our perspective on its promises and
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