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Regulatory Allospecific T Cell Clones Abrogate Chronic Allograft Rejection

Ana Maria Waaga-Gasser^*,, Martin R. Grimm^*, Jens Lutz, Volkmar Lange^*, Susanne M. Lenhard^*,, Beatriz Aviles, Joana E. Kist-van Holthe, Tatiana Lebedeva, Dimitry Samsonov, Detlef Meyer^*, Wayne W. Hancock, Uwe Heemann, Martin Gasser^*, and Anil Chandraker

^* Department of Surgery I, Molecular Oncology and Immunology, University of Würzburg, Würzburg, Germany; Transplantation Research Center, Brigham and Women's Hospital and Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts; Department of Nephrology, University of Munich, Klinikum rechts der Isar, Munich, Germany; and Department of Pathology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania

Correspondence: Dr. Anil Chandraker, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115. Phone: 617-732-7412; Fax: 617-732-6392; E-mail: achandraker{at}rics.bwh.harvard.edu

Received for publication February 10, 2008. Accepted for publication December 15, 2008.

True alloantigen-specific tolerance is the ultimate goal of solid organ transplantation, eliminating the need for long-term immunosuppression. Recent evidence suggests that Th1-derived cytokines are associated with rejection and Th2-derived cytokines with long-term allograft survival, but the roles of these subsets in rejection and tolerance are incompletely understood. Here, we analyzed the functional and regulatory capacities of T cell clones derived from tolerant and rejecting rats (Wistar rat donors, Lewis rat recipients). We generated and subcloned T cell lines from lymphocytes derived from either acutely rejecting grafts or from the grafts of CTLA4-Ig–treated tolerant rats. Pretransplantation adoptive transfer of T cell clones generated from rejected grafts (Th1 clones) accelerated acute rejection or promoted development of chronic rejection, whereas transfer of T cell clones generated from tolerized grafts (Th2 clones) protected rats from acute rejection and progressive organ dysfunction. When Th1 and Th2 clones were injected simultaneously, Th2 clones specifically regulated activation of Th1 clones. Rats that received injections of Th2 clones accepted long-term donor-specific skin grafts but acutely rejected third-party skin grafts. Tolerant rats treated with Th2 clones demonstrated an increased number of regulatory CD4⁺CD25⁺Foxp3⁺ cells and strong mononuclear cell staining for IL-10 but negligible IFN-, IL-17, and IL-23 compared with untreated rats or those treated with Th1 clones. In summary, these results demonstrate the regulatory functions of Th2 cells in a clinically relevant allogeneic transplant model and provide new insight into the functional role of Th2 cells in preventing the process of chronic rejection.

Copyright © 2009 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673