Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0085110 (SCID)
 11,041 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Interleukin-12 (IL-12) is important in the regulation of resistance to Toxoplasma gondii in mice with severe combined immunodeficiency (SCID). The protective ability of IL-12 in SCID mice appears to be through its activity on natural killer (NK) cells to induce production of interferon-gamma (IFN-gamma). In this study we assessed the role of IL-12 in the acute stage of toxoplasmosis in immunocompetent mice. Administration of IL-12 to BALB/c mice infected with the virulent C56 strain of T. gondii remarkably delayed time to death. The protective activity of IL-12 was abrogated by administration of monoclonal antibodies to IFN-gamma or tumour necrosis factor-alpha (TNF-alpha), and by depletion of NK cells using an antisera against asialoGM1. Whereas BALB/c mice infected with the ME49 strain of T. gondii survived infection, administration of anti-IL-12 to infected mice resulted in 100% mortality accompanied by decreased serum levels of IFN-gamma. Furthermore, this treatment significantly reversed the suppression of spleen cell proliferation to concanavalin A (Con A), which is associated with the acute stage of infection, and resulted in decreased ex vivo production of IFN-gamma, IL-2, IL-4 and IL-10 in response to Con A. Our results indicate an important role for IL-12 in mediating resistance to T. gondii during acute infection in immunocompetent mice, that NK cells are required for this protective activity, and that IL-12 is involved in the immunosuppression which accompanies this infection.
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PMID:Studies on the role of interleukin-12 in acute murine toxoplasmosis. 789 Mar

We have studied the peripheral T cell repertoire of two patients with severe combined immunodeficiency who were successfully treated with human histocompatibility leukocyte antigen (HLA)-mismatched fetal liver stem cell transplantation. The patients presented a split chimerism. T cells were of donor origin, whereas the B cells/monocytes were of the host phenotype. Interestingly, the natural killer (NK) cells in one patient were donor derived and in the other patient of host origin. The NK cells were functional but did not have antihost or donor reactivity. Despite the HLA mismatch between donor and host cells, complete tolerance was achieved in vivo, and a specific unresponsiveness of peripheral blood mononuclear cells from both patients toward the host cells was demonstrated in vitro. Nevertheless, we could isolate T cell receptor (TCR)alpha beta, CD4+ or CD8+, T cell clones specifically reacting with HLA class I and II molecules of the host. The CD4+ host-reactive T cell clones from both patients produced interleukins 2 and 5, interferon-gamma, granulocyte/macrophage colony-stimulating factor but are specifically defective in interleukin 4 production. The frequencies of CD8+ host-reactive T cells were high, and were in the same range as those observed for CD8+ alloreactive T cells. In contrast, no donor-reactive CD8+ T cells or host or donor-reactive TCR gamma delta + T cells were detected. These data indicate that, after fetal stem cell transplantation, donor-reactive, but not host-reactive cells, are deleted from the T cell repertoire. Therefore, a peripheral mechanism of suppression or clonal anergy, rather than clonal deletion, is involved in maintaining in vivo tolerance toward the host.
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PMID:Chimerism and tolerance to host and donor in severe combined immunodeficiencies transplanted with fetal liver stem cells. 845 37

In order to investigate activation of the innate immune system in murine toxoplasmosis, T- and B-cell-deficient SCID mice and their co-isogenic immunocompetent C.B-17 counterparts were orally infected with a low-virulent strain of Toxoplasma gondii (DX strain). SCID mice developed a fatal necrotizing toxoplasmosis, whereas CD4+ and CD8+ T cells contributing to inflammatory infiltrates conferred resistance to immunocompetent mice. Significant amounts of interferon-gamma (IFN-gamma) were detectable in SCID mice. The most likely source for this cytokine is activated natural killer (NK) cells. In comparison to immunocompetent mice IFN-gamma levels were reduced in cerebrospinal fluid (CSF) and serum of SCID mice at days 7 and 14 of disease. Similar amounts of tumour necrosis factor (TNF) were detected in both strains of mice. In addition, immunohistochemistry showed major histocompatibility complex (MHC) class II antigen expression on SCID and C.B-17 microglial cells and macrophages demonstrating activation of these cells in both strains. However, the up-regulation of MHC class II antigen on microglia was less pronounced in SCID mice, presumably due to reduced levels of IFN-gamma. Interleukin-6 (IL-6) levels in CSF and serum were elevated in both strains and correlated with systemic and intracerebral disease activity. In conclusion, our results demonstrate activation of macrophages and NK cells as the predominant defence mechanisms of the comprised SCID immune system during toxoplasma infection. This implies a major role for the innate immune system during early stages of toxoplasmosis although T cells are necessary to control the infection efficiently.
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PMID:Expression of major histocompatibility complex class II antigens and levels of interferon-gamma, tumour necrosis factor, and interleukin-6 in cerebrospinal fluid and serum in Toxoplasma gondii-infected SCID and immunocompetent C.B-17 mice. 847 25

