The In Vivo Mechanism of Action of CTLA4Ig1

• Published in: The Journal of immunology (1950) Vol. 156; no. 6; pp. 2294 - 2299
• Main Authors: Judge, Thomas A., Tang, Aimin, Spain, Lisa M., Gratiot-Deans, Jeanne, Sayegh, Mohamed H., Turka, Laurence A.
• Format: Journal Article
• Language: English
• Published: 15.03.1996
• ISSN: 0022-1767; 1550-6606

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-γ) 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.