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)

Radiation-induced L8313 leukemia bearing mice (L8313 mice) had marked granulocytosis with splenomegaly. Hemopoietic stem cells and progenitors increased in the spleen but not in the bone marrow. Spleen conditioned-medium and serum from L8313 mice induced the formation of granulocyte-macrophage colonies (CFU-GM), erythroid bursts (BFU-E) and mixed colonies (CFU-Mix). Bone marrow conditioned medium did not show such activity. A cell line (STIL-3) was established from the spleen cells of L8313 mice. Surface marker analysis showed that the established cells were suppressor T cell. The cells produced IL-3 and GM-CSF in vitro, and induce essentially the same "leukemic" response in recipient mice. Inoculation of STIL-3 in diffusion chamber also induced leukemoid reaction, i.e. a marked granulocytosis with splenomegaly. Therefore, L8313 leukemia may be linked to an abnormality of growth and production of hemopoietic factors in hemopoietic regulatory cells.
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PMID:Physiopathological studies on granulocyte-macrophage colony stimulating factor and multi colony stimulating factor producing leukemia, L8313, induced by irradiation of C3H mice. 287 75

The effects of an autologous transplanted mammary tumor (RIII-T3) on hemopoiesis in RIII mice are described. Tumor-bearing animals died 30 to 40 days after inoculation and displayed splenomegaly, extreme neutrophilia, and moderately increased monocyte levels in the spleen, peripheral blood, and bone marrow. The precursors of neutrophils and monocytes, granulocyte/macrophage colony-forming cells (GM-CFC) were elevated in the spleen, bone marrow, and peripheral blood. RIII-T3-conditioned medium stimulated bone marrow GM-CFC and caused the myelomonocytic cell line, WEHI-3B, to differentiate in vitro. The conditioned medium did not stimulate erythroid, megakaryocyte, or eosinophil colony formation. When conditioned medium was fractionated, two peaks of activity corresponding to GM-CSF and G-CSF were observed, suggesting that the extreme neutrophilia observed in tumor-bearing animals may result from chronic exposure of the hemopoietic system to these hemopoietic hormones.
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PMID:Effects of a murine mammary tumor on in vivo and in vitro hemopoiesis. 387 4

Recombinant human (rh) granulocyte-macrophage colony-stimulating factor (GM-SCF) is currently being tested in clinical trials for the treatment of acute myeloid leukemias with two main intentions: reduction of neutropenia and recruitment of leukemic blasts into cell cycle to enhance cytarabine (ara-C) mediated cytotoxicity. We report a case of a fatal spleen rupture in a patient with acute monocytic leukemia (AML M5b) who was treated according to a clinical phase I/II protocol with rh GM-CSF priming and standard induction chemotherapy TAD 9 (thioguanine/ara-C/daunorubicin). During treatment we observed rapidly rising peripheral blast counts and the development of an acute abdomen. Ultrasound examination revealed splenomegaly due to diffuse cellular infiltration and spleen rupture. The patient died 17 days later due to pneumonia and renewed spleen hemorrhage. Bone marrow progenitor assays before treatment showed exclusive growth of monocytoid blast cell colonies (CFU-L). Colony growth could be stimulated with rh GM-CSF and blocked dose-dependently by a monoclonal anti-GM-CSF antibody. CFU-L proliferation also increased after stimulation with rh interleukin-3 (rh IL-3) and supra-additively with rh granulocyte colony-stimulating factor (rh G-CSF) combined with rh GM-CSF. Furthermore, rh GM-CSF induced surface marker expression of CDw 65 and CD 11b on isolated CFU-L blasts. After short-term suspension culture, rh GM-CSF enhanced the expression of CD 29- and CD 11b-adhesion molecules on peripheral blast cells. In summary, this case represents a fatal spleen rupture occurring during rh GM-CSF priming and induction chemotherapy for acute monocytic leukemia. Although the etiology of this spleen rupture remains uncertain, in view of our data we suggest special caution, when further testing this therapy protocol in acute leukemias with monocytic subtype and high peripheral blast cell counts.
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PMID:Fatal spleen rupture during induction chemotherapy with rh GM-CSF priming for acute monocytic leukemia. Clinical case report and in vitro studies. 845 Jun 76

