The in vivo mechanism of action of CTLA4Ig.
A single dose of CTLA4Ig, an inhibitor of CD28-mediated T cell costimulation, given 2 days after transplantation induces specific unresponsiveness to alloantigens in vivo. However, the mechanisms responsible are unknown. Using pigeon cytochrome c as a model Ag, we monitored the effect of CTLA4Ig on the fate of Ag-reactive T cells in normal mice and on pigeon cytochrome c-specific TCR transgenic cells adoptively transferred into congenic mice. CTLA4Ig significantly inhibits immunization with pigeon cytochrome c. In particular, ELISA and ELISPOT assays indicate an 80 to 90% reduction in Th1 (i.e, IL-2 and IFN-gamma) cytokine production and in the numbers of cytokine-producing cells. Interestingly, despite this profound reduction in cytokine-producing cells, Ag-reactive T cells expand in CTLA4Ig-treated animals, although the degree of expansion is reduced by 50% compared with that in control Ig-treated animals. Thus, loss of Th1 cytokine production in CTLA4Ig-treated animals is not fully explained by the decreased expansion of Ag-specific T cells. These results suggest two mechanisms of action for CTLA4Ig in vivo: inhibition of expansion of Ag-reactive cells and induction of anergy in the residual population.
Judge
T A
TA
Department of Medicine, University of Pennsylvania, Philadelphia 19104, USA.
Tang
A
A
Spain
L M
LM
Deans-Gratiot
J
J
Sayegh
M H
MH
Turka
L A
LA
D000069594:Abatacept; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000008:administration & dosage / Q000494:pharmacology*; D060908:CTLA-4 Antigen; D010856:Columbidae; D003574:Cytochrome c Group / Q000276:immunology; D016207:Cytokines / Q000037:antagonists & inhibitors; D004306:Dose-Response Relationship, Immunologic; D006968:Hypersensitivity, Delayed / Q000276:immunology / Q000517:prevention & control; D007108:Immune Tolerance / Q000187:drug effects; D018796:Immunoconjugates; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000494:pharmacology*; D016219:Immunotherapy, Adoptive; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018417:Th1 Cells / Q000187:drug effects* / Q000378:metabolism
D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D003574:Cytochrome c Group; D016207:Cytokines; D018796:Immunoconjugates; D007166:Immunosuppressive Agents; D000069594:Abatacept