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Expression of a Chimeric Antigen Receptor Specific for Donor HLA Class I Enhances the Potency of Human Regulatory T Cells in Preventing Human Skin Transplant Rejection
Author(s) -
Boardman D. A.,
Philippeos C.,
Fruhwirth G. O.,
Ibrahim M. A. A.,
Hannen R. F.,
Cooper D.,
MarelliBerg F. M.,
Watt F. M.,
Lechler R. I.,
Maher J.,
Smyth L. A.,
Lombardi G.
Publication year - 2017
Publication title -
american journal of transplantation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.89
H-Index - 188
eISSN - 1600-6143
pISSN - 1600-6135
DOI - 10.1111/ajt.14185
Subject(s) - immunology , adoptive cell transfer , human leukocyte antigen , chimeric antigen receptor , medicine , transplantation , polyclonal antibodies , peripheral blood mononuclear cell , antigen , t cell receptor , major histocompatibility complex , cell therapy , t cell , cancer research , immune system , biology , microbiology and biotechnology , stem cell , in vitro , biochemistry
Regulatory T cell (Treg) therapy using recipient‐derived Tregs expanded ex vivo 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 CAR s were engineered: one comprising a CD 28‐ CD 3ζ signaling domain ( CAR ) and one lacking an intracellular signaling domain (Δ CAR ). CAR Tregs were specifically activated and significantly more suppressive than polyclonal or Δ CAR Tregs in the presence of HLA ‐A2, without eliciting cytotoxic activity. Furthermore, CAR and Δ 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.