In vitro immunomodulatory properties of tucaresol in HIV infection.
The immunomodulatory properties of tucaresol (compound 589C80) were tested on in vitro antigen- and mitogen-stimulated proliferation and cytokine production by peripheral blood mononuclear cells (PBMC) of HIV-infected individuals and healthy controls (HC). Results showed that tucaresol: (1) increases influenza A virus-, gp 160 peptide-, and HLA alloantigen-stimulated proliferation as well as interleukin (IL)-2 and interferon gamma (IFN gamma) production by PBMC of HIV-infected individuals with higher CD4 counts (>500/microl) but had only a marginal immunomodulatory effect on PBMC of patients with lower CD4 counts (<500/microl); (2) did not modify IL-10 production; (3) augmented CD25 expression on mitogen-stimulated T cells of HC but not of HIV-infected individuals; and (4) marginally increased CTL activity. The immunomodulatory properties of tucaresol were confirmed by PCR analyses; additional data showed that tucaresol costimulated CD3-dependent triggering of T cells and that this stimulation was independent of CD28 costimulation. The immunomodulatory effects of tucaresol on T cell functions are characterized by a bell-shaped dose response curve; the action of the compound is optimal in the 100 to 300 microM range. Analyses of mitogen-stimulated apoptosis demonstrated that the lack of effect of tucaresol at higher doses is not the result of increased cell death, suggesting a role of functional impairment. These data confirm that tucaresol can stimulate T helper cell function and enhance the production of type 1 cytokines, thus eliciting cell-mediated immunity, and warrant its potential utility in the therapy of HIV infection.
Clerici
M
M
Cattedra di Immunologia, Universita' degli Studi di Milano, DiSP LITA Vialba, Via G.B. Grassi 57, 20154, Milan, Italy. mago@mailserver.unimi.it
Cogliati
M
M
Rizzardini
G
G
Colombo
F
F
Fossati
S
S
Rhodes
J
J
Bray
D
D
Piconi
S
S
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000941:Antigens / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001547:Benzaldehydes / Q000276:immunology* / Q000494:pharmacology; D001565:Benzoates / Q000276:immunology* / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000737:chemistry; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects; D002455:Cell Division / Q000276:immunology; D015658:HIV Infections / Q000188:drug therapy*; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis / Q000378:metabolism; D007376:Interleukin-2 / Q000096:biosynthesis / Q000235:genetics; D007963:Leukocytes, Mononuclear / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D015375:Receptors, Interleukin-2 / Q000032:analysis / Q000235:genetics
D000276:Adjuvants, Immunologic; D000941:Antigens; D001547:Benzaldehydes; D001565:Benzoates; D007376:Interleukin-2; D012333:RNA, Messenger; D015375:Receptors, Interleukin-2; D007371:Interferon-gamma; C059629:tucaresol