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Mycobacterium tuberculosis (MTB) can induce apoptosis in monocytes/macrophages both in vitro and in vivo, and this phenomenon is associated with mycobacterial survival. The present study addresses the possibility that apoptotic and inflammatory pathways could coexist through a caspase-l-mediated mechanism. In this context, a caspase-1 inhibitor (YVAD), but not caspase-3 (DEVD) or caspase-4 (LEVD) inhibitors, was able to strongly inhibit MTBinduced apoptosis. Moreover, caspase-1 activity was confirmed by the increased maturation of interleukin (IL)-1β. Of interest, IL-1β and tumor necrosis factor (TNF)-α were produced massively in the course of infection, and both were inhibited by YVAD pretreatment. To determine whether TNF-α was produced actively by apoptotic cells, the intracytoplasmatic cytokine content and apoptotic phenotype were analyzed at the single-cell level. Results showed a progressive increase of TNF-α production in annexin V-positive cells. These results indicate that MTB-induced apoptosis is associated with proinflammatory cytokine production. [ABSTRACT FROM AUTHOR]

The functional recovery of the immune system in HIV-infected persons receiving HAART and the role of adjuvant immune therapy are still matters of intensive investigation. We analysed the effects of HAART combined with cytokines in 22 naive asymptomatic individuals, randomized to receive HAART (n = 6), HAART plus a low dose (1000 000 U/daily) of rIL-2 (n = 8), and HAART plus rIL-2 after previous administration of granulocyte colony-stimulating factor (n = 8). After 3 months of therapy, increased CD4+ T cell counts and diminished viral loads were observed in all patients, independently of cytokine addition. A decreased expression of CD95 (Apo 1/Fas) was evident in all groups when compared with values before therapy. The percentages of peripheral blood mononuclear cells (PBMC) expressing CD95 after therapy decreased by 15%, 22% and 18% in the three treatment groups, respectively (P < 0·05). Analysis of PBMC subsets demonstrated that CD95 expression was significantly reduced on CD45RA+CD62L+ naive T cells (25·3%, 22·4%, and 18·6%, respectively; P < 0·05) in each group, after therapy. Accordingly, all patients showed a reduced rate of in vitro spontaneous apoptosis (P < 0·05). Another effect induced by HAART was a significant increase in IL-2Rα expression on total PBMC (P < 0·05), independently of cytokine addition. Altogether, our results suggest that very low dose administration of rIL-2 (1000 000 U/daily) may be not enough to induce a significant improvement in the immune system as regards HAART alone. The employment of higher doses of recombinant cytokines and/or different administration protocols in clinical trials might however contribute to ameliorate the immune reconstitution in patients undergoing HAART. [ABSTRACT FROM AUTHOR]

Vgamma9Vdelta2 T lymphocytes are broadly reactive against various intracellular pathogens and display both lytic and proliferative responses to human immunodeficiency virus (HIV)-infected cells. HIV infection of peripheral blood mononuclear cell cultures led to absolute increases in Vgamma9Vdelta2 T cells accompanied by decreased p24 levels. Strong gammadelta T cell activation with nonpeptidic mycobacterial phosphoantigens (TUBAg1 extract or synthetic isopentenyl pyrophosphate) resulted in potent inhibition of HIV replication through soluble released factors. Subsequent analyses showed that phosphoantigen-activated gammadelta T cells produced substantial amounts of beta-chemokines (macrophage inflammatory protein [MIP]-1alpha, MIP-1beta, and regulated-on-activation, normal T-cell-expressed and -secreted beta-chemokine [RANTES]), which represent the natural ligand for the CCR5 HIV coreceptor. Accordingly, anti-beta-chemokine antibodies neutralized the inhibition of monocytotropic HIV strains by gammadelta T cell-released factors. Moreover, a T-tropic HIV strain using the CXCR4 coreceptor for virus entry was potently inhibited. Together, these data reveal that phosphoantigen-activated gammadelta T cells are an important source of CC chemokines and may suppress HIV replication through cell-released antiviral factors. [ABSTRACT FROM AUTHOR]

