Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038002 (splenomegaly)
 9,873 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The SV40 large T gene under the control of immunoglobulin enhancer induced hyperproliferation of multilineage hematopoiesis in transgenic mice. Huge splenomegaly was the major gross abnormality; mice were rather anemic, and neither leukoerythroblastosis nor invasion into tissues such as liver, kidneys or lymph nodes was common. In the latter phases of the disease, the proliferating cell type tended to shift to a variety of single-lineage hematopoiesis, but the majority of mice still showed the presence of multilineage hematopoiesis; such cells were somewhat dysplastic but low in neoplastic potential. A long-term observation by transplantation of the hematopoietic cells into lethally irradiated C57BL/6 mice resulted in a variety of neoplastic growths in the recipients; not only was myelodysplastic hypercellularity seen, but also single-lineage hematopoietic malignancies such as B cell lymphomas/leukemias, histiocytic malignancies and even myeloid leukemias. The disease bore the proliferative feature solely in the spleen and bone marrow, and the transition from multilineage myelodysplasia into single-lineage hematopoiesis at some frequency is reminiscent of myelodysplastic syndromes (MDS) in humans. The results that the SV40 large T antigen was expressed in every proliferating cell, and that there was no apparent increase in any colony-stimulating cytokine(s), together with the results of the transplantation assays, suggested that the hyperproliferation of the hematopoietic cells was a direct consequence of the expression of SV40 large T antigen in these cells themselves.
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PMID:MDS-like experimental myelodysplasia: multilineage abnormal hematopoiesis in transgenic mice harboring the SV40 large T antigen under an immunoglobulin enhancer. 850 May 78

We investigated whether gamma interferon (IFN-gamma; a Th1 cytokine), tumor necrosis factor alpha (TNF-alpha), and interleukin-4 (IL-4; a Th2 cytokine) modulate nitric oxide (NO) production in vivo during blood stage infection with Plasmodium chabaudi AS. Treatment of resistant C57BL/6 mice, which resolve infection with P. chabaudi AS and produce increased levels of IFN-gamma, TNF-alpha, and NO early during infection, with anti-IFN- gamma plus anti-TNF-alpha monoclonal antibodies (MAbs) resulted in a reduction of both splenic inducible NO synthase mRNA and serum NO3- levels by 50 and 100%, respectively. Treatment with the anti-TNF-alpha MAb alone reduced only serum NO3- levels by 35%, and treatment with the anti-IFN-gamma MAb alone had no effect on NO production by these mice during infection. Susceptible A/J mice, which succumb to infection with P. chabaudi AS and produce increased levels of IL-4 but low levels of IFN-gamma, TNF-alpha, and NO early during infection, were treated with an anti-IL-4 MAb. The latter treatment had no effect on NO production by this mouse strain during infection. In addition, our results also demonstrate that treatment of resistant C57BL/6 mice with anti-IFN-gamma plus anti-TNF-alpha MAbs affects, in addition to NO production, other traits of resistance to P. chabaudi AS malaria such as the peak level of parasitemia and the development of splenomegaly. Furthermore, the change in spleen weight was shown to be an IFN-gamma-independent effect of TNF-alpha. Treatment of susceptible A/J mice during infection with an anti IL-4 MAb had no effect on these markers of resistance. Thus, these results demonstrate that TNF-alpha and IFN-gamma are critical in the regulation of NO production and other traits of resistance during P. chabaudi AS malaria in C57BL/6 mice. These data also indicate that treatment with an anti-IL-4 antibody alone is not able to induce NO production or confer resistance to A/J mice against P. chabaudi AS malaria.
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PMID:In vivo regulation of nitric oxide production by tumor necrosis factor alpha and gamma interferon, but not by interleukin-4, during blood stage malaria in mice. 855 72

