Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Antibiotics, Antineoplastic / pharmacology
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Antibodies, Monoclonal / pharmacology
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Cell Differentiation / drug effects
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Cell Differentiation / immunology
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Forkhead Transcription Factors / immunology
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Graft Survival / drug effects*
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Graft Survival / immunology
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HLA-DQ Antigens / pharmacology*
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HLA-DQ alpha-Chains
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Humans
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Interleukin-2 Receptor alpha Subunit / antagonists & inhibitors
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Interleukin-2 Receptor alpha Subunit / immunology
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Islets of Langerhans / immunology*
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Islets of Langerhans Transplantation*
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Isoantigens / pharmacology*
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Mice
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Mice, Inbred BALB C
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Peptides / pharmacology*
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Sirolimus / pharmacology
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T-Lymphocytes, Regulatory / immunology*
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Transforming Growth Factor beta / antagonists & inhibitors
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Transforming Growth Factor beta / immunology
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Transplantation Immunology / drug effects
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Transplantation, Homologous
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Up-Regulation / drug effects
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Up-Regulation / immunology
Substances
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Antibiotics, Antineoplastic
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Antibodies, Monoclonal
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Forkhead Transcription Factors
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Foxp3 protein, mouse
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HLA-DQ Antigens
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HLA-DQ alpha-Chains
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HLA-DQA1 antigen
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Interleukin-2 Receptor alpha Subunit
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Isoantigens
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Peptides
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Transforming Growth Factor beta
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Sirolimus