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)

Secreted growth factors are integral components of the bone marrow (BM) niche and can regulate survival, proliferation, and differentiation of committed hematopoietic stem cells (HSCs). However, downstream genes activated in HSCs by early-acting cytokines are not well characterized. To better define intracellular cytokine signaling in HSC function, we have analyzed mice lacking expression of both signal transducer and activator of transcription 5a (STAT5a) and STAT5b (STAT5ab(-/-)). These studies specifically avoided possible autoimmune and/or splenomegaly disease-mediated indirect effects on HSC function by using 2 independent approaches: (1) by crossing onto the C57Bl/6 RAG2(-/-) background, and (2) by generation of wild-type chimeric mice reconstituted with transplanted STAT5ab(-/-) BM cells. These experiments demonstrated that STAT5-deficient HSCs have cell autonomous defects in competitive long-term repopulating activity. Furthermore, in the chimeric mice, injected wild-type BM cells showed a progressive multilineage competitive repopulating advantage in vivo, demonstrating that steady-state hematopoiesis was also highly STAT5-dependent. Consistent with the in vivo repopulating deficiency, when Sca-1(+)c-kit(+)lin(-) (KLS) cells were isolated and stimulated with growth factors in vitro, up to a 13-fold reduced expansion of total nucleated cells was observed in response to cocktails containing interleukin 3 (IL-3), IL-6, stem cell factor (SCF), Flt3 ligand, and thrombopoietin. Notably, a 10-fold reduction in expansion was observed with IL-3 and SCF. However, STAT5 activation was not required for regeneration of the KLS pool in vivo following transplant or for secondary repopulating ability. These studies support a major role for STAT5 activation as a cellular determinant of cytokine-mediated HSC repopulating potential but not self-renewal capacity.
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PMID:Cell intrinsic defects in cytokine responsiveness of STAT5-deficient hematopoietic stem cells. 1239 7

We present a case of angioimmunoblastic T cell lymphoma (AITL) with autoimmune thrombocytopenia. A 85-year-old man was admitted to our hospital with thrombocytopenia, generalized lymphadenopathy, pleural effusion, and splenomegaly in June 2000. Blood chemistry revealed hemoglobin and platelet counts of 8.8 g/dL and 26 x 10(9)/L, respectively. The level of platelet-associate-IgG was 2568.9 ng/10(7) cells. The direct Coombs test was positive. The level of serum IL-6 was 10.2 pg/ml. Megakaryocytes in the bone marrow increased. Lymph node biopsy showed diffuse proliferation of atypical lymphoid cells with a clear cytoplasm accompanied by plasma cells and small vessels. He was diagnosed as having AITL with autoimmune thrombocytopenia and hemolytic anemia. He received repeated platelet transfusion, and a limited effect of prednisolone therapy on his platelet count was observed. Combination chemotherapy lessened the extent of the lymphadenopathy and slightly elongated the interval of platelet transfusion. We next performed splenic irradiation and a slight increase in the platelet count was observed. He died of pneumonia in August 2000. Autoimmune thrombocytopenia associated with AITL is rare and the therapy containing prednisolone and chemotherapy is reported to be partly effective. Our case showed a minor response of autoimmune thrombocytopenia to splenic irradiation. Therapeutic intervention for hypersplenism should be considered if thrombocytopenia is not improved by chemotherapy alone.
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PMID:[Angioimmunoblastic T cell lymphoma (AITL) with autoimmune thrombocytopenia]. 1241 89

We demonstrate a new design for immunomodulatory CpG DNA containing two sequences each with as few as five or six-nucleotides joined together via 3(')-3(') linkers. These do not require the -PuPu(Py)CGPyPy- hexameric motif generally found essential for CpG DNA immune stimulation. These novel, short-immunomers show potent immunostimulatory activity manifested by IL-12 and IL-6 secretion in murine spleen cell and PBMC cultures and splenomegaly in vivo. Short-immunomers show strong activation of NF-kappaB and stress-activated signaling pathways and induce cytokines in J774 cell cultures. The same sequences also induce cytokines in healthy human PBMC cultures whereas conventional CpG DNA requires different optimal sequences for murine and human immune cells. Additionally, short-immunomers inhibit IL-5 secretion and induce IFN-gamma secretion in conalbumin-sensitized mouse spleen cell cultures, suggesting reversal of established Th2 responses to Th1 type responses. Short-immunomer also inhibits growth of MCF-7 human tumor xenograft in nude mice. This is the first report of activity with such short DNA sequences and also of sequences lacking hexameric motifs proposed in earlier studies.
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PMID:CpG penta- and hexadeoxyribonucleotides as potent immunomodulatory agents. 1255 51

