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 demonstrated to interact with two different ligands: B7-1 and B7-2. AS101 (ammonium trichloro[dioxoethylene-O,O']tellurate), a synthetic immunomodulator 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-bearing mice with AS101 results in a clear predominance of Th1 responses with a concomitant decrease in Th2 response. Our present study demonstrates that AS101 differentially affects B7-1 and B7-2 molecule expression on mouse macrophages: it up-regulates B7-1 expression in a dose-dependent manner without affecting B7-2 expression, which leads to a profound macrophage costimulatory activity of purified T cells with soluble anti-CD3. Our results also demonstrate the differential inhibitory effect of IL-10 on T cell activation in the presence of AS101-stimulated accessory cells (AC). We show that when stimulated with AS101, AC-dependent T cell activation was more resistant to inhibition by IL-10 compared with AC stimulated by LPS. This was due to the partial resistance of AS101-stimulated macrophages to the down-regulation of B7-1 expression by IL-10. In vivo studies with AS101-treated tumor-bearing mice revealed that the predominance in Thl responses--marked by an increase in IFN-gamma and a decrease in IL-4--may be associated in part with the ability of AS101 to up-regulate B7-1 expression, which is also related to its antitumoral effects. These results suggest that AS101 may be clinically effective in conditions involving dysfunctional cytokine production.
Kalechman
Y
Y
Cancer, AIDS, Immunology Research, (CAIR), Department of Life Sciences, Bar Ilan University, Ramat Gan, Israel.
Sredni
B
B
D000276:Adjuvants, Immunologic / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015703:Antigens, CD / Q000096:biosynthesis / Q000187:drug effects*; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D018122:B7-1 Antigen / Q000096:biosynthesis / Q000187:drug effects*; D051940:B7-2 Antigen; D017252:CD3 Complex / Q000276:immunology; D005030:Ethylenes / Q000494:pharmacology* / Q000627:therapeutic use; D016753:Interleukin-10 / Q000037:antagonists & inhibitors / Q000494:pharmacology; D007376:Interleukin-2 / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects; D008262:Macrophage Activation / Q000187:drug effects; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000187:drug effects*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D013691:Tellurium / Q000494:pharmacology* / Q000627:therapeutic use; D015854:Up-Regulation / Q000276:immunology
D000276:Adjuvants, Immunologic; D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000970:Antineoplastic Agents; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D017252:CD3 Complex; C497965:Cd86 protein, mouse; D005030:Ethylenes; D007376:Interleukin-2; D008562:Membrane Glycoproteins; D016753:Interleukin-10; C054105:ammonium trichloro(dioxoethylene-O,O'-)tellurate; D013691:Tellurium