Inhibition of the alloimmune response through the generation of regulatory T cells by a MHC class II-derived peptide.
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.
Zang
Weiping
W
Division of Nephrology, Mount Sinai School of Medicine, New York, NY 10029, USA.
Lin
Marvin
M
Kalache
Safa
S
Zhang
Nan
N
Krüger
Bernd
B
Waaga-Gasser
Ana Maria
AM
Grimm
Martin
M
Hancock
Wayne
W
Heeger
Peter
P
Schröppel
Bernd
B
Murphy
Barbara
B
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D051858:Forkhead Transcription Factors / Q000276:immunology; D006085:Graft Survival / Q000187:drug effects* / Q000276:immunology; D006683:HLA-DQ Antigens / Q000494:pharmacology*; D059848:HLA-DQ alpha-Chains; D006801:Humans; D053645:Interleukin-2 Receptor alpha Subunit / Q000037:antagonists & inhibitors / Q000276:immunology; D007515:Islets of Langerhans / Q000276:immunology*; D016381:Islets of Langerhans Transplantation; D007519:Isoantigens / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D010455:Peptides / Q000494:pharmacology*; D020123:Sirolimus / Q000494:pharmacology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000276:immunology; D014181:Transplantation Immunology / Q000187:drug effects; D014184:Transplantation, Homologous; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology
D000903:Antibiotics, Antineoplastic; D000911:Antibodies, Monoclonal; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D006683:HLA-DQ Antigens; D059848:HLA-DQ alpha-Chains; C069050:HLA-DQA1 antigen; D053645:Interleukin-2 Receptor alpha Subunit; D007519:Isoantigens; D010455:Peptides; D016212:Transforming Growth Factor beta; D020123:Sirolimus