Because IL-12 restores allogeneic cytotoxic T lymphocyte (CTL) activity by T cells of aged mice in vitro, we initially assessed whether IL-12 could overcome age-related deficits when given to aged mice in vivo. Growth of P815(H-2(d)) was enhanced in aged compared with young BALB/c (H-2(d)) mice and tumor growth was curtailed by IL-12 in both age groups. Unexpectedly, secondary CTL stimulated ex vivo with P815 were reduced in IL-12-treated mice compared with controls. Primary CTL generated ex vivo across MHC differences in IL-12 treated BALB/c and C57BL/6 young mice were reduced by 90-99%, were dose- and time-dependent, and were associated with reduced allo-stimulated NK-like activity and [3H]thymidine incorporation. IFN-gamma was elevated in sera and in supernatants from allo-stimulated cultures from IL-12-treated mice, while IL-4 was reduced in such supernatants, suggesting that, despite reduced CTL, IL-12 was associated with increased Th1- and reduced Th2-type cytokine production. IL-12 also induced splenomegaly, primarily due to increased numbers of cells lacking markers of mature T, B and NK cells, or macrophages, or polymorphonuclear leukocyte morphology. IFN-gamma mutant mice exhibited reduced splenic enlargement in response to IL-12, suggesting that the splenomegaly was due, in part, to IFN-gamma production. However, reduced CTL generation was not due entirely to dilution of CTL precursor cells because spleen cellularity and size increased 3-fold while CTL activity decreased 10- to 100-fold, and CTL generation normalized to CD8(+) T effector cells was still significantly reduced in IL-12-treated mice. Interestingly, purified CD4(+) and CD8(+) T cells from IL-12-treated normal mice exhibited greater proliferative and cytolytic activities respectively compared with controls. Thus, effector T cells in IL-12-treated mice were not impaired, but exhibited augmented responsiveness, suggesting that IL-12 induced complex interactions among spleen cell populations and that these effects, in part, are mediated by IFN-gamma.
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PMID:IL-12 administered in vivo to young and aged mice. Discrepancy between the effects on tumor growth in vivo and cytotoxic T lymphocyte generation ex vivo: dependence on IFN-gamma. 867 53

The aim of this study was to evaluate the therapeutic efficacy of locally administered low-dose interleukin-2 (IL-2) alone or together with interferon-gamma (IFN-gamma) in a herpes simplex virus type 2-transformed murine (H238) fibrosarcoma model. In vitro incubation showed that IL-2, but not IFN-gamma, had a significant inhibitory effect on DNA synthesis in H238 cells. In vivo experiments were performed with BALB/c mice to determine the optimal time of treatment with each cytokine after subcutaneous (sc) tumor implantation. The greatest antitumor effect with IL-2 (1 x 10(5) total international units, sc) was noted when treatment was administered during the first week after tumor injection, whereas with IFN-gamma (500 total units, intraperitoneally) treatment during the second week proved best. Combination of the two agents produced complete tumor regression in 44.4% of mice; regression with single-modality treatment was 0-11%. The presence of H238 tumor induced splenomegaly and enhanced the oxidative burst capacity of phagocytes. Peripheral blood leukocyte counts were low in tumor-bearing groups, regardless of treatment. IL-2 and IFN-gamma were nondetectable in the plasma of tumor-bearing or control mice; however, total TGF-beta 1 was 248% higher with IL-2 treatment compared with tumor-bearing nontreated controls. These results show that IL-2 and IFN-gamma can significantly inhibit the growth of highly aggressive H238 tumors and support further investigations with these agents.
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PMID:Immunotherapy with low-dose interleukin-2 and interferon-gamma in a murine tumor model. 874 82

Murine AIDS (MAIDS) induced by infection of C57BL/6 mice with a mixture of retroviruses known as LP-BM5 is characterized by lymphadenopathy, splenomegaly, and T and B cell dysfunction. By labeling with bromodeoxyuridine in vivo, we found vigorous CD4 T cell proliferation during the initial stages of infection, yet a loss in their ability to function both in vivo and in vitro. In addition, a significant fraction of the CD4 T cell population in infected mice undergoes spontaneous apoptosis in vivo. Upon in vitro stimulation with anti-CD3 plus PMA, anergic CD4 T cells from mice with MAIDS fail to progress through the cell cycle (G0/G1 arrest), and a fraction of the cells undergoes apoptosis. The addition of IL-2 along with TCR-mediated stimulation not only fails to rescue CD4 T cells from apoptosis, but enhances activation-induced cell death. To further understand the regulation of the suicide pathway(s) of anergic CD4 T cells vs the cytokine synthesis pathway(s) of normal CD4 T cells, we evaluated their expression of Bcl-2 protein. As infection progresses, the expression of Bcl-2 among CD4 T cells declines and drops further when CD4 T cells are restimulated through the TCR in vitro. These results suggest that this CD4 T cell immunodeficiency in MAIDS includes a TCR-induced program of activation-induced cell death and an uncoupling from cytokine synthesis pathways and proliferation of CD4 T cells. The decline in Bcl-2 expression may be in part responsible for this reprogramming.
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PMID:TCR triggering of anergic CD4 T cells in murine AIDS induces apoptosis rather than cytokine synthesis and proliferation. 875 10

