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.

Important note: Information in this article was accurate in 1996. The state of the art may have changed since the publication date.

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.

Blood. 1996 Mar 15;87(6):2361-8. Unique Identifier : AIDSLINE MED/96203800
Oyaizu N; McCloskey TW; Than S; Pahwa S; Department of Pediatrics, North Shore University Hospital-Cornell; University Medical College, New York, NY 11030, USA.

Abstract: Evidence is accumulating that T cells from human immunodeficiency virus type 1 (HIV-1)-infected individuals show accelerated cell death through apoptosis. We have recently demonstrated that the cross-linking of 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-gamma] in the absence of interleukin-2 [IL-2] or IL-4 secretion). These upregulated cytokines (TNF-alpha/IFN-gamma) largely contributed to upregulation of the apoptosis-inducing cell surface molecule, Fas (APO-1/CD95) and apoptosis induction. The present study investigated the effect of vesnarinone as a novel immunomodulating agent on CD4XL-induced T-cell apoptosis. The addition of vesnarinone to peripheral blood mononuclear cells (PBMC) significantly inhibited CD4XL-induced lymphocyte apoptosis. This apoptosis-inhibitory effect of vesnarinone was associated with the blocking of CD4XL-induced TNF-alpha IFN-gamma secretion and of Fas antigen upregulation. However, vesnarinone did not block effects 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 cytokine secretion observed in HIV-infection, an agent such as vesnarinone may be of therapeutic value in slowing disease progression.

Keywords: Adjuvants, Immunologic/*PHARMACOLOGY Antibodies, Monoclonal/IMMUNOLOGY Antigens, CD4/*IMMUNOLOGY Antigens, CD95/*BIOSYNTHESIS/GENETICS Apoptosis/*DRUG EFFECTS CD4-Positive T-Lymphocytes/CYTOLOGY/*DRUG EFFECTS/IMMUNOLOGY Depression, Chemical Gene Expression Regulation/*DRUG EFFECTS Human HIV Seronegativity *Immunologic Capping Lymphokines/*SECRETION Quinolines/*PHARMACOLOGY Support, Non-U.S. Gov't Support, U.S. Gov't, P.H.S. JOURNAL ARTICLE
960930
M9690940

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