BH3 mimetics antagonizing restricted prosurvival Bcl-2 proteins represent another class of selective immune modulatory drugs
- Author(s)
- Carrington, EM; Vikstrom, IB; Light, A; Sutherland, RM; Londrigan, SL; Mason, KD; Huang, DCS; Lew, AM; Tarlinton, DM;
- Details
- Publication Year 2010-06-15,Volume 107,Issue #24,Page 10967-10971
- Journal Title
- PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
- Publication Type
- Journal Article
- Abstract
- Death by apoptosis shapes tissue homeostasis. Apoptotic mechanisms are so universal that harnessing them for tailored immune intervention would seem challenging; however, the range and different expression levels of pro-and anti-apoptotic molecules among tissues offer hope that targeting only a subset of such molecules may be therapeutically useful. We examined the effects of the drug ABT-737, a mimetic of the killer BH3 domain of the Bcl-2 family of proteins that induces apoptosis by antagonizing Bcl-2, Bcl-X(L), and Bcl-W (but not Mcl-1 and A1), on the mouse immune system. Treatment with ABT-737 reduced the numbers of selected lymphocyte and dendritic cell subpopulations, most markedly in lymph nodes. It inhibited the persistence of memory B cells, the establishment of newly arising bone marrow plasma cells, and the induction of a cytotoxic T cell response. Preexisting plasma cells and germinal centers were unaffected. Notably, ABT-737 was sufficiently immunomodulatory to allow long-term survival of pancreatic allografts, reversing established diabetes in this model. These results provide an insight into the selective mechanisms of immune cell survival and how this selectivity avails a different strategy for immune modulation.
- Publisher
- NATL ACAD SCIENCES
- Keywords
- CELL-DEATH; TRANSPLANTATION; INHIBITOR; MEMORY; EXPRESSION; APOPTOSIS; SURVIVAL; MCL-1; BAX; DIFFERENTIATION
- Publisher's Version
- https://doi.org/10.1073/pnas.1005256107
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2010-06-15 12:00:00