Interleukin (IL-12) protein has been shown to elicit diverse immunological responses and potent antitumor activity. We demonstrate here that intradermal injection of IL-12 cDNA induces systemic biological effects characteristic of the cytokine in vivo. Intradermal injection of IL-12 cDNA resulted in local expression of IL-12 mRNA, which correlated with a 10-fold increase in natural killer activity and a 3-4-fold increase in anti-CD3-induced IFN-gamma production in cultured splenocytes. Furthermore, when challenged with Renca tumor cells at a distant site, the day of tumor emergence was significantly delayed, and tumor growth was reduced in mice that received IL-12 cDNA, compared to mice given injections of plasmid vector alone. A number of the mice receiving IL-12 cDNA injections remained tumor free months after tumor challenge. In contrast to mice receiving recombinant IL-12 protein, no splenomegaly was detected when natural killer activity was significantly induced in mice receiving injections of IL-12 cDNA. Because purified plasmid DNA is more economical to prepare and has a longer shelf-life than recombinant proteins, and intradermal administration of cDNA encoding IL-12 did not cause splenomegaly, our findings suggest that the in vivo injection of cDNA encoding IL-12 may be a less toxic and more cost-effective alternative to IL-12 protein therapy in some clinical or experimental therapeutic applications.
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PMID:Injection of complementary DNA encoding interleukin-12 inhibits tumor establishment at a distant site in a murine renal carcinoma model. 875 1

A murine AIDS model, induced by LP-BM5 murine leukemia virus (MuLV), has helped to investigate pathogenesis of acquired immunodeficiency syndrome (AIDS), cofactor involvement, and new treatment tests. LP-BM5 MuLV-infected mice characteristically develop hypergammaglobulinemia, splenomegaly, lymphadenopathy, T-cell functional deficiency, B-cell dysfunction, and, in the later stages, neurological signs including paralysis as well as susceptibility to opportunistic infections. The similarities between murine AIDS and human AIDS are striking, with similar changes in immune functions, T-cell differentiation, cytokine production, disease resistance, and oxidative stress. The well-characterized murine immunological system, availability of inbred strains, economy of using mice versus primate model, and similarities in immunodeficiency caused by human immunodeficiency virus (HIV) encouraged rapid development of the LP-BM5 murine AIDS model in the past decade.
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PMID:Murine AIDS, a key to understanding retrovirus-induced immunodeficiency. 897 19

Inbred male CBA/J mice with chronic Schistosoma mansoni infections develop two distinct syndromes. Hypersplenomegaly syndrome (HSS) demonstrates pathologic similarities to the hepatosplenic form of chronic human schistosomiasis, and moderate splenomegaly syndrome (MSS) resembles the asymptomatic intestinal form. Immunoaffinity-purified Abs against S. mansoni soluble egg Ags (SEA) from infected patients' sera differ idiotypically according to the donor's clinical form of the disease. We now show that immunoaffinity-purified anti-SEA Abs (Id) from MSS or HSS mice parallel idiotypic preparations of the analogous human clinical form by their differential ability to stimulate the proliferation of anti-Id T cells. MSS Id preparations stimulate spleen cells from either MSS or HSS animals. In contrast, HSS Id does not stimulate spleen cells from either group. In an anti-SEA ELISA, MSS and HSS Id preparations contained comparable levels of IgM and IgG1. However, the MSS Id preparation had higher levels of SEA-specific IgG2a and IgG2b than did HSS Id. The Ig isotypes of these Id preparations suggested differences in cytokine expression patterns. Studies of the cytokine profiles of the spleen cells responding to anti-SEA Id preparations demonstrated that while Id preparations from acutely infected mice stimulate IL-4 and IL-10 production, Id preparations from chronic MSS mice stimulate IFN-gamma production. HSS Id did not stimulate the production of any of these cytokines. The possibility that distinct immunoregulatory environments may contribute to the development of MSS and HSS correlates with earlier hypotheses that hepatosplenic pathology results at least in part from a lack of development or expression of appropriate regulatory Ids.
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PMID:Immunoregulatory idiotypes stimulate T helper 1 cytokine responses in experimental Schistosoma mansoni infections. 910 46