NF-ATp is a member of a family of genes that encodes the cytoplasmic component of the nuclear factor of activated T cells (NF-AT). In this study, we show that mice with a null mutation in the NF-ATp gene have splenomegaly with hyperproliferation of both B and T cells. They also display early defects in the transcription of multiple genes encoding cytokines and cell surface receptors, including CD40L and FasL. A striking defect in early IL-4 production was observed after ligation of the TCR complex by treatment with anti-CD3 in vivo. The transcription of other cytokines including IL-13, GM-CSF, and TNF alpha was also affected, though to a lesser degree. Interestingly, the cytokines IL-2 and IFN gamma were minimally affected. Despite this early defect in IL-4 transcription, Th2 development was actually enhanced at later timepoints as evidenced by increased IL-4 production and IgE levels in situations that favor the formation of Th2 cells both in vitro and in vivo. These data suggest that NF-ATp may be involved in cell growth, and that it is important for the balanced transcription of the IL-4 gene during the course of an immune response.
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PMID:Hyperproliferation and dysregulation of IL-4 expression in NF-ATp-deficient mice. 861 34

Seven patients, 3 men and 4 women 48-72 years of age and suffering from idiopathic myelofibrosis were given a combination of recombinant human erythropoietin (r-hu-Epo), interferon-alpha-2b (IFN) and GM-CSF, in an attempt to treat their pancytopenia and marrow fibrosis. The dose of r-hu-Epo was 200 U/kg 3 times weekly, that of IFN was 3 x 10(6)/U 3 times weekly, and that of GM-CSF was 250 micrograms/m2/daily. The duration of therapy ranged from 3 to 6 months for r-hu-Epo and IFN and was 3 weeks for GM-CSF. The treatment regimen had a beneficial effect on all patients. The levels of hemoglobin increased in all patients but particularly in 5 (2 of whom had been dependent on red blood cell transfusions). Splenomegaly decreased significantly in 4 patients. Fibrosis in the bone marrow decreased in 2 patients. Three patients also had an increase in the number of white blood cells during the therapy with GM-CSF. We observed mild side effects in 6 of our patients. One patient had severe side effects from IFN and treatment was discontinued. In conclusion, the combination of r-hu-Epo, IFN and GM-CSF may improve the anemia (due to r-hu-Epo), increase the white blood cell count (due to GM-CSF) and reduce the marrow fibrosis (probably due to IFN) in patients with idiopathic myelofibrosis.
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PMID:Combination therapy with recombinant human erythropoietin, interferon-alpha-2b and granulocyte-macrophage colony-stimulating factor in idiopathic myelofibrosis. 870 5

Phosphorothioate oligonucleotides with certain sequences or structure motifs can stimulate the immune system. We administered to mice a 27-mer phosphorothioate oligonucleotide (sequence 5'-TCG TCG CTG TCT CCG CTT CTT CTT GCC-3'), which has previously been shown to cause splenomegaly and hypergamma-globulinemia on in vivo administration in mice, and studied the pattern and kinetics of cytokine production at both the splenic mRNA and serum protein levels. Following i.p. administration of 50 mg/kg of oligonucleotide, significant increases in the splenic mRNA levels of IL-6, IL-12p40, IL-1 beta, and IL-1Ra and serum levels of IL-6, IL-12, MIP-1 beta, and MCP-1 were observed. In contrast, no significant differences in splenic mRNA levels of IL-2, IL-4, IL-5, IL-9, IL-13, IL-15, IFN-gamma, or MIF or serum levels of IL-2, IL-4, IL-5, IL-10, IFN-gamma, or GM-CSF were detected. The induction of IL-12 secretion was dependent on the sequence and dose of the oligonucleotides. One oligonucleotide (sequence 5'-GAG AAC GCT CGA CCT TCG AT-3') induced a high level of IL-12 secretion even at 5 mg/kg, whereas another oligonucleotide (sequence 5'-CTC TGC CAC CCA TCT CTC TCC TTC T-3') did not induce significant IL-12 secretion even at 50 mg/kg. IL-12 secretion induced by various doses of oligonucleotide has the same kinetics but differs in magnitude. These studies show a distinct pattern and kinetics of cytokine production following oligonucleotide administration and further demonstrate that cytokine induction is not a general property of phosphorothioate oligonucleotides but is dependent on the sequence and dose of the oligonucleotides.
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PMID:Pattern and kinetics of cytokine production following administration of phosphorothioate oligonucleotides in mice. 936 8

