期刊
JOURNAL OF IMMUNOLOGY
卷 184, 期 2, 页码 624-636出版社
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.0900936
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资金
- Transplantation Society Research Fellowship
- American Heart Association
- Starzl Transplantation Institute Young Investigator Award
- Joseph A. Patrick Research Fellowship in Transplantation
- National Institutes of Health [R01 AI067541, R01 AI060994, P50-GM-53789, R33-HL-089082, T32 AI74490]
- Commonwealth of Pennsylvania
- Pittsburgh Lifesciences Greenhouse
- American Society
- American Liver Foundation
Minimization of immunosuppression and donor-specific tolerance to MHC-mismatched organ grafts are important clinical goals. The therapeutic potential of regulatory T cells (Tregs) has been demonstrated, but conditions for optimizing their in vivo function posttransplant in nonlymphocyte-depleted hosts remain undefined. In this study, we address mechanisms through which inhibition of the mammalian target of rapamycin (Rapa) synergizes with alloantigen-specific Treg (AAsTreg) to permit long-term, donor-specific heart graft survival in immunocompetent hosts. Crucially, immature allogeneic dendritic cells allowed AAsTreg selection in vitro, with minimal expansion of unwanted (Th17) cells. The rendered Treg potently inhibited T cell proliferation in an Ag-specific manner. However, these AAsTreg remained unable to control T cells stimulated by allogeneic mature dendritic cells, a phenomenon dependent on the release of proinflammatory cytokines. In vivo, Rapa administration reduced danger-associated IIL-6 production, T cell proliferation, and graft infiltration. Based on these observations, AAsTreg were administered posttransplant (day 7) in combination with a short course of Rapa and rendered >80% long-term (>150 d) graft survival, a result superior to that achieved with polyclonal Treg. Moreover, graft protection was alloantigen-specific. Significantly, long-term graft survival was associated with alloreactive T cell anergy. These findings delineate combination of transient mammalian target of Rapa inhibition with appropriate AAsTreg selection as an effective approach to promote long-term organ graft survival. The Journal of Immunology, 2010, 184: 624-636.
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