期刊
AMERICAN JOURNAL OF TRANSPLANTATION
卷 17, 期 4, 页码 931-943出版社
WILEY
DOI: 10.1111/ajt.14185
关键词
basic (laboratory) research; science; translational research; science; cellular biology; immunosuppression; immune modulation; molecular biology; alloantigen; gene therapy; immune regulation; T cell biology; animal models: murine
资金
- Department of Health via the National Institute for Health Research Comprehensive Biomedical Research Centre
- King's College London
- King's College Hospital NHS Foundation Trust
- British Heart Foundation (BHF) [RG/13/12/30395]
- Medical Research Council (MRC) Centre for Transplantation, King's College London, UK - MRC [MR/J006742/1]
- British Heart Foundation [RG/14/2/30616, FS/11/64/28945, RG/13/12/30395] Funding Source: researchfish
- Medical Research Council [MR/J006742/1, MR/L022699/1] Funding Source: researchfish
- MRC [MR/L022699/1] Funding Source: UKRI
Regulatory T cell (Treg) therapy using recipient-derived Tregs expanded exvivo is currently being investigated clinically by us and others as a means of reducing allograft rejection following organ transplantation. Data from animal models has demonstrated that adoptive transfer of allospecific Tregs offers greater protection from graft rejection compared to polyclonal Tregs. Chimeric antigen receptors (CAR) are clinically translatable synthetic fusion proteins that can redirect the specificity of T cells toward designated antigens. We used CAR technology to redirect human polyclonal Tregs toward donor-MHC class I molecules, which are ubiquitously expressed in allografts. Two novel HLA-A2-specific CARs were engineered: one comprising a CD28-CD3 signaling domain (CAR) and one lacking an intracellular signaling domain (CAR). CAR Tregs were specifically activated and significantly more suppressive than polyclonal or CAR Tregs in the presence of HLA-A2, without eliciting cytotoxic activity. Furthermore, CAR and CAR Tregs preferentially transmigrated across HLA-A2-expressing endothelial cell monolayers. In a human skin xenograft transplant model, adoptive transfer of CAR Tregs alleviated the alloimmune-mediated skin injury caused by transferring allogeneic peripheral blood mononuclear cells more effectively than polyclonal Tregs. Our results demonstrated that the use of CAR technology is a clinically applicable refinement of Treg therapy for organ transplantation.
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