Rapamycin Prolongs Cardiac Allograft Survival in a Mouse Model by Inducing Myeloid‐Derived Suppressor Cells. Issue 9 (5th May 2015)

• Record Type: Journal Article
• Authors: Nakamura, T.; Nakao, T.; Yoshimura, N.; Ashihara, E.
• Is Part Of: American journal of transplantation. Volume 15:Issue 9(2015:Sep.)
• Page Start: 2364
• Page End: 2377
• Publication Date: 2015-05-05
• Subjects: Transplantation of organs, tissues, etc -- Periodicals; 617.95
• DOI: 10.1111/ajt.13276
• Languages: English
• ISSNs: 1600-6135

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="ajt13276-sec-0001" sec-type="section"> <p>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.</p> </sec> </abstract>