Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0153470 (Spleen)
 4,015 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We previously reported that streptococcal preparation (OK-432), which is a TNF inducer, inhibits insulitis and development of autoimmune diabetes in nonobese diabetic (NOD) mice and Bio-Breeding (BB) rats, as animal models of insulin-dependent diabetes mellitus. We have recently shown that recombinant human (h)TNF-alpha also suppresses development of diabetes in NOD mice. In this study we have extended our observation on TNF to BB rats in order to see whether TNF generally inhibits autoimmune diabetes. A total of 5 x 10(4) U of rhTNF-alpha was administered i.p., twice a week to male and female BB rats from 4 to 27 wk of age. The cumulative incidence of diabetes by 27 wk of age in nontreated rats was 36.4% (8/22), whereas that in hTNF-alpha-treated rats was 0% (0/21) (p less than 0.001). The hTNF-alpha-treated rats did not lose body weight and maintained normal blood glucose concentrations. Immunologic and histologic examinations were performed at the end of the experiment. Spleen cell cytotoxicities for NK-sensitive YAC-1 and rat insulinoma (RINm5F) cells in hTNF-alpha-treated rats significantly decreased in comparison with nontreated and nondiabetic BB rats. Intensity of insulitis was also inhibited in hTNF-alpha-treated rats. Interestingly, a huge hepatomegaly and splenomegaly was found in two of the 21 hTNF-alpha-treated rats. The latter consisted of W3/13dull+ and W3/25dull+ cells, which did not exhibit cytotoxicity for either YAC-1 or RINm5F cells. These results indicate that the chronic and systemic administration of TNF has a regulatory role in autoimmune diabetes in BB rats as well as in NOD mice, and that these animals may have a defect in TNF-mediated immunoregulation.
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PMID:Inhibition of type 1 diabetes in BB rats with recombinant human tumor necrosis factor-alpha. 238 63

We analyzed the T cell-independent production of IFN-gamma in the severe combined immunodeficiency (scid) mutant mouse. Spleen cells from scid mice secreted high levels of IFN-gamma in response to heat-killed Listeria monocytogenes (HKLM), but not to the T cell stimulus ConA. This response was ablated by prior removal of adherent macrophages. IFN-gamma secretion in vitro was preceded by the rapid production of TNF and was inhibited by addition of neutralizing mAb to TNF. Moreover, injection of scid mice with anti-TNF mAb increased the severity of infection with live Listeria and inhibited macrophage activation for class II-MHC expression. Finally, IFN-gamma secretion and class II-MHC expression were also inhibited by an antibody to asialoGM1, a reagent known to impair host NK cell function. These results suggest that TNF is a critical cytokine in the T cell-independent pathway of macrophage activation in scid mice.
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PMID:Tumor necrosis factor is involved in the T cell-independent pathway of macrophage activation in scid mice. 249 25

In order to clarify the effect of recombinant human tumor necrosis factor (rHu-TNF) on the antitumor T cell immune response, we examined the effect of rHu-TNF on the generation of cytotoxic T cells (CTL) against syngeneic tumor cells. Spleen cells from X5563 plasmacytoma-transplanted mice were stimulated in vitro with mitomycin C-treated X5563 cells in the presence or absence of rHu-TNF. The generation of CTL was augmented in a dose-dependent manner by the addition of rHu-TNF. The augmenting effect of rHu-TNF was more marked when indomethacin was added to the culture. The augmenting effect was observed only when rHu-TNF was added at the early stage of the generation of CTL. The cell surface phenotype of CTL generated was L3T4- and Lyt2+. The augmentation was shown not only by the chromium-51 release assay but also by the Winn assay. As to the specificity, the augmentation of CTL generation was observed by the addition of rHu-TNF when responder-primed spleen cells were stimulated with the tumor cells in vitro. On the other hand, augmentation was not observed when responder spleen cells were not stimulated with the tumor cells in vitro, or when responder spleen cells were obtained from normal mice. The CTL generated was not cytotoxic against other tumor cells of the same haplotype. Thus, rHu-TNF augmented the generation of CTL against syngeneic tumor cells in an antigen-specific manner. The in vivo effect of rHu-TNF was examined by administering rHu-TNF into X5563-bearing mice. The spleen cells of rHu-TNF-injected mice generated a much higher CTL activity against X5563 cells in vitro than did the spleen cells of uninjected mice. From these results, a possibility can be considered that in some cases, rHu-TNF may exert its antitumor activity by stimulating the immune system.
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PMID:Augmentation of the generation of cytotoxic T lymphocytes against syngeneic tumor cells by recombinant human tumor necrosis factor. 264 56

