Mammalian target of rapamycin inhibition and alloantigen-specific regulatory T cells synergize to promote long-term graft survival in immunocompetent recipients.
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 IL-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.
Raimondi
Giorgio
G
Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA. raimondig@upmc.edu
Sumpter
Tina L
TL
Matta
Benjamin M
BM
Pillai
Mahesh
M
Corbitt
Natasha
N
Vodovotz
Yoram
Y
Wang
Zhiliang
Z
Thomson
Angus W
AW
D000276:Adjuvants, Immunologic; D000818:Animals; D006085:Graft Survival / Q000187:drug effects / Q000276:immunology*; D016027:Heart Transplantation / Q000379:methods*; D006801:Humans; D007121:Immunocompetence; D047908:Intracellular Signaling Peptides and Proteins / Q000187:drug effects*; D007519:Isoantigens / Q000276:immunology; D017710:Lymphocyte Transfusion / Q000379:methods; D008565:Membrane Proteins / Q000008:administration & dosage / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects*; D037182:T-Cell Antigen Receptor Specificity / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000637:transplantation*; D058570:TOR Serine-Threonine Kinases; D016896:Treatment Outcome
D000276:Adjuvants, Immunologic; D047908:Intracellular Signaling Peptides and Proteins; D007519:Isoantigens; D008565:Membrane Proteins; C084881:flt3 ligand protein; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases