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Query: UMLS:C0001175 (AIDS)
 120,706 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Infection of mice with Toxoplasma gondii has been shown to induce a transient state of immune down-regulation. Earlier reports have demonstrated the role of cytokines, in particular IL-10, in this host response. Here evidence is presented that T. gondii, a major opportunistic pathogen of the newborn and those with AIDS, is able to induce CD4(+) T cell apoptosis in the infected murine host. We have examined the changes in the CD4(+) T cell population that occur during acute infection in an experimental mouse model. Seventy-six percent of the CD4(+) T cell population increased in volume by day 7 post-infection and expressed T cell maturation markers (CD44(hi), IL-2Rhi, Mel-14(lo)). Further noted was a clonal activation of several CD4(+) T cell to mitogen or parasite antigen stimulation was observed, in particular Vbeta5 T cells. Addition of rIL-2 partially restored the CD4(+) T cell proliferative response in vitro. The T cell activation marker CTLA-4 could not be detected and the co-stimulatory molecule, CD28, was down-regulated. Electrophoretic and morphologic analysis of these cells post-culture demonstrated a DNA fragmentation pattern and cell death consistent with apoptosis. These studies demonstrate for the first time in a protozoan parasite that activation induced CD4(+) T cell unresponsiveness occurs during acute T. gondii infection in mice, and may be important in immune down-regulation and parasite persistence in the infected host.
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PMID:Activation-mediated CD4+ T cell unresponsiveness during acute Toxoplasma gondii infection in mice. 867 78

Murine acquired immunodeficiency syndrome (MAIDS) induced by defective LP-BM5 murine leukemia virus (MuLV) is a disease with many similarities to human AIDS. Our previous studies demonstrated that the depressed hematopoiesis observed in LP-BM5-infected marrow cultures could be attributed to a defective hematopoietic stroma. We report now the generation of permanent stroma cell lines from noninfected and LP-BM5-infected marrow cultures. Retrovirus infection was confirmed by the polymerase chain reaction for detecting viral genome expression of the p12 envelope glycoprotein. The ability of these cell lines to support in vitro hematopoiesis was evaluated. The results demonstrated that when cocultured with normal or infected nonadherent mononuclear cells, noninfected cell lines efficiently supported the production of hematopoietic progenitors, whereas in virus-infected progenitors was suppressed. Expression of cytokine genes in stromal cell lines was also examined. All cell lines expressed equivalent levels of transcripts for interleukin (IL)-1 beta, IL-2, IL-3, IL-6, IL-7, IL-10, interferon, tumor necrosis factor-alpha and stem cell factor. However, infection was associated with higher expression of IL-4 and transforming growth factor-beta 1. These findings demonstrate that infected stomal cell lines generate a defective hematopoietic microenvironment to produce altered cytokine expression and faulty hematopoiesis. Further characterization of these defective cell lines should assist elucidation of the mechanism(s) whereby retroviruses alter hematopoiesis ultimately leading to the generation of immunodeficiency.
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PMID:Suppression of hematopoietic support function is associated with overexpression of interleukin-4 and transforming growth factor-beta 1 in LP-BM5 murine-leukemia-virus-infected stromal cell lines. 867 44

C57BL/6 mice were injected with different doses of human T-cell receptor (TCR) V beta 8.1 CDR1 peptide at different times after murine retrovirus (LP-BM5) infection. Injection with TCR V beta 8.1 CDR1 peptide largely prevented the retrovirus-induced reduction in B- and T-cell proliferation, and T-helper 1 (Th1) cytokines [interleukin-2 (IL-2) and interferon-gamma (IFN-gamma)] secretion. It also suppressed T-helper 2 (Th2) cytokines (IL-6 and IL-10) production, which was stimulated by retrovirus infection. These effects were accomplished using at least 100 micrograms of peptide per mouse and the most effective dose of peptide had to be given within 4 weeks after retrovirus infection. Immunization with doses above 100 micrograms/mouse as long as 4 weeks postinfection maintained natural killer (NK) cell activity during retrovirus infection. Reducing the dose of peptide or delaying it until the disease progressed towards early murine acquired immune deficiency syndrome (AIDS) allowed development of immune dysfunction. These studies provide data suggesting that immune dysfunction, induced by murine retrovirus infection, was largely prevented by TCR V beta CDR1 peptide injection.
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PMID:T-cell-receptor dose and the time of treatment during murine retrovirus infection for maintenance of immune function. 869 80

