The monocyte-derived cytokines, tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta), are central regulators of the immune response, but the physiologic stimuli for their release remain largely undefined. Engagement of three monocyte glycoproteins, LFA-3, CD44, and CD45, by specific monoclonal antibodies immobilized on plastic induced TNF-alpha and IL-1 beta release. In addition, TNF-alpha was released when monocyte LFA-3 bound immobilized, purified CD2, which is its physiologic receptor. Thus, a receptor-ligand interaction that mediates cell-cell adhesion can transmit the necessary signals for the release of monokines.
Because of the probable role of HIV-infected monocyte/macrophages in the pathogenesis and progression of AIDS, it is essential that antiretroviral therapy address viral replication in cells of this lineage. Several dideoxynucleosides have been shown to have potent in vitro and, in the case of 3'-azido-2',3'-dideoxythymidine (AZT) and 2',3'-dideoxycytidine (ddC), in vivo activity against HIV. However, because these compounds must be phosphorylated (activated) in target cells, and because monocyte/macrophages may have levels of kinases that differ from those in lymphocytes, we investigated the capacity of these drugs to suppress HIV replication in monocyte/macrophages using HIV-1/HTLV-IIIBa-L (a monocytotropic isolate). In the present study, we observed that HTLV-IIIBa-L replication in fresh human peripheral blood monocyte/macrophages was suppressed by each of three dideoxynucleosides: 3'-azido-2',3'-dideoxythymidine (AZT), 2',3'-dideoxycytidine (ddC), and 2',3'-dideoxyadenosine (ddA). Similar results were observed in 5-d-cultured monocyte/macrophages, although higher concentrations of the drugs were required. We then studied the metabolism of AZT and ddC in such cells. The phosphorylation of ddC to a triphosphate moiety was somewhat decreased in monocyte/macrophages as compared with H9 T cells. On the other hand, the phosphorylation of AZT in monocyte/macrophages was markedly decreased to 25% or less of the level in T cells. However, when we examined the level of the normal endogenous 2'-deoxynucleoside triphosphate pools, which compete with 2',3'-dideoxynucleoside triphosphate for viral reverse transcriptase, we found that the level of 2'-deoxycytidine-triphosphate (dCTP) was six- to eightfold reduced, and that of 2'-deoxythymidine-triphosphate (dTTP) was only a small fraction of that found in T cell lines. These results suggest that the ratio of dideoxynucleoside triphosphate to normal deoxynucleoside triphosphate is a crucial factor in determining the antiviral activity of dideoxynucleosides in HIV target cells, and that the lower levels of dTTP may account for the antiretroviral activity of AZT in the face of inefficient phosphorylation of this compound.
The present study demonstrates the graded effect of in vitro corticosteroids (CSs) on
The ability of endocrine organs to express human immune response-associated antigens (Ia), such as HLA-DR, is a subject of intense current interest. In this study, the effects of various potential modulators of thyroid follicular cell HLA-DR expression were examined using in vitro cultures. A culture supernatant containing T-cell-derived lymphokines caused DR antigen expression on 13-18% of thyroid cells; more consistent effects were produced by recombinant gamma-interferon, which led to 46-100% of the thyroid cells becoming HLA-DR positive after 3 days in culture. This effect was both time and concentration dependent and occurred in thyroid cells derived from patients with Graves' disease (n = 7) and Hashimoto's thyroiditis (n = 2) as well as from three subjects with no autoimmune thyroid disease. Thyroid cells stained with the monoclonal antibodies 4F2 and 5E9, which recognize cell activation antigens, regardless of whether they were treated with gamma-interferon. The lectin phytohemagglutinin also induced HLA-DR antigen expression (21-91% of cells positive). This response was dependent on T cell contamination of thyroid cell suspensions, since the effect was inhibited by cyclosporin A. HLA-DQ antigen expression, identified by the Leu-10 monoclonal antibody, was also induced on thyroid cells by gamma-interferon and phytohemagglutinin. In contrast, neither recombinant alpha-interferon nor interleukin-2 induced HLA-DR antigens. Irradiation reduced the response of thyroid cells to gamma-interferon, but two of the known inhibitors of macrophage Ia expression, prostaglandin E2 and (Bu)2cAMP, did not affect gamma-interferon-induced thyroid cell HLA-DR expression. We were unable to detect interleukin-1 production by thyroid cells. These results suggest that 1) under normal circumstances, thyroid cells are 4F2 and 5E9 positive, but are incapable of expressing Ia antigens and, thus, of activating T cells to initiate autoimmune thyroiditis; and 2) once activated, for example by a virus, T cells could release gamma-interferon and induce thyroid cell HLA-DR and -DQ antigen expression; these Ia-positive thyroid cells could then have a role in maintaining or enhancing the autoimmune response.
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