Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0021051 (immunodeficiency)
 71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The murine acquired immunodeficiency syndrome (MAIDS) caused by a defective murine leukemia virus produces severe immunodeficiency with abnormal lymphoproliferation and hypergammaglobulinemia. The presence of both CD4+ T cells and B cells is critical for the development of this disease. Remarkably elevated mRNA expression for IFN-gamma and IL-10 was observed in spleen cells of C57BL/6 mice starting from the early phase of viral infection. IFN-gamma production was induced by spleen cells from virus-infected mice upon stimulation with concanavalin A or lipopolysaccharide in both the early and late phases of MAIDS progression. When mice that had been passively administered anti-IFN-gamma mAb were infected with the virus, the development and progression of lymphadenopathy, immunodeficiency and elevated levels of serum IgG2a associated with MAIDS were delayed. Treatment with anti-IL-4 or anti-IL-10 mAb in place of anti-IFN-gamma mAb did not induce the delayed progression of MAIDS. These data support the concept that IFN-gamma-dependent pathway may be involved in the development of MAIDS.
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PMID:An IFN-gamma-dependent pathway plays a critical role in the pathogenesis of murine immunodeficiency syndrome induced by LP-BM5 murine leukemia virus. 769 11

C57BL/6 mice infected with a murine leukemia virus (MuLV) mixture designated LP-BM5 develop an immunodeficiency syndrome termed MAIDS, characterized by a variety of T and B cell abnormalities, including elevated levels of IgE, suggesting that IL-4 expression is increased in these animals. It has been suggested that the immunodeficiency associated with MAIDS is caused by a conversion of immune responses normally characterized by Th1 development towards a Th2-dominated response. Mice of the same strain, infected with Leishmania major, mount a protective Th1 response with the induction of high levels of IFN-gamma and undetectable IL-4. We therefore infected mice with L. major at differing time points before and after virus infection and assessed the effects on T cell responsiveness, cytokine production and survival to L. major, as well as the effect on MAIDS-associated pathology. We have also immunized C57BL/6 mice with trinitrophenol-keyhole limpet haemocyanin (TNP-KLH), which leads to a predominantly Th2 response, and compared the effects of MAIDS on the response to TNP-KLH with the effect of MAIDS on L. major infection. Our results show that significant immunodeficiency with regard to infection by L. major is only apparent after 8 weeks of LP-BM5 MuLV infection, by which time T and B cell defects are well advanced. Further, we have found that the strongly polarized Th1 response stimulated by L. major infection can modulate the effect of MAIDS on T cells, leading to the survival of antigen-specific T cells. Our results suggest that the impairment of immune responses to either TNP-KLH or L. major is due not to an alteration of the balance of Th1/Th2 subsets but to a general loss of reactivity in antigen-specific CD4+ cells. However, prior activation of Th1 but not Th2 cells can inhibit the development of lymphoproliferation and immunodeficiency caused by MAIDS.
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PMID:Modulation of specific T cell responses by concurrent infection with Leishmania major and LP-BM5 murine leukemia viruses. 771 9

A decrease in natural killer (NK) cell function has been related to the progression of human immunodeficiency virus (HIV) infection. In the present study, we assessed the ability of a streptococcus-derived biologic response modifier, OK-432, to augment NK lysis of uninfected K562 and U937 cells and HIV-infected U937 cells by peripheral blood mononuclear cells (PBMC) from HIV-seropositive homosexual men. Optimal two- to fourfold increases in lysis of the three targets were observed after pretreatment of PBMC from HIV-negative subjects for 4 h with 2 micrograms of OK-432 per ml. This effect was related primarily to gamma interferon (IFN-gamma) production induced by OK-432 and was not linked to production of tumor necrosis factors alpha and beta or to monocytes in the cultures. The enhancing effect of OK-432 on NK cell function was diminished but still evident in PBMC from subjects with relatively early-phase (< 3-year) HIV infection and high CD4+ cell counts and was lower in subjects with longer-term HIV infection (> 3 years), in association with reduced production of IFN-gamma. Augmentation of NK cell activity in HIV-infected men by OK-432 was comparable to that induced by treatment of cells with 1,000 U of IFN-alpha or interleukin 2 per ml. The data suggest that the NK cell-enhancing effects of OK-432 are at least in part mediated by IFN-gamma and that OK-432 may be effective in treatment of patients with early-phase HIV infection.
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PMID:Enhancement of natural killer cell activity in human immunodeficiency virus-infected subjects by in vitro treatment with biologic response modifier OK-432. 771 19

