title: Adenosine triphosphate-competitive mTOR inhibitors: a new class of immunosuppressive agents that inhibit allograft rejection.
abstract: The mechanistic/mammalian target of rapamycin (mTOR) is inhibited clinically to suppress T cell function and prevent allograft rejection. mTOR is the kinase subunit of two mTOR-containing complexes, mTOR complex (mTORC) 1 and 2. Although mTORC1 is inhibited by the macrolide immunosuppressant rapamycin (RAPA), its efficacy may be limited by its inability to block mTORC1 completely and its limited effect on mTORC2. Adenosine triphosphate (ATP)-competitive mTOR inhibitors are an emerging class of mTOR inhibitors that compete with ATP at the mTOR active site and inhibit any mTOR-containing complex. Since this class of compounds has not been investigated for their immunosuppressive potential, our goal was to determine the influence of a prototypic ATP-competitive mTOR inhibitor on allograft survival. AZD8055 proved to be a potent suppressor of T cell proliferation. Moreover, a short, 10-day course of the agent successfully prolonged murine MHC-mismatched, vascularized heart transplant survival. This therapeutic effect was associated with increased graft-infiltrating regulatory T cells and reduced CD4(+) and CD8(+) T cell interferon-γ production. These studies establish for the first time, that ATP-competitive mTOR inhibition can prolong organ allograft survival and warrant further investigation of this next generation mTOR inhibitors.
authors.affiliation: Department of Surgery, School of Medicine, Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA.
authors.forename: B R
authors.initials: BR
authors.lastname: Rosborough
authors.forename: D
authors.initials: D
authors.lastname: Raïch-Regué
authors.forename: Q
authors.initials: Q
authors.lastname: Liu
authors.forename: R
authors.initials: R
authors.lastname: Venkataramanan
authors.forename: H R
authors.initials: HR
authors.lastname: Turnquist
authors.forename: A W
authors.initials: AW
authors.lastname: Thomson
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D001483:Base Sequence; D001667:Binding, Competitive; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D017931:DNA Primers; D006084:Graft Rejection / Q000517:prevention & control*; D006085:Graft Survival; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009025:Morpholines / Q000493:pharmacokinetics / Q000494:pharmacology*; D016133:Polymerase Chain Reaction; D020123:Sirolimus / Q000493:pharmacokinetics / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D017931:DNA Primers; D007166:Immunosuppressive Agents; D009025:Morpholines; D000255:Adenosine Triphosphate; C546624:(5-(2,4-bis((3S)-3-methylmorpholin-4-yl)pyrido(2,3-d)pyrimidin-7-yl)-2-methoxyphenyl)methanol; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
keywords: Basic (laboratory) research; T cell; biology; immune modulation; immunosuppressant; immunosuppression; mechanistic target of rapamycin (mTOR); science