1. Sub-lethal doses of recombinant of tumour necrosis factor alpha (TNF alpha) were administered i.v. to young conscious male Wistar rats. Temperature changes and alterations in serum zinc and albumin concentrations and weight and composition of liver, kidney, spleen, tibialis muscle and skin were measured. Temperatures were monitored for 8 h and tissue parameters 8 and 22 h post-injection. 2. Doses above 10 micrograms/kg caused fevers of increasing magnitude and duration with latencies of 2 h. At doses of 200 micrograms/kg or more fevers were preceded by a fall in rectal temperature of up to 1.1 degrees C. 3. Weight loss by skin and tibialis and gain by liver occurred 22 h post-injection. Spleen and kidney weight and zinc and spleen protein contents were unaffected. Serum albumin and zinc fell 22 and 8 h after injection respectively. Liver zinc was elevated at both times and inversely correlated at 8 h with serum values. A degree of dose dependence of zinc and albumin changes existed. A gain in protein was evident in liver 8 h post-injection and a loss by muscle at 22 h. Paradoxical effects were observed in skin protein concentration. 4. TNF alpha mimicked many of the metabolic effects of E. coli endotoxin reported in the literature and showed similar effects to those described for interleukin 1 (IL1).
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PMID:Temperature and metabolic changes in rats after various doses of tumour necrosis factor alpha. 279 83

Mice infected with the protozoan parasite Trypanosoma cruzi are primed for the production of tumour necrosis factor/cachectin. Active infection is not required for stimulation of TNF production as formalin-fixed, but not heat-killed, parasites can act as a priming stimulus. Both epimastigote and trypomastigote stages of the parasite can prime for TNF production but on a per cell basis, trypomastigotes are more potent stimulators than epimastigotes and live parasites prime more efficiently than killed preparations. Although the priming effect of epimastigotes and trypomastigotes is dose-dependent when assayed 10 days after parasite injection, parasitemia levels in the infected mice do not correlate with the level of TNF production. Spleen cells from infected mice are also primed for the production in vitro of TNF in response to LPS or T. cruzi. These results suggest that TNF may be constitutively produced in vivo and that the priming for TNF production, or the production itself, may be regulated during the course of the infection in mice.
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PMID:Tumour necrosis factor (cachectin) production during experimental Chagas' disease. 314 Oct 92

Guanine ribonucleosides with single substitutions at the C8 position (monosubstituted) or with dual substitutions at the C8 and N7 positions (disubstituted) up-regulate a spectrum of immunologic responses, including cytolytic responses to tumor cells. The current studies were undertaken to determine the effects of dual substitution on a number of nucleoside-inducible immunological parameters. To do so, two monosubstituted analogues, 8-bromoguanosine and 8-mercaptoguanosine, were directly compared with two disubstituted analogues, 7-methyl-8-oxoguanosine and 7-allyl-8-oxoguanosine (loxoribine). All of the compounds enhance natural killer (NK) activity, lymphocyte proliferation, and antibody production in dose-dependent fashion. However, the potency and maximal activity of the disubstituted analogues are considerably greater than those of the monosubstituted analogues. Spleen cells stimulated for 48 h with the disubstituted compounds produce immunoreactive interleukin (IL) 1 alpha, IL-6, tumor necrosis factor-alpha (TNF alpha), and interferon-gamma (IFN gamma). Monosubstituted analogues induce lower quantities of IL-6, TNF alpha, and IFN gamma and fail to induce detectable levels of IL-1 alpha. Total IFN activity, assessed by viral inhibition assay, is also lower for the monosubstituted analogues. Augmentation of antibody secretion by B cells is diminished for neither mono- nor disubstituted compounds upon incubation with anti-cytokine antibodies. In contrast, anti-IFN alpha beta markedly reduces the effects of monosubstituted analogues on NK activity but has less marked effects on NK induction by the disubstituted compounds. A similar pattern of differences is seen for lymphocyte proliferation. Thus, although the analogues induce synthesis of several cytokines, to date only IFN alpha beta appears directly involved in enhancement of NK activity and lymphocyte proliferation. The present data do not, however, exclude the existence of an autocrine stimulatory mechanism not susceptible to inhibition by anti-cytokine antibodies.
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PMID:Enhancement of immunostimulatory activity by dual substitution of C8-substituted guanine ribonucleosides: correlation with increased cytokine secretion. 764 61