Cryptosporidium parvum preparations were studied for their ability to induce specific proliferation of cultured human peripheral blood mononuclear cells (PBMC) from both immunocompetent and human immunodeficiency virus-positive persons, some of whom had transient cryptosporidiosis. The proliferation of PBMC from sensitized donors induced by C. parvum preparations was due mainly to antigen-specific rather than nonspecific activation, as indicated by the kinetics of the proliferative response, inhibition of the PBMC proliferation by a monoclonal antibody directed against major histocompatibility complex class II-specific HLA-DR molecule, and lack of proliferation of umbilical cord blood PBMC. PBMC from immunocompromised patients did not proliferate in response to C. parvum-specific antigens. The supernatants of PBMC obtained from immunocompetent donors contained interleukin-10 and interferon (IFN)-gamma after PBMC were exposed to C. parvum preparations. High IFN-gamma values were found in patients who had recovered from cryptosporidiosis, suggesting that IFN-gamma plays a role in resolving this infection.
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PMID:Crude extract and recombinant protein of Cryptosporidium parvum oocysts induce proliferation of human peripheral blood mononuclear cells in vitro. 779 13

Approximately a third of adults and half of children with acquired immunodeficiency syndrome (AIDS) eventually suffer from neurological manifestations, including dysfunction of cognition, movement, and sensation. Among the various pathologies reported in the brain of patients with AIDS is neuronal injury and loss. A paradox arises, however, because neurons themselves are for all intents and purposes not infected by human immunodeficiency virus type 1 (HIV-1). This paper reviews evidence suggesting that at least part of the neuronal injury observed in the brain of AIDS patients is related to excessive influx of Ca2+. There is growing support for the existence of HIV- or immune-related toxins that lead indirectly to the injury or death of neurons via a potentially complex web of interactions between macrophages (or microglia), astrocytes, and neurons. Human immunodeficiency virus-infected monocytoid cells (macrophages, microglia, or monocytes), especially after interacting with astrocytes, secrete substances that potentially contribute to neurotoxicity. Not all of these substances are yet known, but they may include eicosanoids, that is, arachidonic acid and its metabolites, as well as platelet-activating factor. Macrophages activated by HIV-1 envelope protein gp120 also appear to release arachidonic acid and its metabolites. These factors can lead to increased glutamate release or decreased glutamate reuptake. In addition, gamma interferon (IFN-gamma) stimulation of macrophages induce release of the glutamate-like agonist quinolinate. Human immunodeficiency virus-infected or gp120-stimulated macrophages also produce cytokines, including tumor necrosis factor-alpha and interleukin-1 beta, which contribute to astrogliosis. A final common pathway for neuronal susceptibility appears to be operative, similar to that observed in stroke, trauma, epilepsy, neuropathic pain, and several neurodegenerative diseases, possibly including Huntington's disease, Parkinson's disease, and amyotrophic lateral sclerosis. This mechanism involves the activation of voltage-dependent Ca2+ channels and N-methyl-D-aspartate (NMDA) receptor-operated channels, and therefore offers hope for future pharmacological intervention. This review focuses on clinically tolerated calcium channel antagonists and NMDA antagonists with the potential for trials in humans with AIDS dementia in the near future.
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PMID:AIDS-related dementia and calcium homeostasis. 784 72

Patients with common variable immunodeficiency (CVID) are heterogeneous in the clinical manifestation of the disease as well as in the underlying mechanisms leading to the immunodeficiency. In a previous study we identified a subgroup of patients with a primary immunodeficiency disease affecting IL-2 and IFN-gamma gene expression. The T cells of these patients revealed impaired proliferative response and reduced levels of IL-2 and IFN-gamma-specific mRNA after antigen stimulation in vitro, while cellular and molecular response to phorbol ester and the calcium ionophore ionomycin (PMA+IM) or anti-CD3 monoclonal antibodies (MoAbs) (OKT3) were comparable to those of healthy control individuals. Here we show that stimulation of these patients' T cells with tetanus toxoid (TT) resulted in dramatically reduced levels of IL-2, IL-9 and IFN-gamma mRNA, while IL-3 gene expression in three patients was comparable or even increased to the healthy controls. As expected, addition of exogenous IL-2 to tetanus toxoid pulsed cultures had virtually no effect on IL-2 transcription, but corrected the defect in IL-9 gene expression, while IFN-gamma mRNA levels were still reduced. In conclusion, these data suggest that recombinant IL-2 alone is not able to induce the IL-9 gene adequately in our patients, but clearly increases IL-9 mRNA levels in combination with tetanus toxoid.
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PMID:Reduced IL-2 expression upon antigen stimulation is accompanied by deficient IL-9 gene expression in T cells of patients with CVID. 787 81

Interleukin-12 (IL-12) is a disulfide-linked heterodimeric cytokine originally identified as a product of EBV-transformed B cell lines. Monocyte/macrophages are the physiologically most relevant producers of IL-12, in response to both Gram-positive and -negative bacteria, bacterial products, and intracellular parasites. Although IL-12 has an enhancing effect on the survival and growth of early hematopoietic progenitor cells, most of the IL-12 biological activity has been described on T and NK cells, on which it induces production of lymphokines, primarily IFN-gamma, enhances cytotoxic activity, and, in cooperation with other stimuli, increases proliferation. IL-12 is an inducer of development of T helper type 1 (Th-1) cells and the equilibrium between IL-12 and IL-4 is probably important for the balance in vivo between Th-1 and Th-2 responses. IL-12 has an important role in the host resistance to infection, in particular to intracellular pathogens, by activating macrophages through induction of IFN-gamma from NK and T cells and by enhancing cell-mediated immune responses, dependent on Th-1 cell development. Peripheral blood mononuclear cells from HIV-seropositive individuals are impaired in their ability to produce IL-12 in response to bacterial stimulation, and IL-12 restores in vitro some of the depressed immunological functions, suggesting that a defect in IL-12 production may have a pathogenic role in the immunodeficiency of HIV-infected individuals. Natural IL-12 appears to provide a regulatory link between innate resistance and the development of the antigen-specific adaptive immune response and the recombinant protein has therapeutic potential because of its activity against tumors and infections and its effectiveness as an adjuvant enhancing cell-mediated immunity in vaccination.
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PMID:Interleukin-12: a bridge between innate resistance and adaptive immunity with a role in infection and acquired immunodeficiency. 792 92