Toxoplasma gondii is a highly infectious intracellular parasite which, if left unchecked by the immune system, rapidly overwhelms its intermediate hosts, as illustrated by the pathogenesis of toxoplasmic encephalitis in patients with AIDS. In order to insure both its host's and consequently its own survival simultaneously, T. gondii induces a potent gamma-interferon (IFN-gamma)-dependent cell-mediated immunity early in infection that controls the replication of the protozoan and facilitates transformation into the dormant cyst stage. The protective IFN-gamma is derived from three sources: natural killer cells; and CD4+ and CD8+ T lymphocytes, which can partially compensate for each other in knockout mice lacking the appropriate major histocompatibility complex-restricting elements. At least two properties of the parasite appear to be responsible for the early induction of these effector cells. The first is a hydrophobic molecule (or group of related molecules) that triggers interleukin 12 (IL-12), tumour necrosis factor alpha and IL-1beta synthesis in macrophages. This response can also promote HIV replication in the same cells. The second is a superantigen activity that drives IFN-gamma-producing Vbeta5+ CD8+ T cells. These potentially lethal responses are later regulated through the triggering of IL-10 and by the induction of anergy in the superantigen-stimulated Vbeta5+ T cell population.
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PMID:Induction and regulation of host cell-mediated immunity by Toxoplasma gondii. 872 32

Two hallmarks of immunopathogenesis in the progression of HIV-infected individuals to AIDS are the loss of T helper (Th) cell function in response to antigens and the critical reduction in CD4+ T cell numbers. It is probable that these two phenomena are related. We observed that: (1) the failure to detect antigen-stimulated Th cell responses in vitro correlates with increased pokeweed mitogen/staphylococcal enterotoxin B (P/S)-stimulated and antigen-stimulated T cell death; and (2) both of these events are similarly modulated by immunoregulatory cytokines. Interleukin 2 (IL-2) and IL-12 (Th1-type cytokines), as well as antibodies to IL-4 and IL-10 (which are Th2-type cytokines) restore in vitro Th cell responses to recall antigens such as influenza virus and HIV envelope synthetic peptides (env). P/S-induced T cell death affects both CD4+ and CD8+ T cell subsets, whereas death induced by stimulation with env affects only CD4+ T cells. In both examples, Th1-type cytokines and antibodies to Th2-type cytokines protect against T cell death. In contrast, IL-4 and IL-10 do not protect against death, and anti-IL-12 antibody can enhance T cell death. Our findings indicate that the loss of Th cell function and increased T cell death seen in vitro are correlated, and that in vivo HIV infection gives rise to inappropriate cytokines resulting in immune dysfunction and immunopathogenesis.
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PMID:Cytokines in immune regulation/pathogenesis in HIV infection. 872 35

It has been established that human immunodeficiency virus (HIV) replication occurs throughout the course of disease in the lymphoid tissue. We have developed a model system to study the effect of cytokines and other agents on HIV replication using cocultures of DCs and T cells that reflect the cell-to-cell interactions that occur in the microenvironment of lymphoid tissue. Dendritic cells from peripheral blood, when pulsed with small amounts of HIV, induce infection in autologous, unstimulated CD4-positive T cells. Using this system, cytokines, anti-cytokine antibodies, and inhibitors of cellular activation were added to cultures and the effects on cellular proliferation and activation and HIV production were measured. Cytokines that increased T cell proliferation, such as IL-2 and IL-4, enhanced HIV replication, while the effect of IL-12 was more complex. HIV production was inhibited by blocking endogenously produced IL-2, as well as by adding IL-10, which blocks IL-2 secretion, antigen-presenting cell function, and T cell activation. Proinflammatory cytokines induced modest enhancement of viral replication in cocultures of HIV-pulsed DCs and CD4-positive T cells. Thus, using a model of HIV replication that more closely mimics the in vivo microenvironment of lymphoid tissue may allow a better analysis of the effect of cytokines and cytokine networks, as well as agents that modify immune activation on HIV replication.
AIDS Res Hum Retroviruses 1996 Jun 10
PMID:Cytokine regulation of HIV replication induced by dendritic cell-CD4-positive T cell interactions. 873 27