Rheumatoid arthritis (RA) is a polygenic autoimmune disease. The autoimmunity develops from synergistic actions of genetic and environmental factors. We generated a double-mutant mouse by crossing two murine models of RA, a gp130 mutant knock-in mouse (gp130F759/F759) and an HTLV-1 pX transgenic mouse (pX-Tg), in a C57BL/6 background, which is resistant to arthritis. The mice spontaneously developed severe arthritis with a much earlier onset than the gp130F759/F759 mice and with a much higher incidence than did the pX-Tg mice. The symptoms of gp130F759/F759 mice, including lymphoadenopathy, splenomegaly, hyper-gamma-globulinemia, autoantibody production, increases in memory/activated T cells and granulocytes in the peripheral lymphoid organs, and a decrease in the class II MHC(bright) CD11c+ population, were augmented in the double mutants. Marked reductions in incidence, severity and immunological abnormalities were seen in the triple mutant, IL-6-/-/gp130F759/F759/pX-Tg, indicating that the arthritis in the double mutant is IL-6 dependent. gp130F759/F759/pX-Tg is a unique mouse model for RA.
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PMID:The point mutation of tyrosine 759 of the IL-6 family cytokine receptor gp130 synergizes with HTLV-1 pX in promoting rheumatoid arthritis-like arthritis. 1497 19

The oncogenic EBV protein LMP1 mimics a dysregulated CD40 receptor in vitro. To compare CD40 and LMP1-mediated events in vivo, transgenic mice were engineered to express mouse CD40 (mCD40tg) or a protein with extracellular mCD40 and cytoplasmic LMP1 (mCD40-LMP1tg). Transgenic and CD40(-/-) mice were bred so that only the transgenic CD40 molecule is expressed in B cells, macrophages, and dendritic cells. mCD40-LMP1tg mice had normal lymphocyte subsets, and immunization elicited an antibody response featuring normal isotype switching, affinity maturation, and germinal center (GC) formation. However, unimmunized mCD40-LMP1tg mice had expanded immature and germinal center B cells, produced autoantibodies, exhibited marked splenomegaly and lymphadenopathy, and elevated serum IL-6. Thus, signaling through the LMP1 cytoplasmic tail results in amplified and abnormal mimicry of CD40 functions in vivo, indicating possible ways in which LMP1 contributes to the pathogenesis of EBV-associated human disease.
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PMID:Expression of the cytoplasmic tail of LMP1 in mice induces hyperactivation of B lymphocytes and disordered lymphoid architecture. 1530 5

In this study, we demonstrated that Uncaria tomentosa extract (UTE) protects mice from a lethal dose of Listeria monocytogenes when administered prophylactically at 50, 100, 150 and 200 mg/kg for 7 days, with survival rates up to 35%. These doses also prevented the myelosuppression and the splenomegaly caused by a sublethal infection with L. monocytogenes, due to increased numbers of granulocyte-macrophage progenitors (CFU-GM) in the bone marrow. Non-infected mice treated with 100 mg/kg UTE also presented higher numbers of CFU-GM in the bone marrow than the controls. Investigation of the production of colony-stimulating factors revealed increased colony-stimulating activity (CSA) in the serum of normal and infected mice pre-treated with UTE. Moreover, stimulation of myelopoiesis and CSA occurred in a dose-dependent manner, a plateaux being reached with the dose of 100 mg/kg. Further studies to investigate the levels of factors such as IL-1 and IL-6 were undertaken. We observed increases in the levels of IL-1 and IL-6 in mice infected with L. monocytogenes and treated with 100 mg/kg of UTE. White blood cells (WBC) and differential counting were also performed, and our results demonstrated no significant changes in these data, when infected mice were pre-treated with 100 mg/kg of UTE. All together, our results suggest that UTE indirectly modulates immune activity and probably disengages Listeria-induced supression of these responses by inducing a higher reserve of myeloid progenitors in the bone marrow in consequence of biologically active cytokine release (CSFs, IL-1 and IL-6).
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PMID:Uncaria tomentosa extract increases the number of myeloid progenitor cells in the bone marrow of mice infected with Listeria monocytogenes. 1591 28

Toxocara canis is a nematode of the Ascaridae family that normally parasites the small intestine of canid species. Humans are accidentally infected upon ingestion of embryonated eggs, and can manifest several clinical alterations such as fever, hepatomegaly, splenomegaly, respiratory symptoms, muscle pain and anorexia. In the present work, we investigated the kinetics of tissue distribution of L2 larva in lungs, liver, kidney, brain, skeletal muscle and myocardium. Also, we analyzed the blood and bronchoalveolar lavage fluid (BAL) for levels of IL-6, IFN-gamma, eotaxin and Regulated on Activation Normal T Cell Expressed and Secreted (RANTES) in experimental murine T. canis infection. We observed liver, lung and kidney lesions correlated to larva migration as early as the first day of infection. After the seventh post-infection day, larva could also be detected in brain, skeletal muscle and heart, as an indicator of biphasic migration pattern. Increased inflammatory activity was detected in BAL and plasma of infected animals, as was an intense eosinophil migration associated with an increase in the levels of all the cytokines studied. In conclusion, our results establish a tight correlation between tissue lesions caused by larva migration and increased plasma levels of pro-inflammatory and eosinophil chemotactic cytokines. Thus, murine T. canis infection may prove to be useful in understanding the role of cytokines in infection.
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PMID:Influence of murine Toxocara canis infection on plasma and bronchoalveolar lavage fluid eosinophil numbers and its correlation with cytokine levels. 1616 64