Spleen cells from BALB/c mice bearing a syngeneic tumor (CSA1 M) 2 to 3 wk after inoculation with CSA1 M cells produced IL-2, IFN-gamma, and TNF upon in vitro cultures. This was previously demonstrated to be a result of collaboration between tumor-primed CD4+ T cells and APCs binding CSA1 M tumor Ags in vivo. The IL-2- and IFN-gamma-producing capacities decreased with the progress of tumor-bearing stages. This was parallel to the levels of IL-2 and IFN-gamma mRNAs expressed by cultured spleen cells. In contrast, comparable levels of TNF mRNA were expressed by all groups of cultured cells. However, large amounts of TNF were secreted by the cells from early but not from late tumor-bearing mice. TNF was produced mainly by the non-T cell fraction upon stimulation with CD4+ T cell-derived IFN-gamma. Therefore, the reduced TNF production by whole spleen cells from late tumor-bearing mice was restored by addition of rIFN-gamma to their cultures. Reciprocally to the progressive decrease in the production of IFN-gamma/TNF, the capacities of tumor-bearing mice to produce TGF-beta and IL-6 increased along with tumor growth. TGF-beta suppressed production of IL-2, IFN-gamma, and TNF, but not of IL-6. Moreover, IFN-gamma/TNF production was negatively regulated by IL-6. Taken together with the fact that the growth of CSA1 M cells is completely inhibited by the combination of TNF and IFN-gamma, these results demonstrate that the tumor-bearing state induces an abnormal cytokine network under which the production of antitumor cytokines is negatively regulated.
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PMID:Regulatory mechanisms for production of IFN-gamma and TNF by antitumor T cells or macrophages in the tumor-bearing state. 786

Treatment of B16 melanoma-bearing mice with recombinant tumour necrosis factor (rTNF) caused a marked inhibition of tumour growth but did not result in the complete cure of the tumour-bearing mice. In contrast, combination therapy of B16-bearing mice with r-TNF and recombinant interleukin 2 (rIL-2) potentiated the therapeutic effect of rTNF and 30% of the mice were totally cured from tumour. Spleen cells obtained from B16-bearing mice showed markedly decreased immune responses including IL-2 production, IL-2 responsiveness and mixed lymphocyte reaction owing to the existence of suppressor macrophages. However, spleen cells obtained from mice cured with rTNF plus rIL-2 showed the same level of T cell responsiveness as that from normal mice. The decreased induction of alloantigen-specific cytotoxic T lymphocytes (CTL) in B16-bearing mice was also recovered after treatment with rTNF plus rIL-2. Moreover, B16-specific CTL, which could not be induced in normal or B16-bearing mice, was effectively induced from the spleen cells of B16-cured mice by rTNF and rIL-2. These results demonstrated that local therapy of melanoma with rTNF and rIL-2 was effective and induced systemic antitumour immunity in vivo.
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PMID:Potentiation of therapeutic effect of recombinant tumor necrosis factor against B16 mouse melanoma by combination with recombinant interleukin 2. 821 34

129/Sv mice are resistant to induction of experimental autoimmune encephalomyelitis (EAE) induced with myelin oligodendrocyte glycoprotein peptide (MOG35-55). Mice of this strain lacking the gene coding for the ligand-binding chain of the IFN-gamma receptor develop EAE with high morbidity and mortality. Spleen cells from sensitized IFN-gammaR-/- mice proliferated extensively when stimulated with MOG peptide in culture and produced high levels of IFN-gamma and TNF but no detectable IL-4. Transfer of spleen cells from sensitized IFN-gammaR-/- mice produced EAE in both IFN-gammaR+/+ and IFN-gammaR-/- recipients. Disease was severe in IFN-gammaR-/- recipients and mortality high (77%). Surviving mice remained moribund until termination of the experiments. IFN-gammaR+/+ recipients developed disease of equal severity, but with no mortality, and recovered significantly. These results indicate that IFN-gamma is not essential for the generation or function of anti-MOG35-55 effector cells but does play an important role in down-regulating EAE at both the effector and induction phase of disease.
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PMID:IFN-gamma plays a critical down-regulatory role in the induction and effector phase of myelin oligodendrocyte glycoprotein-induced autoimmune encephalomyelitis. 887 15

Using mice double deficient for tumor necrosis factor and lymphotoxin alpha (TNF/LT alpha-/-) we have demonstrated that TNF and/or LT alpha are important for morphogenesis of secondary lymphoid organs and for T-cell-dependent antibody responses. In the present study we attempted to identify the receptors involved in those functions of TNF and LT alpha. Spleen morphology and antibody responses were investigated in wild-type, TNFR1-/-, TNFR2-/-, and TNF/LT alpha-/- mice immunized with SRBC. TNF/LT alpha-/- mice, which have a complete disruption of the TNF/LT alpha signaling system including the lymphotoxin beta (LT beta) receptor pathway, displayed an abnormal splenic microarchitecture and isotype switch did not take place. TNFR1-/- and TNFR2-/- mice displayed a normal splenic morphology and mounted an IgM and IgG antibody response to SRBC. However, the IgG production in TNFR1-/- mice was abnormal, with titers leveling off after 6 days following primary immunization, and with a minimal response to a second antigen challenge. Immunofluorescence analysis of spleen sections revealed in this strain a lack of follicular dendritic cell (FDC) network and of germinal centers. In conclusion, while normal splenic microarchitecture and isotype switch might require the LT beta receptor, differentiation of the FDC network, development of germinal centers, a sustained IgG response, and probably the development of memory cells depend on signaling via TNFR1.
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PMID:Tumor necrosis factor receptor-1 signaling is required for differentiation of follicular dendritic cells, germinal center formation, and full antibody responses. 891 32


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