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

D. A. Boardman, C. Philippeos, G. O. Fruhwirth, M. A A Ibrahim, R. F. Hannen, D. Cooper, F. M. Marelli-Berg, F. M. Watt, R. I. Lechler, J. Maher, L. A. Smyth, G. Lombardi*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

225 Citations (Scopus)
251 Downloads (Pure)

Abstract

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 CARs were engineered: one comprising a CD28-CD3ζ signaling domain (CAR) and one lacking an intracellular signaling domain (ΔCAR). CAR Tregs were specifically activated and significantly more suppressive than polyclonal or ΔCAR Tregs in the presence of HLA-A2, without eliciting cytotoxic activity. Furthermore, CAR and ΔCAR 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.

Original languageEnglish
Pages (from-to)931-943
JournalAmerican journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons
Volume17
Issue number4
Early online date27 Dec 2016
DOIs
Publication statusPublished - 30 Mar 2017

Keywords

  • Alloantigen
  • Animal models: murine
  • Basic (laboratory) research/science
  • Cellular biology
  • Gene therapy
  • Immune regulation
  • Immunosuppression/immune modulation
  • Molecular biology
  • T cell biology
  • Translational research/science

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