Haptoglobin (Hp) is an acute phase protein that removes free hemoglobin (Hb) released during hemolysis. Hp has also been shown to be toxic for malaria parasites. alpha(+)-Thalassemia is a hemoglobinopathy that results in subclinical hemolytic anemia. alpha(+)-Thassemia homozygosity confers protection against severe malarial disease by an as yet unidentified mechanism. Hp levels were measured in a serial cross-sectional survey of children in Madang Province, Papua New Guinea (PNG). Hp levels were related to age, Hp genotype, Hb levels, parasitemia, splenomegaly, and alpha(+)-thalassemia genotype. Surprisingly, children who were homozygous for alpha(+) -thalassemia had significantly higher levels of Hp than did heterozygotes, after controlling for relevant confounders. We suggest that this is the result of either reduced mean cell Hb associated with alpha(+) -thalassemia homozygosity or an elevated IL-6-dependent acute phase response.
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PMID:Haptoglobin levels are associated with haptoglobin genotype and alpha+ -Thalassemia in a malaria-endemic area. 1676 May 5

The commercially available HERBSnSENSEStrade mark Cordyceps (HSCS) belongs to a cultivated strain of Cordyceps sinensis whose immunomodulatory activities has been renowned in traditional Chinese medicine (TCM) for centuries. The present report is the first that describes its immunomodulatory features through a series of in vitro and in vivo experiments. We measured, in peripheral blood mononuclear cells the in vitro effects of HSCS on the gene expression of cytokines and cytokine receptors, cytokine release, and surface expression of cytokine receptors using cDNA expression array, cytometric bead array (CBA), and immunoflorescence staining, respectively, as well as macrophage phagocytosis and monocyte production of H2O2 using flow cytometry. Sixty female BALB/c mice were fed with either HSCS (40 mg/kg/day) or water consecutively for 14 days. Proliferation, cytokine liberation, and CD3/4/8 expression of splenic cells were measured using 5-bromo-2'-deoxyuridine proliferation ELISA, CBA, and cytometry immunoflorescence staining, respectively. In vitro results demonstrated that HSCS induced the production of interleukin(IL)-1beta, IL-6, IL-10 and tumor necrosis factor alphaalpha from PBMC, augmented surface expression of CD25 on lymphocytes, and elevated macrophage phagocytosis and monocyte production of H2O2. In vivo results showed that HSCS did not induce splenomegaly and cytokine overliberation. Our results possibly provide the biochemical basis for future clinical trials.
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PMID:Immunomodulatory activities of HERBSnSENSES Cordyceps -- in vitro and in vivo studies. 1687 1

A 48-year-old man infected with an HIV-1 experienced intermittent bouts of fever, lymphadenopathy, elevated CRP level, and thrombocytopenia, each lasting about 2 weeks, and recurring at 2-3 month intervals. His CD4 count was about 500/microL, and he had never received antiretroviral therapy (ART). In March 2005, he experienced the same symptoms, accompanied by liver damage, splenomegaly, pleural fluid, and a high serum soluble IL-2 receptor level. Examination of a cervical lymph node specimen resulted in a diagnosis of Castleman disease, plasma cell type. Immunohistochemical studies confirmed the presence of HHV-8 and Ebstein-Barr virus (EBV). Since the plasma HHV-8 DNA and serum IL-6 were elevated during the flare-up, were negative between episodes, he was treated with ART to control the Castleman disease. He remained asymptomatic for 3 months, but, similar symptoms recurred with a high level of HHV-8 DNA in his PBMCs. Oral valganciclovir was them started at 1,800 mg twice daily, and his symptoms immediately improved. The HHV-8 DNA level in the PBMCs decreased markedly over the course of 4 weeks, and valganciclovir was discontinued. One week later, he experienced another flare-up, and was successfully treated with 10 days of valganciclovir 1,800 mg, followed by maintenance with valganciclovir 900 mg. ART was discontinued, because the valganciclovir plus ART caused severe fatigue. No subsequent flare-ups have been observed, and, no HHV-8 DNA has been detected in his PBMCs. Castleman disease is an unusual complication in patients with HIV-1 and HHV-8 infection, but it should be included in the differential diagnosis of patients who exhibit a relapsing systemic inflammatory syndrome and lymphoadenopathy. Further study is needed to determine the appropriate usage and timing of the anti-HHV-8 and HIV-1 medication.
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PMID:[A case of HIV-1 and HHV-8-associated Castleman disease with a relapsing high fever and lymphoadenopathy]. 1692 87


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