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World J Transplant. Mar 24, 2016; 6(1): 183-192
Published online Mar 24, 2016. doi: 10.5500/wjt.v6.i1.183
Immunosuppressive potency of mechanistic target of rapamycin inhibitors in solid-organ transplantation
Alberto Baroja-Mazo, Beatriz Revilla-Nuin, Pablo Ramírez, José A Pons
Alberto Baroja-Mazo, Beatriz Revilla-Nuin, Pablo Ramírez, José A Pons, Murcia’s BioHealth Research Institute (IMIB-Arrixaca), CIBER-ehd, 30120 Murcia, Spain
Pablo Ramírez, José A Pons, Division of Gastroenterology and Hepatology and Liver Transplant Unit, University Hospital Virgen de la Arrixaca, 30120 Murcia, Spain
Author contributions: All authors equally contributed to this paper with conception and design of the study, literature review and analysis, drafting and critical revision and editing, and final approval of the final version.
Supported by Novartis España and by grant to Pons JA as Principal Investigator from Instituto Salud Carlos III, No. PI12/02042.
Conflict-of-interest statement: There is no conflict of interest associated with any of the senior author or other coauthors contributed their efforts in this manuscript.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: José A Pons, MD, PhD, Division of Gastroenterology and Hepatology and Liver Transplant Unit, University Hospital Virgen de la Arrixaca, Ctra, Madrid-Cartagena s/n, 30120 Murcia, Spain. joseapons.imib.arrixaca@gmail.com
Telephone: +34-968-369500 Fax: +34-968-369776
Received: November 5, 2015
Peer-review started: November 6, 2015
First decision: December 4, 2015
Revised: December 22, 2015
Accepted: January 5, 2016
Article in press: January 7, 2016
Published online: March 24, 2016
Processing time: 133 Days and 21.5 Hours
Abstract

Mammalian target of rapamycin, also known as mechanistic target of rapamycin (mTOR) is a protein kinase that belongs to the PI3K/AKT/mTOR signaling pathway, which is involved in several fundamental cellular functions such as cell growth, proliferation, and survival. This protein and its associated pathway have been implicated in cancer development and the regulation of immune responses, including the rejection response generated following allograft transplantation. Inhibitors of mTOR (mTORi) such as rapamycin and its derivative everolimus are potent immunosuppressive drugs that both maintain similar rates of efficacy and could optimize the renal function and diminish the side effects compared with calcineurin inhibitors. These drugs are used in solid-organ transplantationtoinduceimmunosuppression while also promoting the expansion of CD4+CD25+FOXP3+ regulatory T-cells that could favor a scenery of immunological tolerance. In this review, we describe the mechanisms by which inhibitors of mTOR induce suppression by regulation of these pathways at different levels of the immune response. In addition, we particularly emphasize about the main methods that are used to assess the potency of immunosuppressive drugs, highlighting the studies carried out about immunosuppressive potency of inhibitors of mTOR.

Keywords: Everolimus; Immunosuppression; Mechanistic target of rapamycin inhibitor; Rapamycin; Tolerance

Core tip: Inhibitors of mechanistic target of rapamycin (mTOR), rapamycin and its derivative everolimus, have been used as immunosuppressive drugs during the last decade. Several reviews have been written on the use of these drugs compared to classical calcineurin inhibitors, however few has been reviewed about immunosuppressive potency of such compounds. Our aim is to summarize the principal studies about potency of the immunosuppressants, highlighting the studies carried out with inhibitors of mTOR.