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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

Research output: Contribution to journalArticle

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

In: American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons, Vol. 17, No. 4, 17.04.2017, p. 931-943.

Research output: Contribution to journalArticle

Harvard

Boardman, DA, Philippeos, C, Fruhwirth, GO, Ibrahim, MAA, Hannen, RF, Cooper, D, Marelli-Berg, FM, Watt, FM, Lechler, RI, Maher, J, Smyth, LA & Lombardi, G 2017, '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 : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons, vol. 17, no. 4, pp. 931-943. https://doi.org/10.1111/ajt.14185

APA

Boardman, D. A., Philippeos, C., Fruhwirth, G. O., Ibrahim, M. A. A., Hannen, R. F., Cooper, D., ... Lombardi, G. (2017). 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 : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons, 17(4), 931-943. https://doi.org/10.1111/ajt.14185

Vancouver

Boardman DA, Philippeos C, Fruhwirth GO, Ibrahim MAA, Hannen RF, Cooper D 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. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2017 Apr 17;17(4):931-943. https://doi.org/10.1111/ajt.14185

Author

Boardman, D. A. ; Philippeos, C. ; Fruhwirth, G. O. ; Ibrahim, M. A A ; Hannen, R. F. ; Cooper, D. ; Marelli-Berg, F. M. ; Watt, F. M. ; Lechler, R. I. ; Maher, J. ; Smyth, L. A. ; Lombardi, G. / 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. In: American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2017 ; Vol. 17, No. 4. pp. 931-943.

Bibtex Download

@article{8b27619d501d4ee2840f1864e75af1c9,
title = "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",
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.",
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",
author = "Boardman, {D. A.} and C. Philippeos and Fruhwirth, {G. O.} and Ibrahim, {M. A A} and Hannen, {R. F.} and D. Cooper and Marelli-Berg, {F. M.} and Watt, {F. M.} and Lechler, {R. I.} and J. Maher and Smyth, {L. A.} and G. Lombardi",
note = "This article is protected by copyright. All rights reserved.",
year = "2017",
month = "4",
day = "17",
doi = "10.1111/ajt.14185",
language = "English",
volume = "17",
pages = "931--943",
journal = "American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons",
issn = "1600-6135",
publisher = "Wiley-Blackwell",
number = "4",

}

RIS (suitable for import to EndNote) Download

TY - JOUR

T1 - 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

AU - Boardman, D. A.

AU - Philippeos, C.

AU - Fruhwirth, G. O.

AU - Ibrahim, M. A A

AU - Hannen, R. F.

AU - Cooper, D.

AU - Marelli-Berg, F. M.

AU - Watt, F. M.

AU - Lechler, R. I.

AU - Maher, J.

AU - Smyth, L. A.

AU - Lombardi, G.

N1 - This article is protected by copyright. All rights reserved.

PY - 2017/4/17

Y1 - 2017/4/17

N2 - 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.

AB - 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.

KW - Alloantigen

KW - Animal models: murine

KW - Basic (laboratory) research/science

KW - Cellular biology

KW - Gene therapy

KW - Immune regulation

KW - Immunosuppression/immune modulation

KW - Molecular biology

KW - T cell biology

KW - Translational research/science

UR - http://www.scopus.com/inward/record.url?scp=85011340458&partnerID=8YFLogxK

U2 - 10.1111/ajt.14185

DO - 10.1111/ajt.14185

M3 - Article

C2 - 28027623

VL - 17

SP - 931

EP - 943

JO - American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons

JF - American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons

SN - 1600-6135

IS - 4

ER -

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