title: Distinctive Expression of Bcl-2 Factors in Regulatory T Cells Determines a Pharmacological Target to Induce Immunological Tolerance.
abstract: Distinctive molecular characteristics of functionally diverse lymphocyte populations may represent novel pharmacological targets for immunotherapy. The intrinsic apoptosis pathway is differently regulated among conventional and regulatory T cells (Tregs). Targeted pharmacological modulation of this pathway with a small molecule Bcl-2/Bcl-xL inhibitor (ABT-737) caused a selective depletion of effector T cells and a relative enrichment of Tregs in vivo. Treatment with ABT-737 resulted in a tolerogenic milieu, which was exploited to alleviate graft-versus-host disease, to prevent allograft rejection in a stringent fully MHC-mismatched skin transplantation model and to induce immunological tolerance in combination with bone marrow transplantation. This concept has the potential to find various applications for immunotherapy, since it allows pharmacologic exploitation of the immunomodulatory properties of Tregs without the need for cell manipulation ex vivo.
authors.affiliation: Nephrology, Institute of Physiology, University of Zürich, Zürich, Switzerland; Division of Nephrology, University Hospital Zürich, Zürich, Switzerland.
authors.forename: Sarah Sharon
authors.initials: SS
authors.lastname: Gabriel
authors.affiliation: Nephrology, Institute of Physiology, University of Zürich, Zürich, Switzerland; Division of Nephrology, University Hospital Zürich, Zürich, Switzerland.
authors.forename: Nina
authors.initials: N
authors.lastname: Bon
authors.affiliation: Nephrology, Institute of Physiology, University of Zürich, Zürich, Switzerland; Division of Nephrology, University Hospital Zürich, Zürich, Switzerland.
authors.forename: Jin
authors.initials: J
authors.lastname: Chen
authors.affiliation: Transplantation Immunology, Department of Surgery, Medical University of Vienna , Vienna , Austria.
authors.forename: Thomas
authors.initials: T
authors.lastname: Wekerle
authors.affiliation: Transplantation Research Immunology Group, Nuffield Department of Surgical Sciences, University of Oxford , Oxford , UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Bushell
authors.affiliation: Nephrology, Institute of Physiology, University of Zürich, Zürich, Switzerland; Division of Nephrology, University Hospital Zürich, Zürich, Switzerland; Department of Internal Medicine, Cantonal Hospital Graubünden, Chur, Switzerland.
authors.forename: Thomas
authors.initials: T
authors.lastname: Fehr
authors.affiliation: Division of Nephrology, University Hospital Zürich , Zürich , Switzerland.
authors.forename: Pietro Ernesto
authors.initials: PE
authors.lastname: Cippà
keywords: ABT-737; Bcl-2; Bcl-XL; Mcl-1; apoptosis; regulatory T cells; tolerance; transplantation