DIFFERENTIAL EFFECT OF THE IMMUNOMODULATOR AS101 ON B7-1 AND B7-2 COSTIMULATORY MOLECULES - ROLE IN THE ANTITUMORAL EFFECTS OF AS101

The CD28 receptor on T cells with its ligand B7, representing the best characterized example of costimulation, has recently been demonstrate d to interact with two different ligands: B7-1 and B7-2. AS101 (ammoni um trichloro[dioxoethylene-0,0']tellurate), a synthetic immunomodulato r with minimal toxicity, was previously shown to stimulate both mouse and human cells to proliferate and secrete a variety of cytokines. We recently found that treatment of advanced cancer patients or tumor-bea ring mice with AS101 results in a clear predominance of Th1 responses with a concomitant decrease in Th2 response. Our present study demonst rates that AS101 differentially affects B7-1 and B7-2 molecule express ion on mouse macrophages: it up-regulates B7-1 expression in a dose-de pendent manner without affecting B7-2 expression, which leads to a pro found macrophage costimulatory activity of purified T cells with solub le anti-CD3. Our results also demonstrate the differential inhibitory effect of IL-10 on T cell activation in the presence of AS101-stimulat ed accessory cells (AC). We show that when stimulated with AS101, AC-d ependent T cell activation was more resistant to inhibition by IL-10 c ompared with AC stimulated by LPS. This was due to the partial resista nce of AS101-stimulated macrophages to the down-regulation of B7-1 exp ression by IL-10. In vivo studies with AS101-treated tumor-bearing mic e revealed that the predominance in Th1 responses-marked by an increas e in IFN-gamma and a decrease in IL-4-may be associated in part with t he ability of AS101 to up-regulate B7-1 expression, which is also rela ted to its antitumoral effects. These results suggest that AS101 may b e clinically effective in conditions involving dysfunctional cytokine production.