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Inhibition of the Alloimmune Response through the Generation of Regulatory T Cells by a MHC Class II-Derived Peptide¹

Weiping Zang^*, Marvin Lin^*, Safa Kalache^*, Nan Zhang, Bernd Krüger^*, Ana Maria Waaga-Gasser, Martin Grimm, Wayne Hancock, Peter Heeger^*,, Bernd Schröppel^*, and Barbara Murphy^2,*,

^* Division of Nephrology and Transplant Institute, Mount Sinai School of Medicine, New York, NY 10029; Department of Surgery, Molecular Oncology and Immunology, University of Würzburg, Würzburg, Germany; and Division of Transplantation Immunology, Children’s Hospital of Philadelphia, Philadelphia, PA 19104

We have previously shown that HLA-DQA1, a peptide derived from a highly conserved region of MHC class II, prevents alloreactive T cell priming and effector function in vivo, although underlying mechanisms are obscure. In this study, we demonstrate that 28% of mice treated with HLA-DQA1 combined with low-dose rapamycin achieved permanent engraftment of fully MHC-disparate islet allografts and significantly prolonged survival in the remaining animals (log rank, p < 0.001). Immunohistologic examination of the grafts from HLA-DQA1/rapamycin-treated animals revealed up-regulated expression of TGF-ß and FoxP3. In vivo administration of blocking anti-TGF-ß or depleting anti-CD25 mAb augmented T cell alloimmunity and prevented the long-term engraft induced by HLA-DQA1. In vitro experiments further showed that HLA-DQA1 induced differentiation of CD4⁺ T cells into CD4⁺CD25⁺FoxP3⁺ regulatory T cells. Together, these data provide the first demonstration that HLA-DQA1, a MHC class II-derived peptide, can prolong allograft survival via a TGF-β and regulatory T cell-dependent mechanisms.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Research Grant R01 AI 49289 (to B.M.).

² Address correspondence and reprint requests to Dr. Barbara Murphy, Division of Nephrology, Mount Sinai School of Medicine, 1 Gustave L. Levy Place, Box 1243, New York, NY 10029. E-mail address: Barbara.Murphy{at}mssm.edu

³ Abbreviation used in this paper: Treg, regulatory T cell.