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)

Systemic lupus erythematosus (SLE) is characterized by immune abnormalities explained by the overproduction of Th(2)cytokines such as autoantibody production and polyclonal B cell activation. We examined the effect of administering a DNA plasmid encoding IL-12 on the lupus-like disease of MRL/MP-lpr/lpr (MRL/lpr) mice. Treatments were delivered intramuscularly every 4 weeks, starting at 4 weeks of age. This intervention significantly inhibited the accumulation of CD4(-)CD8(-)T cells, and reduced lymphadenopathy and splenomegaly. A significant decrease in serum IgG anti-DNA autoantibody titers was observed, and plasmid IL-12 therapy was also associated with a reduction in the proteinuria and glomerulonephritis characteristic of this disease. Serum IFN-gamma level was increased by inoculating IL-12 encoding plasmid, suggesting that the cytokine balance was skewed towards Th(1). The clinical implications of this suppression of autoimmune disease are also discussed.
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PMID:IL-12-encoding plasmid has a beneficial effect on spontaneous autoimmune disease in MRL/MP-lpr/lpr mice. 1088 Feb 49

The contribution of granulocyte-macrophage colony-stimulating factor (GM-CSF), a hematopoietic and immunoregulatory cytokine, to resistance to blood-stage malaria was investigated by infecting GM-CSF-deficient (knockout [KO]) mice with Plasmodium chabaudi AS. KO mice were more susceptible to infection than wild-type (WT) mice, as evidenced by higher peak parasitemia, recurrent recrudescent parasitemia, and high mortality. P. chabaudi AS-infected KO mice had impaired splenomegaly and lower leukocytosis but equivalent levels of anemia compared to infected WT mice. Both bone marrow and splenic erythropoiesis were normal in infected KO mice. However, granulocyte-macrophage colony formation was significantly decreased in these tissues of uninfected and infected KO mice, and the numbers of macrophages in the spleen and peritoneal cavity were significantly lower than in infected WT mice. Serum levels of gamma interferon (IFN-gamma) were found to be significantly higher in uninfected KO mice, and the level of this cytokine was not increased during infection. In contrast, IFN-gamma levels were significantly above normal levels in infected WT mice. During infection, tumor necrosis factor alpha (TNF-alpha) levels were significantly increased in KO mice and were significantly higher than TNF-alpha levels in infected WT mice. Our results indicate that GM-CSF contributes to resistance to P. chabaudi AS infection and that it is involved in the development of splenomegaly, leukocytosis, and granulocyte-macrophage hematopoiesis. GM-CSF may also regulate IFN-gamma and TNF-alpha production and activity in response to infection. The abnormal responses seen in infected KO mice may be due to the lack of GM-CSF during development, to the lack of GM-CSF in the infected mature mice, or to both.
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PMID:Granulocyte-macrophage colony-stimulating factor-deficient mice have impaired resistance to blood-stage malaria. 1111 98

The immunological resistance of a host to viral infections may be strongly influenced by cytokines such as interleukin-12 (IL-12) and gamma interferon (IFN-gamma), which promote T helper type 1 responses, and IL-4, which promotes T helper type 2 responses. We studied the role of these cytokines during primary and secondary immune responses against Friend retrovirus infections in mice. IL-4- and IL-12-deficient mice were comparable to wild-type B6 mice in the ability to control acute and persistent Friend virus infections. In contrast, more than one-third of the IFN-gamma-deficient mice were unable to maintain long-term control of Friend virus and developed gross splenomegaly with high virus loads. Immunization with a live attenuated vaccine virus prior to challenge protected all three types of cytokine-deficient mice from viremia and high levels of spleen virus despite the finding that the vaccinated IFN-gamma-deficient mice were unable to class switch from immunoglobulin M (IgM) to IgG virus-neutralizing antibodies. The results indicate that IFN-gamma plays an important role during primary immune responses against Friend virus but is dispensable during vaccine-primed secondary responses.
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PMID:Role of interleukin-4 (IL-4), IL-12, and gamma interferon in primary and vaccine-primed immune responses to Friend retrovirus infection. 1113 79

