Resistance to ABT-737 in activated T lymphocytes
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Resistance to ABT-737 in activated T lymphocytes : molecular mechanisms and reversibility by inhibition of the calcineurin-NFAT pathway. / Cippà, P E; Kraus, A K; Lindenmeyer, M T; Chen, J; Guimezanes, A; Bardwell, P D; Wekerle, T; Wüthrich, R P; Fehr, T.
In: CELL DEATH DIS, Vol. 3, 19.04.2012, p. e299.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Resistance to ABT-737 in activated T lymphocytes
T2 - molecular mechanisms and reversibility by inhibition of the calcineurin-NFAT pathway
AU - Cippà, P E
AU - Kraus, A K
AU - Lindenmeyer, M T
AU - Chen, J
AU - Guimezanes, A
AU - Bardwell, P D
AU - Wekerle, T
AU - Wüthrich, R P
AU - Fehr, T
PY - 2012/4/19
Y1 - 2012/4/19
N2 - 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.
AB - 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.
KW - Animals
KW - Biphenyl Compounds
KW - Bone Marrow Transplantation
KW - Calcineurin
KW - Cyclosporine
KW - Drug Resistance
KW - Graft vs Host Disease
KW - Mice
KW - Mice, Inbred C57BL
KW - NFATC Transcription Factors
KW - Nitrophenols
KW - Piperazines
KW - Receptors, Antigen, T-Cell
KW - Signal Transduction
KW - Sulfonamides
KW - T-Lymphocytes
KW - Journal Article
KW - Research Support, Non-U.S. Gov't
U2 - 10.1038/cddis.2012.38
DO - 10.1038/cddis.2012.38
M3 - SCORING: Journal article
C2 - 22513873
VL - 3
SP - e299
JO - CELL DEATH DIS
JF - CELL DEATH DIS
SN - 2041-4889
ER -
