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

• Published in: The Journal of immunology (1950) 2008-12, Vol.181 (11), p.7499-7506
• Main Authors: Zang, Weiping, Lin, Marvin, Kalache, Safa, Zhang, Nan, Kruger, Bernd, Waaga-Gasser, Ana Maria, Grimm, Martin, Hancock, Wayne, Heeger, Peter, Schroppel, Bernd, Murphy, Barbara
• Format: Article
• Language: English
• Subjects: Animals; Antibiotics, Antineoplastic - pharmacology; Antibodies, Monoclonal - pharmacology; Cell Differentiation - drug effects; Cell Differentiation - immunology; Forkhead Transcription Factors - immunology; Graft Survival - drug effects; Graft Survival - immunology; HLA-DQ alpha-Chains; HLA-DQ Antigens - pharmacology; Humans; Interleukin-2 Receptor alpha Subunit - antagonists & inhibitors; Interleukin-2 Receptor alpha Subunit - immunology; Islets of Langerhans - immunology; Islets of Langerhans Transplantation; Isoantigens - pharmacology; Mice; Mice, Inbred BALB C; Peptides - pharmacology; Sirolimus - pharmacology; T-Lymphocytes, Regulatory - immunology; Transforming Growth Factor beta - antagonists & inhibitors; Transforming Growth Factor beta - immunology; Transplantation Immunology - drug effects; Transplantation, Homologous; Up-Regulation - drug effects; Up-Regulation - immunology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.181.11.7499

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-beta and regulatory T cell-dependent mechanisms.