Inhibition of the Alloimmune Response through the Generation of Regulatory T Cells by a MHC Class II-Derived Peptide
| Autor: | Bernd Krüger, Marvin Lin, Weiping Zang, Martin Grimm, Bernd Schröppel, Nan Zhang, Ana Maria Waaga-Gasser, Peter S. Heeger, Safa Kalache, Wayne W. Hancock, Barbara Murphy |
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| Rok vydání: | 2008 |
| Předmět: |
Isoantigens
T cell Immunology Islets of Langerhans Transplantation Priming (immunology) chemical and pharmacologic phenomena T-Lymphocytes Regulatory HLA-DQ alpha-Chains Islets of Langerhans Mice Transforming Growth Factor beta Transplantation Immunology HLA-DQ Antigens MHC class I medicine Animals Humans Transplantation Homologous Immunology and Allergy Cytotoxic T cell IL-2 receptor Sirolimus Mice Inbred BALB C MHC class II Antibiotics Antineoplastic biology Graft Survival Interleukin-2 Receptor alpha Subunit Antibodies Monoclonal FOXP3 Cell Differentiation Forkhead Transcription Factors MHC restriction Molecular biology Up-Regulation Cell biology medicine.anatomical_structure biology.protein Peptides |
| Zdroj: | The Journal of Immunology. 181:7499-7506 |
| ISSN: | 1550-6606 0022-1767 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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