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" Studies on the roles of T helper type I and type II cytokines in HIV immunopathogenesis: "
M. P. Daftarian
F. K. Diaz-Mitoma, A.
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Latin Dissertation
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| Language of Document
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English
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| Record Number
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1112985
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| Doc. No
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TLpq304405537
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| Main Entry
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F. K. Diaz-Mitoma, A.
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M. P. Daftarian
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| Title & Author
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Studies on the roles of T helper type I and type II cytokines in HIV immunopathogenesis:\ M. P. DaftarianF. K. Diaz-Mitoma, A.
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| College
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University of Ottawa (Canada)
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| Date
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1997
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| student score
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1997
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| Degree
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Ph.D.
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| Page No
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158
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| Abstract
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Infection of immune cells with human immunodeficiency virus (HIV) induces dysregulation of cytokines which may play a vital role in HIV pathogenesis. I analyzed the expression of Th1 (interferon-usd\gamma,usd (IFN-usd\gamma)\rbrackusd and Th2 (interleukin-4 (IL-4), IL-10) type cytokines in unstimulated and mitogen stimulated peripheral blood mononuclear cells (PBMC) from HIV seropositive (HIV patients. It was determined that IFN-usd\gammausd mRNA in unstimulated PBMC was significantly decreased and IL-10 mRNA as well as IL-10 protein was significantly increased in patients with <400 CD4 T cells/mm (n = 30) as compared to patients with >400 CD4 T cells/mm (n = 6) and normal controls (n = 16). Mitogen stimulation of PBMC revealed two groups of HIV low and normal IL-10 producers. Production of IL-4 was reduced in HIV individuals with <400 CD4 T cells/mm while it was comparable to that of HIV controls in those with >400 CD4 T cells/mm However, ability to produce IFN-y by mitogen stimulated PBMC and CD4 T cells was not impaired in HIV individuals. These results suggest that PBMC of HIV exhibit dysregulation of Th2 type cytokines which may play a role in HIV immunopathogenesis. In the next set of experiments, the IL-10 production was correlated with the levels of proliferative responses to recall antigens. Low IL-10 producers proliferated in response to recall antigens, and demonstrated enhanced recall antigen-induced proliferation upon addition of anti-IL-10 antibodies and/or IL-12. Conversely, normal IL-10 producers had PBMC that failed to proliferate to recall antigens, and did not demonstrate enhanced recall antigen-induced proliferation upon addition of anti-IL-10 antibodies and/or IL-12. Source of the IL-10 production in PBMC of HIV individuals was shown to be monocytes, while, in HIV controls, it was produced by both T cells and monocytes. The molecular mechanisms underlying the production of IL-10 are not clear. I have demonstrated that monocytes/macrophages are required for IL-10 production by normal activated T cells. IL-10 production was significantly downregulated in both T cell and monocyte depleted PBMC compared to undepleted PBMC, and IL-10 production could be restored following addition of monocyte conditioned medium (MCM), this suggested that IL-10 production by T cells is regulated by monokine(s) produced by activated monocytes. The monokine(s) responsible for IL-10 induction by T cells were further studied. Addition of IL-6 and IL-12 enhanced IL-10 production in monocyte depleted PBMC in a dose dependent and additive manner. With respect to regulation of IL-10 produced by monocytes, tumor necrosis factor usd\alphausd (TNF-usd\alpha)usd was found to induce IL-10 production by resting purified monocytes. Taken together, these findings suggest that IL-10 production by human T cells and monocytes is differentially regulated. IL-12 and IL-6 induce the expression of IL-10 by PHA stimulated T cells whereas TNF-usd\alphausd induces IL-10 production by monocytes. Since IL-10 inhibits production of IL-6, IL-12 and TNF-usd\alpha,usd these results may indicate a potential mechanism of negative feedback regulation of the immune system. Furthermore, mitogen stimulated PBMC from HIV individuals produced significantly lower levels of IL-12 than did those from HIV-controls. A defect in IL-12 induction may partially cause IL-10 dysregulation in HIV infection.
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Health and environmental sciences
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Immune deficiency
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Immunology
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