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 post-operative days 0, 2, 4, and 6) led to the recruitment of MDSCs and increased their expression of programmed death-ligand 1 and 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 trans-coronary arterial transfer of MDSCs from rapamycin-treated recipients prolonged allograft survival with the increased existence of CD4⁺/Foxp3⁺ regulatory T cell in the spleen and allograft; this prolonged survival 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 following cardiac transplantation.

A part of this study was published in Am J Transplant, 2015; 9: 2364-2377.

CITATION INFORMATION: Nakamura T, Masuda K, Matsuyama T, Ushigome H, Yoshimura N. Rapamycin Prolongs Cardiac Allograft Survival in a Mouse Model by Inducing Myeloid-Derived Suppressor Cells. Am J Transplant. 2016;16 (suppl 3).

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