MRL-Fas(lpr) mice develop an aggressive form of autoimmunity, characterized by immune complex-mediated glomerulonephritis and massive expansion of lymphoid tissues. Increased MHC class II expression by macrophages and renal parenchymal cells is a prominent feature of MRL-Fas(lpr) mice. Since interferon-gamma (IFN-gamma) is the major and the most potent inducer of MHC class II molecules it could play a pathogenic role in the disease process in MRL-Fas(lpr). We have analyzed IFN-gamma expression in normal and nephritic MRL-Fas(lpr) mice by examining renal and lymphoid IFN-gamma-specific mRNA production, using reverse transcription-polymerase chain reaction (RT-PCR) and Northern blotting. We detect abundant IFN-gamma mRNA expression in the kidney of nephritic MRL-Fas(lpr) by RT-PCR, whereas normal mice display absent or only very weak expression of this cytokine. By RT-PCR, IFN-gamma mRNA is detectable in normal spleen, but is overexpressed in the enlarged spleen and lymph nodes of MRL-Fas(lpr). Northern blotting using total RNA from tissues confirms abundant IFN-gamma expression in spleen and lymph node of MRL-Fas(lpr). We conclude that enhanced renal IFN-gamma mRNA expression is a prominent feature of MRL-Fas(lpr) lupus nephritis. Increased IFN-gamma produced by infiltrating T cells could lead to increased MHC class II expression by renal parenchymal cells, thereby promoting the nephritic process by augmentation of antigen presentation in the kidney of autoimmune MRL-Fas(lpr).
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PMID:Upregulation of lymphoid and renal interferon-gamma mRNA in autoimmune MRL-Fas(lpr) mice with lupus nephritis. 917 26

Intraperitoneal (i.p.) exposure to propanil (3,4-dichloropropionanilide) has previously been shown to affect macrophage cytotoxicity. In this study, we compared the immunotoxic effects of propanil, after different routes of in vivo administration, on cytokine production by thioglycollate-elicited peritoneal macrophages. C57B1/6 mice were treated with either vehicle or 200 mg/kg propanil i.p., or with vehicle, 40, or 400 mg/kg propanil orally. Three or 7 days later, ex vivo production of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) by macrophages after lipopolysaccharide (LPS) stimulation was determined. Both oral and i.p. propanil exposure resulted in up to a 60-70% reduction in IL-6 and TNF-alpha production by the LPS-stimulated macrophages, depending on the route, postexposure time, and dose of propanil administered. Oral exposure to propanil also caused splenomegaly and thymic atrophy in animals in much the same manner as animals exposed via the i.p. route. In vitro exposure to propanil also significantly reduced macrophage cytokine production. Thioglycollate-elicited macrophages from normal mice were cultured in the continuous presence of 0, 10, or 20 microM propanil plus LPS. This exposure caused a significant reduction in IL-6 and TNF protein production by these macrophages in a concentration-dependent manner. Northern blot analysis demonstrated that the message levels of these cytokines were reduced by approximately the same percentage as the protein levels in propanil-treated macrophages, indicating a possible transcriptional or pretranscriptional target(s) for propanil.
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PMID:The immunomodulatory effects of the herbicide propanil on murine macrophage interleukin-6 and tumor necrosis factor-alpha production. 922 36


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