The Bcl-2 family antagonist ABT-737 significantly inhibits multiple animal models of autoimmunity.
The Bcl-2 family of proteins plays a critical role in controlling immune responses by regulating the expansion and contraction of activated lymphocyte clones by apoptosis. ABT-737, which was originally developed for oncology, is a potent inhibitor of Bcl-2, Bcl-x(L), and Bcl-w protein function. There is evidence that Bcl-2-associated dysregulation of lymphocyte apoptosis may contribute to the pathogenesis of autoimmunity and lead to the development of autoimmune diseases. In this study, we report that ABT-737 treatment resulted in potent inhibition of lymphocyte proliferation as measured by in vitro mitogenic or ex vivo Ag-specific stimulation. More importantly, ABT-737 significantly reduced disease severity in tissue-specific and systemic animal models of autoimmunity. Bcl-2 family antagonism by ABT-737 was efficacious in treating animal models of arthritis and lupus. Our results suggest that treatment with a Bcl-2 family antagonist represents a novel and potentially attractive therapeutic approach for the clinical treatment of autoimmunity.
Bardwell
Philip D
PD
Department of Biologics, Abbott Bioresearch Center, Worcester, MA 01605, USA.
Gu
Jijie
J
McCarthy
Donna
D
Wallace
Craig
C
Bryant
Shaughn
S
Goess
Christian
C
Mathieu
Suzanne
S
Grinnell
Chris
C
Erickson
Jamie
J
Rosenberg
Saul H
SH
Schwartz
Annette J
AJ
Hugunin
Margaret
M
Tarcsa
Edit
E
Elmore
Steven W
SW
McRae
Bradford
B
Murtaza
Anwar
A
Wang
Li Chun
LC
Ghayur
Tariq
T
D000818:Animals; D017951:Antigen Presentation / Q000187:drug effects; D001169:Arthritis, Experimental / Q000139:chemically induced / Q000276:immunology / Q000473:pathology; D015551:Autoimmunity / Q000187:drug effects*; D001713:Biphenyl Compounds / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D018450:Disease Progression; D006433:Hemocyanins / Q000276:immunology; D006801:Humans; D006968:Hypersensitivity, Delayed / Q000276:immunology; D016898:Interferon-alpha / Q000494:pharmacology; D008181:Lupus Nephritis / Q000139:chemically induced / Q000276:immunology / Q000473:pathology; D008214:Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D051379:Mice; D009596:Nitrophenols / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013379:Substrate Specificity; D013449:Sulfonamides / Q000494:pharmacology*
C501332:ABT-737; D001713:Biphenyl Compounds; D016898:Interferon-alpha; D009596:Nitrophenols; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; D006433:Hemocyanins; C032808:keyhole-limpet hemocyanin