Adoptive Transfer With In Vitro Expanded Human Regulatory T Cells Protects Against Porcine Islet Xenograft Rejection via Interleukin-10 in Humanized Mice
- Shounan Yi1,2⇓,
- Ming Ji1,
- Jingjing Wu1,
- Xiaoqian Ma1,
- Peta Phillips1,
- Wayne J. Hawthorne1 and
- Philip J. O’Connell1⇓
- 1Centre for Transplant and Renal Research, Westmead Millennium Institute, Westmead Hospital, Westmead, New South Wales, Australia
- 2The Key Laboratory of Diabetes Immunology of the Ministry of Education at the 2nd Xiangya Hospital of Central South University, Changsha, Hunan, China
- Corresponding authors: Philip J. O’Connell, , and Shounan Yi, .
S.Y. and M.J. contributed equally to this work.
T cell-mediated rejection remains a barrier to the clinical application of islet xenotransplantation. Regulatory T cells (Treg) regulate immune responses by suppressing effector T cells. This study aimed to determine the ability of human Treg to prevent islet xenograft rejection and the mechanism(s) involved. Neonatal porcine islet transplanted NOD-SCID IL2rγ−/− mice received human peripheral blood mononuclear cells (PBMC) with in vitro expanded autologous Treg in the absence or presence of anti-human interleukin-10 (IL-10) monoclonal antibody. In addition, human PBMC-reconstituted recipient mice received recombinant human IL-10 (rhIL-10). Adoptive transfer with expanded autologous Treg prevented islet xenograft rejection in human PBMC-reconstituted mice by inhibiting graft infiltration of effector cells and their function. Neutralization of human IL-10 shortened xenograft survival in mice receiving human PBMC and Treg. In addition, rhIL-10 treatment led to prolonged xenograft survival in human PBMC-reconstituted mice. This study demonstrates the ability of human Treg to prevent T-cell effector function and the importance of IL-10 in this response. In vitro Treg expansion was a simple and effective strategy for generating autologous Treg and highlighted a potential adoptive Treg cell therapy to suppress antigraft T-cell responses and reduce the requirement for immunosuppression in islet xenotransplantation.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db11-1306/-/DC1.
M.J. is currently affiliated with the Department of Physiology, Xiangya Medical School, Central South University, Changsha, Hunan, China.
X.M. is currently affiliated with the Cell Transplant and Gene Therapy Institute, 3rd Xiangya Hospital of Central South University, Changsha, Hunan, China.
- Received September 19, 2011.
- Accepted January 18, 2012.
- © 2012 by the American Diabetes Association.
Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.