INHIBITION OF CD4 CROSS-LINKING-INDUCED LYMPHOCYTES APOPTOSIS BY VESNARINONE AS A NOVEL IMMUNOMODULATING AGENT - VESNARINONE INHIBITS FAS EXPRESSION AND APOPTOSIS BY BLOCKING CYTOKINE SECRETION

Evidence is accumulating that T cells from human immuno-deficiency vir us type 1 (HIV-1)-infected individuals show accelerated cell death thr ough apoptosis. We have recently demonstrated that the cross-linking o f CD4 molecules (CD4XL) results in death of normal peripheral T cells through apoptosis and imbalanced cytokine secretion (ie, induction of tumor necrosis factor-alpha [TNF-alpha] and interferon-gamma [IFN-gamm a] in the absence of interleukin-2 [IL-2] or IL-4 secretion). These up regulated cytokines (TNF-alpha/IFN-gamma) largely contributed to upreg ulation of the apoptosis-inducing cell surface molecule, Fas (APO-1/CD 95) and apoptosis induction. The present study investigated the effect of vesnarinone as a novel immunomodulating agent on CD4XL-induced T-c ell apoptosis. The addition of vesnarinone to peripheral blood mononuc lear cells (PBMC) significantly inhibited CD4XL-induced lymphocyte apo ptosis. This apoptosis-inhibitory effect of vesnarinone was associated with the blocking of CD4XL-induced TNF-alpha and IFN-gamma secretion and of Fas antigen upregulation. However, vesnarinone did not block ef fects of exogenously supplemented TNF-alpha/IFN-gamma on Fas induction . These data suggest that vesnarinone inhibits CD4XL-induced TNF-alpha /IFN-gamma secretion, thereby blocking subsequent Fas upregulation and apoptosis induction. Given the potent pathogenic role of imbalanced c ytokine secretion observed in HIV-infection, an agent such as vesnarin one may be of therapeutic value in slowing disease progression. (C) 19 96 by The American Society of Hematology.