Mammalian Target of Rapamycin Inhibition and Alloantigen-Specific Regulatory T Cells Synergize To Promote Long-Term Graft Survival in Immunocompetent Recipients

Abstract

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.

Impact of immunosuppressive drugs on the therapeutic efficacy of ex vivo expanded human regulatory T cells

“…Similar results were obtained in a murine model of heart transplant in which the adoptive transfer of a small number of alloantigen-specific Treg in the presence of a low dose of RAPA induced long-term survival of cardiac allografts. 50 The beneficial effect of RAPA on Tregs was also observed in a humanized-mouse model where segments of human arterial were transplanted into immunodeficient mice reconstituted with allogeneic human peripheral blood cells. In this model, the authors showed that the presence of RAPA enhanced the ability of sub-therapeutic numbers of human Tregs to prevent transplant rejection.…”

Dendritic Cell Immune Therapy to Break or Induce Tolerance

“…Nevertheless, it is becoming evident that, according to the differentiation protocol used, tolerogenic DCs acquired different immune modulatory properties by up-regulating a variety of inhibitory molecules [74, 75•] and the ability to promote the induction of a specific subset of Tregs [7,11]. Despite the number of pre-clinical studies demonstrating feasibility and efficacy of tolerogenic DC immunotherapy [76][77][78][79][80][81], and the efforts dedicated to developing methods to generate clinical-grade tolerogenic DCs [75•, 82], only a limited number of clinical trials have been performed or planned [2,12,82].…”

Protein Kinase C Inhibitor Generates Stable Human Tolerogenic Dendritic Cells

“…Ex vivo-generated tDCs are considered to have strong potential for use in cellular therapy for these conditions. In fact, injection of ex vivo-generated tDCs has been shown to be beneficial in animal models of graft rejection (8)(9)(10) and autoimmune diseases, including collagen-induced arthritis (11,12), diabetes (13)(14)(15)(16), and experimental autoimmune encephalomyelitis (17). Human tDCs can be cultured in vitro from DC precursors using different compounds (7,18).…”