CD8-depleted PBMCs from 20 HIV-1-seropositive donors were incubated in the presence of no cytokines, rIL-2, rIL-12, or both. HIV-1 replication, measured by culture supernatant p24 Ag, was increased to a comparable extent by either rIL-2 or rIL-12 in five of seven asymptomatic subjects and was not induced by either cytokine in the remaining two asymptomatic subjects. Recombinant IL-2 induced increased p24 in cultures from 8 of 13 symptomatic subjects, but rIL-12 did only in cell lines from 5 symptomatic subjects and then only marginally. In IL-2 containing cultures from subjects with minor symptoms of HIV infection, the mean p24 Ag was 320 +/- 217 pg/ml versus 27 +/- 6 in IL-12-containing cultures (p = 0.03). When rIL-12 was added with rIL-2, p24 Ag levels were reduced fourfold compared to cultures from this group incubated with only rIL-2 (p = 0.03). Neither cytokine had much effect on viral replication in CD8-depleted PBMCs from subjects who had had a major AIDS infection, although the number of CD4 cells in four of six of those cultures was markedly reduced. IL-4, IFN-gamma, and IL-10 production induced by exposure to IL-2 and/or IL-12 were also measured. In CD8-depleted cultures from all infected asymptomatic donors and from some symptomatic donors, addition of rIL-12 to rIL-2 decreased IL-4 and increased both IFN-gamma and IL-10 production. Cytokine-induced production of IL-4, IFN-gamma, and IL-10 was greater in cultures from asymptomatic donors than in cultures from symptomatic subjects. Our results suggest that IL-12 immunotherapy may be complicated by enhancement of viral expression in asymptomatic individuals.
AIDS Res Hum Retroviruses 1996 May 20
PMID:Effect of interleukin 12 on in vitro HIV type 1 replication depends on clinical stage. 874 76

We investigated cytokine production and accessory cell function in human macrophage hybridoma cell lines and primary monocytes after infection with HIV-1. HIV-1 infection induced IL-10 production in the macrophage hybridoma cell line with loss of IL-12 1 wk after infection. There were also significant increases in production of IL-10 (537 +/- 521 vs 687 +/- 625 pg/ml) while there was a reduction in IL-12 (6.3 +/- 3.1 vs 1.2 +/- 1.0 pg/ml, p = 0.021) in the primary monocytes 5 days after HIV-1 infection. In addition, the hybridoma cell lines and primary monocytes failed to support PHA, Con A, PWM, or anti-CD3- induced T cell proliferation 1 wk after infection. The viability of the T cells cocultured with the HIV-1-infected macrophage cell lines or the primary monocytes as determined by propidium iodide staining was unaltered and there was no increase in apoptosis-specific DNA strand breaks or increased expression of Bcl-2 in the T cells. No soluble suppressor factor was present, since UV-inactivated supernatants from the hybridoma cell line and primary monocytes failed to inhibit mitogen- and anti-CD3-induced T cell proliferation. Early events in T cell activation, including calcium flux and phosphotyrosine kinase activity, were intact in the T cells cocultured with the HIV-1- infected hybridomas and monocytes but there was reduced IL-2 production. Addition of exogenous IL-2 restored the proliferative responses. Taken together, these data suggest that alteration of cytokine production and accessory cell function for mitogens and anti-CD3-induced T cell proliferation independent of induction of apoptosis, suppressor factor production, or inhibition of T cell signaling occurs very early after HIV-1 infection and may contribute to the global immunosuppression observed in AIDS.
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PMID:Altered cytokine production and accessory cell function after HIV-1 infection. 875 40