Active human visceral leishmaniasis (VL) is characterized by a progressive increase in visceral parasite burden, cachexia, massive splenomegaly, and hypergammaglobulinemia. In contrast, mice infected with Leishmania donovani, the most commonly studied model of VL, do not develop overt, progressive disease. Furthermore, mice control Leishmania infection through the generation of NO, an effector mechanism that does not have a clear role in human macrophage antimicrobial function. Remarkably, infection of the Syrian hamster (Mesocricetus auratus) with L. donovani reproduced the clinicopathological features of human VL, and investigation into the mechanisms of disease in the hamster revealed striking differences from the murine model. Uncontrolled parasite replication in the hamster liver, spleen, and bone marrow occurred despite a strong Th1-like cytokine (IL-2, IFN-gamma, and TNF/lymphotoxin) response in these organs, suggesting impairment of macrophage effector function. Indeed, throughout the course of infection, inducible NO synthase (iNOS, NOS2) mRNA or enzyme activity in liver or spleen tissue was not detected. In contrast, NOS2 mRNA and enzyme activity was readily detected in the spleens of infected mice. The impaired hamster NOS2 expression could not be explained by an absence of the NOS2 gene, overproduction of IL-4, defective TNF/lymphotoxin production (a potent second signal for NOS2 induction), or early dominant production of the deactivating cytokines IL-10 and TGF-beta. Thus, although a Th1-like cytokine response was prominent, the major antileishmanial effector mechanism that is responsible for control of infection in mice was absent throughout the course of progressive VL in the hamster.
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PMID:The hamster as a model of human visceral leishmaniasis: progressive disease and impaired generation of nitric oxide in the face of a prominent Th1-like cytokine response. 1116 Feb 39

A 66-year-old woman was admitted with high fever, systemic lymphadenopathy, hepatosplenomegaly and pancytopenia. Bone marrow aspiration showed infiltration of atypical lymphoid cells and hemophagocytic histiocytes. The findings of lymph node biopsy were compatible with angioimmunoblastic T-cell lymphoma (AILD). A diagnosis of lymphoma-associated hemophagocytic syndrome (LAHS) was made. Treatment with the THP-COP regimen achieved clinical remission except for mild splenomegaly, but relapse of LAHS was confirmed two years after diagnosis. The patient's condition deteriorated rapidly, and she died of multi-organ failure one month later. Autopsy revealed extended, diffuse infiltration of lymphoma cells in almost all organs. Numerous macrophages showing phagocytosis of erythrocytes and nucleated cells were found in the adrenal glands, lungs, bone marrow, spleen and liver. Epstein-Barr virus genomes were not detected by in situ hybridization, but cytotoxic molecules were immunostained with TIA-1 and granzyme B in the lymphoma cells. Elevated serum levels of sIL-2R, IFN-gamma, IL-6 and M-CSF were found at the onset and relapse of lymphoma. Overproduction of these cytokines was considered to have contributed to the pathogenesis of HPS.
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PMID:[Angioimmunoblastic T-cell lymphoma associated with hemophagocytic syndrome at onset and relapse]. 1120 Nov 51

