title: New perspectives on mTOR inhibitors (rapamycin, rapalogs and TORKinibs) in transplantation.
abstract: The macrolide rapamycin and its analogues (rapalogs) constitute the first generation of mammalian target of rapamycin (mTOR) inhibitors. Since the introduction of rapamycin as an immunosuppressant, there has been extensive progress in understanding its complex mechanisms of action. New insights into the function of mTOR in different immune cell types, vascular endothelial cells and neoplastic cells have opened new opportunities and challenges regarding mTOR as a pharmacological target. Currently, the two known mTOR complexes, mTOR complex (mTORC) 1 and mTORC2, are the subject of intense investigation, and the introduction of second-generation dual mTORC kinase inhibitors (TORKinibs) and gene knockout mice is helping to uncover the distinct roles of these complexes in different cell types. While the pharmacological profiling of rapalogs is advanced, much less is known about the properties of TORKinibs. A potential benefit of mTOR inhibition in transplantation is improved protection against transplant-associated viral infections compared with standard calcineurin inhibitor-based immunosuppression. Preclinical and clinical data also underscore the potentially favourable antitumour effects of mTOR inhibitors in regard to transplant-associated malignancies and as a novel treatment option for various other cancers. Many aspects of the mechanisms of action of mTOR inhibitors and their clinical implications remain unknown. In this brief review we discuss new findings and perspectives of mTOR inhibitors in transplantation.
authors.affiliation: Department of Plastic Surgery, University of Pittsburgh, Pittsburgh, PA, USA.|Department of Plastic Surgery, University of Zurich, Zurich, Switzerland.
authors.forename: Matthias
authors.initials: M
authors.lastname: Waldner
authors.affiliation: Starzl Transplantation Institute and Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Fantus
authors.affiliation: Department of Plastic Surgery, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Mario
authors.initials: M
authors.lastname: Solari
authors.affiliation: Starzl Transplantation Institute and Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA. thomsonaw@upmc.edu.|Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA. thomsonaw@upmc.edu.
authors.forename: Angus W
authors.initials: AW
authors.lastname: Thomson
mesh_terms: D000818:Animals; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology / Q000627:therapeutic use; D000076222:Mechanistic Target of Rapamycin Complex 1 / Q000037:antagonists & inhibitors*; D000076225:Mechanistic Target of Rapamycin Complex 2 / Q000037:antagonists & inhibitors*; D008954:Models, Biological; D020123:Sirolimus / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000627:therapeutic use; D014180:Transplantation / Q000379:methods*
chemical_list: D007166:Immunosuppressive Agents; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D020123:Sirolimus
keywords: Raptor; Rictor; immune cells; mammalian target of rapamycin; transplantation
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