Rapamycin Prolongs Cardiac Allograft Survival in a Mouse Model by Inducing Myeloid-Derived Suppressor Cells.
Mammalian target of rapamycin (mTOR) inhibitors are the main immunosuppressive drugs for organ transplant recipients. Nevertheless, the mechanisms by which mTOR inhibitors induce immunosuppression is not fully understood. Myeloid-derived suppressor cells (MDSCs) maintain host immunity; however, the relationship between mTOR inhibitors and MDSCs is unclear. Here, the results from a murine cardiac transplantation model revealed that rapamycin treatment (3 mg/kg, intraperitoneally on postoperative days 0, 2, 4, and 6) led to the recruitment of MDSCs and increased their expression of inducible nitric oxide synthase (iNOS). Immunohistochemical analysis revealed that rapamycin induced the migration of iNOS-expressing MDSCs into the subintimal space within the allograft vessels, resulting in a significant prolongation of graft survival compared with that in the untreated group (67 days vs. 7 days, respectively). These effects were counterbalanced by the administration of an anti-Gr-1, which reduced allograft survival to 21 days. Moreover, adoptive transcoronary arterial transfer of MDSCs from rapamycin-treated recipients prolonged allograft survival; this increase was reversed by the anti-Gr-1 antibody. Finally, co-administration of rapamycin and a mitogen-activated protein kinase kinase (MEK) inhibitor trametinib reversed rapamycin-mediated MDSC recruitment. Thus, the mTOR and Raf/MEK/extracellular signal regulated kinase (ERK) signaling pathways appear to play an important role in MDSC expansion.
Department of Transplantation and Regenerative Surgery, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kamigyo-Ku, Kyoto-Prefecture, Japan.|Department of Clinical and Translational Physiology, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto, Japan.
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Nakamura
Department of Transplantation and Regenerative Surgery, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kamigyo-Ku, Kyoto-Prefecture, Japan.|Department of Clinical and Translational Physiology, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto, Japan.
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Nakao
Department of Transplantation and Regenerative Surgery, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kamigyo-Ku, Kyoto-Prefecture, Japan.
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Yoshimura
Department of Clinical and Translational Physiology, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto, Japan.
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Ashihara
D064591:Allografts; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D005434:Flow Cytometry; D006084:Graft Rejection / Q000188:drug therapy; D006085:Graft Survival / Q000187:drug effects*; D016027:Heart Transplantation; D007108:Immune Tolerance / Q000276:immunology*; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008213:Lymphocyte Activation; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000166:cytology / Q000276:immunology*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
D007166:Immunosuppressive Agents; D052247:Nitric Oxide Synthase Type II; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
Animal models: murine; basic (laboratory) research/science; cellular biology; heart (allograft) function/dysfunction; heart transplantation/cardiology; immune regulation; immunosuppressant; immunosuppression/immune modulation; mechanistic target of rapamycin:sirolimus; translational research/science