The effects of recombinant gp120 on the proliferative responses and cytokine production by normal peripheral blood mononuclear cells (PBMC) were investigated. gp120 inhibited in a dose-dependent fashion the anti-CD3 monoclonal antibody (MAb)- and concanavalin A-induced proliferative responses. The production of interleukin-2 (IL-2) and IL-4 was diminished by gp120 in the anti-CD3- and concanavalin A-stimulated cultures. In unstimulated PBMC, gp120 induced the production of considerable amounts of IL-10, gamma interferon, and tumor necrosis factor alpha. The gp120-induced reduction in the proliferative responses of PBMC was at least partially reversed by the addition of IL-2, anti-CD28 MAb, or transfectants expressing CD80, CD86, or CD40 but not with exogenous IL-4. Also, a neutralizing anti-IL-10 MAb reversed the inhibitory effect of gp120 on the proliferative responses whereas exogenous IL-10 further enhanced this inhibitory effect. These findings indicate that IL-10 plays an important role in the inhibitory effect of gp120 on PBMC proliferation. The ratio of CD3+CD4+ to CD3+CD8+ T cells was the same in gp120-treated and untreated cell cultures. No apoptosis in these two T-cell populations was observed. However, the number of activated CD3+CD4+ T cells and CD3+CD8+ T cells, as judged by CD25, CD69, and HLA-DR expression, was consistently reduced. gp120 induced the expression of IL-10 in the monocyte/macrophage population, and therefore gp120 also reduced the proliferative responses of CD4+ T-cell-depleted PBMC. Taken together, our observations point to the importance of the cytokine pattern changes and, in particular, the role of IL-10 (produced by the monocytes) in the inhibitory effect of gp120. This mechanism of gp120-induced immunosuppression, if operative in vivo, could contribute to the depressed immune responses associated with human immunodeficiency virus infection and thus have important implications for immunotherapeutic strategies to slow down disease progression in AIDS.
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PMID:Human immunodeficiency virus type 1 gp120 induces anergy in human peripheral blood lymphocytes by inducing interleukin-10 production. 876

Spleen cells from mice resistant or sensitive to mouse acquired immune deficiency syndrome (MAIDS) were examined for cytokine mRNA. In MAIDS-resistant BALB/c mice, cytokine transcripts peaked at 1 week after infection with Type 1 cytokines [interleukin-2 (IL-2), tumour necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), IL-12], dominating over Type 2 cytokines (IL-4, IL-10). Expression of cytokines other than IL-2 later declined to levels seen in uninfected mice. In MAIDS-sensitive B6 mice, transcripts for all cytokines were increased at 1 week and, except for IL-2, increased progressively. Spontaneous production of IFN-gamma protein was associated with enhanced mRNA expression at 1 week after infection of either strain, but none was detectable in association with even higher levels of transcripts at later times after infection of B6 mice. Spleen cells from longer-term-infected B6 mice, however, produced substantial amounts of IFN-gamma following treatment with lipopolysaccharide (LPS) or IL-12. Inclusion of anti-IL-12 or anti-TNF-alpha antibodies blocked induction of IFN-gamma by LPS. Induction of IFN-gamma by IL-12 was potentiated by TNF-alpha following stimulation of intact spleen cells and purified CD4+ or CD8+ T cells, as well as negatively selected CD4-8- cells from infected B6 mice. Further studies showed that IFN-gamma knockout mice on a B6 background developed MAIDS with a prolonged time-course, whereas BALB/c knockout mice were unchanged in their resistance to MAIDS. These studies suggest that continuing low-level expression of IFN-gamma, stimulated by IL-12 and TNF-alpha, contributes to the susceptibility of B6 mice to MAIDS but is not required for the resistance of BALB/c mice to disease.
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PMID:Retrovirus-elicited interleukin-12 and tumour necrosis factor-alpha as inducers of interferon-gamma-mediated pathology in mouse AIDS. 877 35


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