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

Article


Boardman, Dominic A., Philippeos, Christina, Fruhwirth, Gilbert O., Ibrahim, Mohammad A. A., Hannen, Rosalind F., Cooper, Dianne, Marelli-Berg, Federica M., Watt, Fiona M., Lechler, Robert I., Maher, John, Smyth, L. and Lombardi, Giovanna 2016. 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. American Journal of Transplantation. 17 (4), pp. 931-943.
AuthorsBoardman, Dominic A., Philippeos, Christina, Fruhwirth, Gilbert O., Ibrahim, Mohammad A. A., Hannen, Rosalind F., Cooper, Dianne, Marelli-Berg, Federica M., Watt, Fiona M., Lechler, Robert I., Maher, John, Smyth, L. and Lombardi, Giovanna
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 which can redirect the specificity of T cells towards designated antigens. We used CAR technology to redirect human polyclonal Tregs towards donor-MHC class I molecules which are ubiquitously expressed in allografts. Two novel HLA-A2-specific CARs were engineered: one comprising a CD28-CD3ζ signalling domain (CAR) and one lacking an intracellular signalling 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 PBMCs 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.

JournalAmerican Journal of Transplantation
Journal citation17 (4), pp. 931-943
ISSN16006135
Year2016
PublisherWiley
Accepted author manuscript
License
Supplemental file
Digital Object Identifier (DOI)doi:10.1111/ajt.14185
Publication dates
Print27 Dec 2016
Publication process dates
Deposited05 Jan 2017
Accepted17 Dec 2016
FunderNational Institute for Health Research Comprehensive Biomedical Research Centre
British Heart Foundation
Medical Research Council Centre for Transplantation
National Institute for Health Research
British Heart Foundation
Medical Research Council
Copyright informationThis is the peer reviewed version of the following article: Boardman, et.al., 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, which has been published in final form at http://dx.doi.org/10.1111/ajt.14185. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving
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