BH3 mimetics antagonizing restricted prosurvival Bcl-2 proteins represent another class of selective immune modulatory drugs.
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.
Autoimmunity and Transplantation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia.
Emma M
EM
Carrington
Ingela B
IB
Vikstrom
Amanda
A
Light
Robyn M
RM
Sutherland
Sarah L
SL
Londrigan
Kylie D
KD
Mason
David C S
DC
Huang
Andrew M
AM
Lew
David M
DM
Tarlinton
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology; D051023:BH3 Interacting Domain Death Agonist Protein / Q000037:antagonists & inhibitors*; D001713:Biphenyl Compounds / Q000494:pharmacology; D006084:Graft Rejection / Q000517:prevention & control; D056724:Immunity, Humoral / Q000187:drug effects; D007155:Immunologic Factors / Q000494:pharmacology; D016381:Islets of Langerhans Transplantation; D007962:Leukocytes / Q000145:classification / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D009596:Nitrophenols / Q000494:pharmacology; D010446:Peptide Fragments / Q000037:antagonists & inhibitors*; D010879:Piperazines / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors*; D013449:Sulfonamides / Q000494:pharmacology; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology; D014184:Transplantation, Homologous
C501332:ABT-737; D051023:BH3 Interacting Domain Death Agonist Protein; C474007:Bax protein (53-86); C494815:Bid protein, mouse; D001713:Biphenyl Compounds; D007155:Immunologic Factors; D009596:Nitrophenols; D010446:Peptide Fragments; D010879:Piperazines; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides