title: Resistance to ABT-737 in activated T lymphocytes: molecular mechanisms and reversibility by inhibition of the calcineurin-NFAT pathway.
abstract: Dynamic regulation of the intrinsic apoptosis pathway controls central and peripheral lymphocyte deletion, and may interfere with the pro-apoptotic potency of B-cell lymphoma 2 inhibitors such as ABT-737. By following a T-cell receptor (TCR) transgenic population of alloantigen-specific T cells, we found that sensitivity to ABT-737 radically changed during the course of allo-specific immune responses. Particularly, activated T cells were fully resistant to ABT-737 during the first days after antigen recognition. This phenomenon was caused by a TCR-calcineurin-nuclear factor of activated T cells-dependent upregulation of A1, and was therefore prevented by cyclosporine A (CsA). As a result, exposure to ABT-737 after alloantigen recognition induced selection of alloreactive T cells in vivo, whereas in combination with low-dose CsA, ABT-737 efficiently depleted alloreactive T cells in murine host-versus-graft and graft-versus-host models. Thus, ABT-737 resistance is not a prerogative of neoplastic cells, but it physiologically occurs in T cells after antigen recognition. Reversibility of this process by calcineurin inhibitors opens new pharmacological opportunities to modulate this process in the context of cancer, autoimmunity and transplantation.
authors.affiliation: Institute of Physiology, University of Zürich, Zürich, Switzerland.
authors.forename: P E
authors.initials: PE
authors.lastname: Cippà
authors.forename: A K
authors.initials: AK
authors.lastname: Kraus
authors.forename: M T
authors.initials: MT
authors.lastname: Lindenmeyer
authors.forename: J
authors.initials: J
authors.lastname: Chen
authors.forename: A
authors.initials: A
authors.lastname: Guimezanes
authors.forename: P D
authors.initials: PD
authors.lastname: Bardwell
authors.forename: T
authors.initials: T
authors.lastname: Wekerle
authors.forename: R P
authors.initials: RP
authors.lastname: Wüthrich
authors.forename: T
authors.initials: T
authors.lastname: Fehr
mesh_terms: D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology*; D016026:Bone Marrow Transplantation; D019703:Calcineurin / Q000378:metabolism*; D016572:Cyclosporine / Q000494:pharmacology; D004351:Drug Resistance / Q000502:physiology*; D006086:Graft vs Host Disease / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D050778:NFATC Transcription Factors / Q000378:metabolism*; D009596:Nitrophenols / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013449:Sulfonamides / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism
chemical_list: C501332:ABT-737; D001713:Biphenyl Compounds; D050778:NFATC Transcription Factors; D009596:Nitrophenols; D010879:Piperazines; D011948:Receptors, Antigen, T-Cell; D013449:Sulfonamides; D016572:Cyclosporine; D019703:Calcineurin