It has been proposed that interferon-gamma (IFN) inhibits collagen synthesis in myeloproliferative disorders through an inhibitory effect on PDGF and TGF-beta. We therefore evaluated the role of IFN-gamma on bone marrow fibrosis in idiopathic myelofibrosis (IMF). After a 3-month observation period, nine patients (five female, four male), median age 64 years (range 43-72 years), received 3 x 3 mU IFN-gamma/week over 6 months and were monitored after withdrawal of IFN-gamma for further 3 months. Three out of nine patients have completed the study according to the protocol. Six patients had to be withdrawn from IFN-gamma due to the following reasons: bacterial infection (three patients), splenic infarction or deterioration of splenomegaly (one patient, each) and refusal to continue IFN-gamma (one patient). Results from seven patients treated for at least 8 weeks were considered measurable. Leukopenia, initially present in one of the evaluated patients, deteriorated during IFN-gamma treatment. This patient died during the observation period shortly after withdrawal of the therapy as a result of septicemia. Transfusion-dependent anemia, initially observed in two of the evaluated patients, deteriorated during the IFN-gamma treatment. Bone marrow fibrosis increased in three patients, whereas it remained unchanged in another and improved in a further patient. Splenomegaly improved in two patients but deteriorated markedly in one. Taking these observations together, four patients had disease progression during IFN-gamma treatment, two had stable disease and one could be qualified as a partial responder. According to these data IFN-gamma cannot be considered as a treatment option for patients with IMF.
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PMID:Ineffectiveness of interferon-gamma in the treatment of idiopathic myelofibrosis: a pilot study. 1126 29

It has been postulated that TNF has a pivotal role in a cytokine cascade that results in joint inflammation and destruction in rheumatoid arthritis (RA). To evaluate this, we examined the response of TNF-deficient (Tnf(-/-)) mice in two models of RA. Collagen-induced arthritis (CIA) was induced by injection of chick type II collagen (CII) in CFA. Tnf(-/-) mice had some reduction in the clinical parameters of CIA and, on histology, significantly more normal joints. However, severe disease was evident in 54% of arthritic Tnf(-/-) joints. Tnf(-/-) mice had impaired Ig class switching, but preserved T cell proliferative responses to CII and enhanced IFN-gamma production. Interestingly, CII-immunized Tnf(-/-) mice developed lymphadenopathy and splenomegaly associated with increased memory CD4(+) T cells and activated lymph node B cells. Acute inflammatory arthritis was also reduced in Tnf(-/-) mice, although again some mice exhibited severe disease. We conclude that TNF is important but not essential for inflammatory arthritis; in each model, severe arthritis could proceed even in the complete absence of TNF. These results call into doubt the concept that TNF is obligatory for chronic autoimmune and acute inflammatory arthritis and provide a rationale for further studies into TNF-independent cytokine pathways in arthritis.
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PMID:Severe inflammatory arthritis and lymphadenopathy in the absence of TNF. 1141 57

Lymphocyte trafficking in the gastrointestinal tract is primarily mediated by interactions with the mucosal addressin cell adhesion molecule 1 and its lymphocyte ligand, alpha(4)beta(7), and partly by L-selectin (L-Sel) interactions with peripheral node addressin coexpressed on some mucosal addressin cell adhesion molecule 1. We inquired whether intestinal responses in mice lacking L-Sel would be enhanced. L-Sel-deficient (L-Sel(-/-)) mice were orally immunized with either Salmonella vaccine vector or Salmonella vector-expressing colonization factor Ag I (CFA/I) from enterotoxigenic Escherichia coli. In L-Sel(-/-) mice, mucosal IgA anti-CFA/I fimbrial responses were greatly reduced, and systemic IgG2a anti-CFA/I fimbrial responses were 26-fold greater compared with C57BL/6 (L-Sel(+/+)) mice. L-Sel(-/-) Peyer's patch (PP) CD4(+) Th cells revealed IFN-gamma-dominated responses and an unprecedented absence of IL-4, whereas the expected mixed Th cell phenotype developed in L-Sel(+/+) mice. PP CD4(+) Th cell anti-Salmonella responses were nearly nonexistent in L-Sel(-/-) mice immunized with either Salmonella vaccine. Splenic CD4(+) Th cell anti-Salmonella responses were reduced but did show cytokine production in Ag restimulation assays. Increased colonization of PP and spleen was noted only with the Salmonella vector in L-Sel(-/-) mice, resulting in increased splenomegaly, suggesting that the Salmonella-CFA/I vaccine was not as infectious or that the presence of the fimbriae improved clearance, possibly because of reduced neutrophil recruitment. However, sufficient anti-Salmonella immunity was induced, because Salmonella vector-immunized L-Sel(-/-) mice showed complete protection against wild-type Salmonella challenge, unlike L-Sel(+/+) mice. This evidence shows that L-Sel is important for development of mucosal immunity, and absence of L-Sel is protective against salmonellosis.
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PMID:Impaired mucosal immunity in L-selectin-deficient mice orally immunized with a Salmonella vaccine vector. 1141 77