T cell-derived lymphokines mediate or modulate various aspects of the immune response and immunodeficiency states related to abnormalities in lymphokine production or regulation are now being recognized. One example of this is seen in the fetus and neonate, in whom a physiologic immunodeficiency appears to reflect in part deficient production of certain lymphokines, including interferon-gamma, IL-4, and IL-5. The deficiency in production of these lymphokines appears to reflect to a large extent the paucity of memory T cells during these periods of life. Diminished lymphokine production has also recently been implicated as the cause for three cases of primary severe combined immunodeficiency. In disorders associated with excess IgE production, including allergy, hyper IgE syndrome, and Omenn's syndrome, excess IL-4 production relative to the production of interferon-gamma may play a contributory role. Regulation of the production of these and other T cell-derived lymphokines appears to be affected predominantly by control of lymphokine gene transcription, the basis for which is just now becoming understood at a molecular level. The elucidation of these regulatory mechanisms offers the promise for understanding the basis for disordered lymphokine production in immunodeficiency states.
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PMID:Lymphokine regulation and the role of abnormal regulation in immunodeficiency. 850 Feb 78

Peripheral blood lymphocytes (PBL) and alloreactive T cell lines of two male infants born to consanguinous parents and presenting with severe combined immunodeficiency (SCID) showed a pronounced deficiency in T cell activation. Although phenotypically normal, the proliferative response of the childrens' T cells was strongly reduced but could be improved by the addition of interleukin-2 (IL-2). Furthermore both childrens' T cells were unable to produce the cytokines IL-2, interferon-gamma (IFN-gamma), IL-4 and tumor necrosis factor-alpha (TNF-alpha). This multiple cytokine production deficiency could not be restored by IL-2 or co-stimulatory signals provided by antigen-presenting cells (APC). Moreover, mRNA for IL-2 and IFN-gamma could not be detected. In contrast, expression of the activation-dependent cell surface markers CD25 and CD69 was within normal limits. To determine whether the functional defect of the patients' T cells was due to the absence or abnormal binding of transcription factors involved in cytokine gene expression, electrophoretic mobility shift assays were used to examine the DNA binding of AP-1, Oct, CREB, SP1, NF-kappa B and the nuclear factor of activated T cells (NF-AT) to their respective response elements in the promoter of the IL-2 gene. Whereas AP-1, NF-kappa B, Oct, CREB and SP1 displayed normal binding activities in nuclear extracts, the binding of NF-AT to its IL-2 promoter response element was barely detectable both before and after T cell stimulation. Our results strongly suggest that this NF-AT/DNA binding defect is responsible for the multiple cytokine deficiency and the SCID phenotype observed in the two infant brothers.
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PMID:Severe combined immunodeficiency due to defective binding of the nuclear factor of activated T cells in T lymphocytes of two male siblings. 881 56

The induction of macrophage tumoricidal activity by swainsonine (8a beta-indolizidine-1 alpha, 2 alpha, 8 beta-triol), an indolizidine alkaloid, has been implicated as possibly an important immune effector mechanism involved in the suppression of tumor growth and metastasis in vital organs such as the lung, liver and spleen (Olden, K. et al. The potential importance of swainsonine in therapy for cancers and immunology. Pharmacol. Ther. 50:285-290; 1991). The present study further explores this possibility by determining whether resident tissue-specific macrophages of several mouse strains can be rendered tumoricidal by systemic administration of swainsonine. We found that systemically administered swainsonine could increase the tumoricidal activity of both alveolar (lung) and splenic macrophages. The activity was enhanced as much as 3- to 4-fold over that obtained with macrophages from organs of control animals and was both dose- and time-dependent. The level and extent of activation by swainsonine was comparable to that achieved with traditional macrophage-activating agents, such as lipopolysaccharide and interferon-gamma. The fact that swainsonine activated highly purified (> 95%) cultures of macrophages from the various sources suggests a direct mechanism of activation. Furthermore, the in vivo activation of macrophages in immune-compromised animals (SCID and nude) lends credence to this suggestion. These findings provide a plausible explanation for the observations that systemically administered swainsonine inhibits organ colonization of metastatic cells and growth of SC tumor xenografts, whereas the growth of tumor cells is not inhibited by swainsonine in culture.
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PMID:Activation of resident tissue-specific macrophages by swainsonine. 883 86

The effects Lactobacillus casei YIT9108 (LC 9018) on antitumor activity and cytokine production in Meth A fibrosarcoma (Meth A)-bearing BALB/c mice were examined. Intrapleural (i.pl.) administration of LC 9018 was effective in prolonging the survival of Meth A-bearing mice, and frequently cured mice of the tumor. However, the results also indicated that the effect of LC 9018 was in part inhibited in mice treated with anti-CD3 or anti-CD8 antibody, but not affected in anti-CD4 antibody-treated mice. In contrast, LC 9018 had little effect on Meth A-bearing SCID or nude mice. These results demonstrated that CD8+ T cells participated in prolonging the survival of Meth A-bearing mice. Moreover, the examination of the production of several cytokines revealed that the production of interferon-gamma and interleukin-6 was, in particular, augmented in the exudated fluid of the thoracic cavity in BALB/c mice injected with LC 9018 i.pl. These results suggested that i.pl. administration of LC 9018 induced those cytokines which had the potential to activate the thoracic macrophages or proliferate the thoracic lymphocytes to the cytotoxic T cells. Taken together, these findings demonstrated that the prolonging effects on survival by i.pl. administration of LC 9018 depended on CD8+ T cells, and the i.pl. administration of LC 9018 into i.pl. Meth A-bearing mice induced several cytokines which participated in the subsequent immunoresponses.
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PMID:Effects on antitumor activity and cytokine production in the thoracic cavity by intrapleural administration of Lactobacillus casei in tumor-bearing mice. 900 21

Cells of the central nervous system (CNS) normally do not express detectable levels of major histocompatibility complex (MHC) Class I antigens. However, MHC Class I expression can be induced after virus infection. We tested the hypothesis that virus-induced Class I expression is mediated by lymphocytes or cytokines using lymphocyte- and cytokine-deficient mice. We used Theiler's murine encephalomyelitis virus (TMEV), which induces CNS demyelination that maps genetically to the D region of MHC Class I and is associated with high levels of Class I products. TMEV infection of severe combined immunodeficiency (SCID) and recombination activation gene-1-deficient mice, which lack B and T lymphocytes, resulted in equivalent H-2D and H-2K expression in brain and spinal cord, according to analysis of the area and intensity of immunoperoxidase staining. Class I antigens were demonstrated as early as 6 hours after infection, and they were more widely distributed than viral RNA, indicating that expression was induced indirectly via a soluble factor. To determine whether cytokines induced the expression, we infected mice lacking receptors for interferon-alpha/beta (IFN-alpha/beta R (-/-)), interferon-gamma (IFN-gamma R(-/-)), and tumor necrosis factor-alpha (TNFRp55(-/-)). TMEV-infected IFN-gamma R(-/-) and TN-FRp55(-/-) mice expressed Class I antigens in the CNS, whereas IFN-alpha/beta R(-/-) mice did not, establishing that IFN-alpha/beta mediated the expression. In contrast to the equivalent expression in SCID mice, we observed greater area and higher intensity of H-2D versus H-2K antigens in infected SCID mice reconstituted with normal spleen cells. Collectively, the data indicate that after TMEV infection, early generalized MHC Class I expression is mediated by IFN-alpha/beta independently of lymphocytes, but the differential regulation of H-2D over H-2K may be controlled by B and/or T lymphocytes.
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PMID:Interferon alpha/beta mediates early virus-induced expression of H-2D and H-2K in the central nervous system. 925 80

Electrolyte transport was investigated during chronic cryptosporidiosis in adult anti-interferon-gamma-treated SCID mice by means of Ussing chamber techniques. In basal conditions, infection of immunocompromised mice with Cryptosporidium parvum resulted in a 30% reduction (P < .05) in the ileal short-circuit (Isc) current related to a 28% reduction (P < .05) in tissue conductance compared with controls. The rises in Isc and transepithelial potential difference induced by glucose (10 mM) were significantly reduced by Cryptosporidium infection (P < .01) compared with controls. In contrast, responses to mucosal glutamine were marginally affected. Electrical parameters of the ileum were not affected by the addition of indomethacin or furosemide, in either control or Cryptosporidium-infected mice. Thus, long-term cryptosporidiosis in immunocompromised animals leads to a reduction in net ion exchanges, decreased paracellular shunting, and impaired Na+-glucose cotransport in the ileum, without prostanoid- or enterotoxin-mediated electrogenic Cl- secretion.
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PMID:Cryptosporidiosis-induced impairment of ion transport and Na+-glucose absorption in adult immunocompromised mice. 929 48

We used Mycobacterium avium infection in severe combined immunodeficiency (SCID) mice to examine T-cell-independent mechanisms of inflammatory cell recruitment. SCID mice infected with a virulent strain of M. avium (TMC724) were able to recruit macrophages to sites of mycobacterial replication and formed organized and coherent granulomas in the absence of functional T cells. Phagocyte recruitment was almost totally ablated by neutralization of either tumour necrosis factor-alpha (TNF-alpha) or interferon-gamma (IFN-gamma) in vivo demonstrating that granuloma formation was dependent on the presence of these cytokines. This was concomitant with a reduction in the in situ cytokine mRNA levels otherwise induced in infected mice, for chemokines, pro-inflammatory and regulatory cytokines, including TNF-alpha, IFN-gamma, macrophage inflammatory protein-1 alpha, interleukin-1 beta (IL-1 beta) and IL-10. Furthermore, in vivo treatment of infected mice with anti-asialo GM-1 antisera, which depletes natural killer (NK) cells, prevented recruitment of inflammatory cells. In vitro studies confirmed that M. avium was able to elicit IFN-gamma from SCID spleen in a dose-dependent manner. These data show for the first time that secretion of IFN-gamma from NK cells can mediate a T-cell-independent pathway of granuloma formation and cellular infiltration in response to mycobacteria.
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PMID:T-cell-independent granuloma formation in response to Mycobacterium avium: role of tumour necrosis factor-alpha and interferon-gamma. 949 81


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