[Immunostimulants].

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.

Adjuvants, Immunologic↗

PubMed1996

CD28 costimulation prevents cell death during primary T cell activation.

CD28 has been demonstrated to play an important role in augmenting T cell proliferation and effector function. Costimulation through CD28 has also been reported to enhance human T cell survival. in this report, we have further investigated the role of CD28 in regulating T cell survival by comparing the survival characteristics of T cells from wild-type and CD28-deficient mice. CD28 costimulation of anti-CD3-activated cells augmented the viability of T cells from wild-type but not from CD28-deficient mice. CTLA4Ig treatment reduced wild-type T cell viability to a level comparable with CD28-deficient T cells. The ability of CD28 to enhance survival during T cell activation correlated positively with its ability to up-regulate the protein product of the cell survival gene bcl-xL. No differences in the expression of either Bcl-2 or Fas were observed between wild-type and CD28-deficient T cells. The CD28-dependent enhancement of cell survival during in vitro activation was found to be independent of Fas expression, as CD28 costimulation enhanced T cell survival to comparable levels in both wild-type and lpr animals. Cell death in CD28-deficient animals and in wild-type animals treated with CTLA4Ig displayed the morphologic characteristics of apoptosis. Additionally, inhibitors of ICE proteases could reverse cell death induced by TCR engagement in the absence of CD28 costimulation. Thus, CD28 costimulation not only enhances the proliferative expansion of cells activated through the TCR but also increases the likelihood that individual cells survive during T cell activation.

Adjuvants, Immunologic↗