Tumor development and aging can each alter immune competence. The present study aimed to determine the impact of Lewis lung carcinoma (LLC) presence on immune parameters of middle-aged (averaging 6.5 months) versus aged (averaging 21.3 months) mice. An age-associated decline in the CD4+ cell frequency was seen in freshly isolated spleen and lymph node cells, as well as in cultures stimulated with immobilized anti-CD3. This decline was not further exacerbated by tumor presence. What was prominently inhibited by tumor was the capacity of either splenic or lymph node CD4+ cells to become stimulated to express IFN-gamma. Spleen and lymph node cultures from aged tumor-bearing mice had the lowest frequency of CD4+IFN-gamma+ cells and the least amount of secreted IFN-gamma. CD8+ cells were not affected by aging, but tumor presence reduced the induction of CD8+IFN-gamma+ cells in lymph node cultures. We previously showed that LLC growth stimulates myelopoiesis, as seen by splenomegaly and the mobilization of immune inhibitory CD34+ progenitor cells. Tumor presence in middle-aged mice reduced spleen cell blastogenesis, which was mediated by CD34+ cells. Aged mice had reduced blastogenesis, and this was further reduced by presence of tumor. However, neither the age-associated immune dysfunction nor the tumor-induced immune suppression in aged mice was due to CD34+ progenitor cells. These studies show how tumor presence can further compromise the immune dysfunction that accompanies aging. In addition, they show that aging impacts on the mechanisms by which tumors inhibit T-cell capabilities, with myelopoiesis-associated CD34+ cells mediating the immune depression of middle-aged tumor-bearers and an independent mechanism being responsible for the immune depression in aged tumor-bearing mice.
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PMID:Impact of aging on immune modulation by tumor. 1157 May 85

Effective eradication of established tumors and generation of a lasting systemic immune response is an important goal for cancer gene immunotherapy. The method of gene delivery may also be critical for the generation of an effective antitumor response. We compared the level of transgene expression and antitumor activity of two different interleukin (IL)-12 DNA preparations (naked DNA versus DNA lipid complex). Established murine adenocarcinoma (CT26) and renal cell carcinoma (Renca) tumors in BALB/c mice were treated by direct intratumoral injection of a nonviral plasmid DNA vector encoding the murine IL-12 (mIL-12) gene, either alone (naked) or in complexes with cationic lipid. Both treatments resulted in the same percentage (87%) of mice undergoing a complete tumor regression of the CT26 tumor. For the Renca tumor model, complete tumor regression was observed in 67 and 75% of animals treated with naked mIL-12 DNA and mIL-12 DNA plus lipid, respectively. Mice that were rendered tumor free for > 50 days by mIL-12 gene therapy rejected a subsequent challenge of parental tumor cells but not of an unrelated, syngeneic tumor. The marked reduction of tumor growth in tumor-bearing mice treated with mIL-12 cDNA was associated with the augmentation of tumor-specific cytotoxic T cells, enhanced production of IFN-gamma in spleen and lymph node cells, and increased splenomegaly and lymphadenopathy. The CD8+: CD4+ ratio in tumor-infiltrating lymphocytes was significantly increased in the tumor-bearing mice treated with mIL-12 DNA alone and mIL-12 cDNA plus lipid as compared with a control vector-treated group. These results indicate that direct intratumoral gene transfer with naked nonviral IL-12 DNA provides an effective and simple method for the treatment of murine tumors, suggesting an approach for clinical application.
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PMID:Intratumoral injection of interleukin-12 plasmid DNA, either naked or in complex with cationic lipid, results in similar tumor regression in a murine model. 1248 17


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