Infection of macrophages (M phi) in vitro with M phi-tropic isolates of simian immunodeficiency virus (SIV) did not affect killing of Cryptococcus neoformans up to 16 days after inoculation (p < 0.05). Conversely, alveolar M phi from animals with SIV-induced AIDS killed C. neoformans less efficiently (10.4 +/- 2.8% killing) and, when stimulated with phorbol myristate, produced less superoxide anion (O2-; 0.15 +/- 0.02 O2-/h/mg M phi protein) than M phi from uninfected monkeys (21.8 +/- 1.6% killing and 0.29 +/- 0.02 O2-/h/mg M phi protein). In contrast, killing and O2- release were accentuated in SIV+ asymptomatic animals (25.8 +/- 2.3% killing and 0.40 +/- 0.04 O2-/h/mg M phi protein; p < 0.05). M phi-mediated killing and O2- production could be restored by culturing the affected cells in supernatants derived from Con A-stimulated PBMC of uninfected or SIV+ asymptomatic monkeys. Supernatants with restorative properties had high IFN-gamma bioactivity (63.4 +/- 11.0 U/ml) and elevated IL-10 concentrations (75.3 +/- 10.4 pg/ml) as compared with PBMC supernatants derived from animals with AIDS (IFN-gamma, 9.7 +/- 4.9 U/ml; IL-10, 24.0 +/- 10.1 pg/ml). Functional restoration was found to be dependent, in part, on the presence of IFN-gamma, as neutralizing Abs to IFN-gamma significantly inhibited functional restoration in active supernatants. Moreover, the inactivity of supernatants from mitogen-stimulated PBMC cultures derived from animals with AIDS was not solely dependent upon the loss of CD4+ lymphocytes, inasmuch as purified pulmonary alveolar and peripheral blood CD4+ T cells from only uninfected and SIV+ asymptomatic animals, and not those from animals with AIDS, produced IFN-gamma upon mitogen stimulation. Collectively, these findings suggest that functional aberrations in alveolar M phi from animals with AIDS are not directly due to virus infection but likely result from changes in the pulmonary microenvironment in association with the multisystemic loss and dysfunction of CD4+ T cells.
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PMID:Macrophage function in simian AIDS. Killing defects in vivo are independent of macrophage infection, associated with alterations in Th phenotype, and reversible with IFN-gamma. 798 75

In addition to the loss of CD4+ T cells in later stages of human immunodeficiency virus (HIV) infection, functional defects of Th cells can already be observed in early infection. Decreased interleukin (IL)-2 and interferon (IFN)-gamma production by CD4+ T cells and diminished delayed type hypersensitivity reactions are indicative for impaired Th1 responses. We studied the cytokine secretion patterns of T-cell clones (TCC) generated by mitogenic stimulation of CD4+ memory T cells. Compared with TCC from HIV-negative controls, TCC isolated from HIV-infected individuals consistently showed increased IL-4 production, often paralleled by increased IL-5 and decreased IFN-gamma production. This resulted in a decreased percentage of Th1 clones with an increase in Th0 clones. To rule out the influence of interindividual differences, we studied two individuals from whom cells were available before and after infection with HIV. Indeed, an increase in Th2 cytokine secretion was observed after HIV-infection. Loss of Th1 and enhanced Th2 responses might further curtail cellular responses resulting in deficiency of cellular immunity in HIV infection.
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PMID:Changes in cytokine secretion patterns of CD4+ T-cell clones in human immunodeficiency virus infection. 799 41

Monocytes treated with 500 IU/ml human recombinant interferon-gamma (rIFN-gamma) 1 day before and continuously after human immunodeficiency virus (HIV) infection showed no evidence of virus replication 7 days after addition of the viral inoculum. There was no HIV-associated cytopathic effect, no reverse transcriptase (RT) activity or p24 detected in culture fluids, and no HIV RNA or DNA in cell lysates. Furthermore, no evidence of HIV infection was evident in replicate cultures in which all IFN-gamma was removed at 7 days and the cells were cultured for an additional 3 weeks without IFN-gamma. The 50% inhibitory dose for reduction of maximum RT activity in HIV-infected monocyte cultures was about 1 IU/ml IFN-gamma. No increase in HIV replication was evident in monocytes treated with IFN-gamma at any concentration (0 to 5000 IU/ml) or at any time (7 days before to 10 days after HIV infection). In side-by-side experiments with identical monocytes and HIV-1 stock, rIFN-gamma was 10 to 20 times more effective than rIFN-alpha 2b for induction of antiviral activity. With both interferons, significant antiviral activity was evident with monocytes treated 1 day before, at the time of, or up to 3 days after infection. At 7 to 10 days after infection (a time at which less than 20% of total cells were infected with HIV) addition of even high concentrations of IFN-alpha or IFN-gamma had no effect on virus replication. These data suggest that the principal action of IFN-alpha and IFN-gamma was directed against the fluid-phase virus. Cell-cell spread of infection within the HIV-infected monocyte culture and extent of virus replication in HIV-infected cells were not affected by interferon treatment.
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PMID:Interferon-gamma protects primary monocytes against infection with human immunodeficiency virus type 1. 808 9


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