The age-related decline in T cell functions is generally considered to be due to changes in the responding αβ T cell populations as a result of impairment of T cell differentiation in the thymus. T cells bearing the γδ TCR are normally a minor subset of circulating T cells, but often the major T cell type among lymphocytes in epithelial tissues. In this paper we show that γδ T cells are expanded in lymph nodes of irradiated mice after syngenic bone marrow transplantation. Interestingly, these γδ T cells express mainly the Vδ3 TCR, which is characteristic of dendritic epithelial T cells that can develop in athymic nude mice and may recognize self antigens. Since the peripheral expansion of Vδ3 T lymphocytes is closely related to bone marrow age, these observations indicate that the age-related propensity to extrathymic development of Vggr;3+ γδ+ T lymphocytes is mainly due to stem cell dysregulation in aging. This phenomenon may contribute to T cell impairment and to the increased natural cytotoxic activity of lymphoid cells in aged mice. [ABSTRACT FROM PUBLISHER]

Human peripheral blood mononuclear cells (PBMC) stimulated in vitro with purified protein derivative (PPD) or with a Candida albicans polysaccharide extract (MPPS) released immune interferon (IFN) and interleukin 2 (IL-2). Kinetic studies showed a biphasic production of IFN with maximum levels at days 3-4 and days 5-6 of culture. In contrast, the IL-2 production is only observed al days 2-3 of culture. The relationship between IFN and IL-2. analysed both in responder and nonresponder PBMC cultures, showed that the early peak of IFN production appears to be IL-2 independent whereas the second peak seems strictly related to the presence of IL-2 culture. Furthermore, monoclonal antibodies against class I and class II products of the major histocompatibility complex (MHC) inhibited IFN production when added at the beginning of culture, whereas only anti-class I antibodies interfered with the release of IFN when added to antigen-primed lymphocytes. [ABSTRACT FROM AUTHOR]

Human T lymphocytes cultured in vitro for 5 days with Candida albicans purified polysaccharide (MPPS) produce and antigen non-specific inhibitor (nsINH) which blocks ceil proliferation when added at the beginning of the culture. The antigen presenting function of antigen pulsed adherent cells (macrophages) is significantly impaired by incubation in nsINH. Further analysis shows that nsINH blocks the production of interleukin-1 both from human mononuclear cells stimulated with lipopolysaccharide. Furthermore, the production of interleukin-2 (IL-2) is also suppressed when MPPS stimulated cells are cultured in presence of nsINH. However nsINH does not affect the appearance of lL-2 responsive cells as the addition of gibbon IL-2 to the culture fully reverses the suppressive effect of nsINH on blast transformation. [ABSTRACT FROM AUTHOR]

Peripheral blood mononuclear cells (PBMC) were stimulated in vitro either with Candida albicans polysaccharide extract (MPPS) or with PPD. Both MPPS and PPD driven lymphocyte proliferation was strictly dependent on the presence of macrophages. In fact purified T cells failed to proliferate unless adherent cells were added. The ability of monocytes to produce interleukin-I (IL-I) was then investigated. Both MPPS and PPD caused the release IL-1 into the culture supernatant, as measured in a direct thymocyte proliferative assay. MPPS and PPD also stimulated the production of IL-1 by the mouse macrophage like line P388D1. These data support the view that the antigen specific activation of human T cells by MPPS and PPD requires both antigen presentation and IL-1 production. [ABSTRACT FROM AUTHOR]

Examines the intracellular mycobacterial viability of mycobacterium tuberculosis (MTB)-induced apoptosis in monocytes. Association of MTB- induces apoptosis with CD14 expression; Correlation between MTB high doses and parasite survival; Role of monocytes on cytokines and chemokines release.