Previously we described activating mutations of hbetac, the common signaling subunit of the receptors for the hematopoietic and inflammatory cytokines, GM-CSF, IL-3, and IL-5. The activated mutant, hbetacFIDelta, is able to confer growth factor-independent proliferation on the murine myeloid cell line FDC-P1, and on primary committed myeloid progenitors. We have used this activating mutation to study the effects of chronic cytokine receptor stimulation. Transgenic mice were produced carrying the hbetacFIDelta cDNA linked to the constitutive promoter derived from the phosphoglycerate kinase gene, PGK-1. Transgene expression was demonstrated in several tissues and functional activity of the mutant receptor was confirmed in hematopoietic tissues by the presence of granulocyte macrophage and macrophage colony-forming cells (CFU-GM and CFU-M) in the absence of added cytokines. All transgenic mice display a myeloproliferative disorder characterized by splenomegaly, erythrocytosis, and granulocytic and megakaryocytic hyperplasia. This disorder resembles the human disease polycythemia vera, suggesting that activating mutations in hbetac may play a role in the pathogenesis of this myeloproliferative disorder. In addition, these transgenic mice develop a sporadic, progressive neurological disease and display bilateral, symmetrical foci of necrosis in the white matter of brain stem associated with an accumulation of macrophages. Thus, chronic hbetac activation has the potential to contribute to pathological events in the central nervous system.
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PMID:Dysregulated hematopoiesis and a progressive neurological disorder induced by expression of an activated form of the human common beta chain in transgenic mice. 983 20

SHIP is an inositol 5' phosphatase that hydrolyzes the PI3'K product PI(3,4,5)P3. We show that SHIP-deficient mice exhibit dramatic chronic hyperplasia of myeloid cells resulting in splenomegaly, lymphadenopathy, and myeloid infiltration of vital organs. Neutrophils and bone marrow-derived mast cells from SHIP-/- mice are less susceptible to programmed cell death induced by various apoptotic stimuli or by growth factor withdrawal. Engagement of IL3-R and GM-CSF-R in these cells leads to increased and prolonged PI3'K-dependent PI(3,4,5)P3 accumulation and PKB activation. These data indicate that SHIP is a negative regulator of growth factor-mediated PKB activation and myeloid cell survival.
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PMID:SHIP is a negative regulator of growth factor receptor-mediated PKB/Akt activation and myeloid cell survival. 1019 78

A leukemoid reaction with granulocytosis and splenomegaly has been observed in animals and humans with a variety of tumors. We have employed four color flow cytometry to characterize the leukemoid reaction induced by the transplantable mouse mammary carcinoma 4T1 in female BALB/c mice. Gr-1(+) myeloid cells with the morphology of granulocytes increased in peripheral blood from <15% pre-transplant to nearly 80% of total CD45(+) leukocytes at four weeks post-transplant. Though the granulocyte:lymphocyte ratio increased markedly, the absolute numbers of CD19(+) B lymphocytes, CD4(+) and CD8(+) T lymphocytes, and the CD4/CD8 ratio in peripheral blood did not change significantly. Femurs from tumor-bearing mice showed myeloid hyperplasia of the fatty marrow. There was a notable increase in cells with a Gr-1(dim)/CD11b(bright) immature granulocyte phenotype, and these cells were also found in peripheral blood and spleen. Spleen weights had increased 8.5-fold by four weeks post-tumor transplant, mainly due to granulocytic hyperplasia. Cultured 4T1 tumor cells constitutively expressed mRNA for the myeloid colony-stimulating factors G-CSF and GM-CSF, and IFN-gamma-inducible M-CSF transcripts were also detected. Tumors excised from mice had transcripts for G-CSF and GM-CSF, but only G-CSF protein was found in high levels in serum of tumor-bearing mice. These data demonstrate that 4T1 tumor-bearing mice exhibit a leukemoid reaction that apparently is caused by the production of colony-stimulating factors produced by the tumor. The 4T1 tumor may serve as an excellent model for the study of this reaction.
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PMID:Murine mammary carcinoma 4T1 induces a leukemoid reaction with splenomegaly: association with tumor-derived growth factors. 1691 66

Inbred male CBA/J mice infected with Schistosoma mansoni develop either hypersplenomegaly syndrome (HSS) or moderate splenomegaly syndrome (MSS) by 20 weeks of infection. Pathologically and immunologically, MSS and HSS closely parallel the intestinal and hepatosplenic clinical forms of schistosomiasis in humans, respectively. By 6 weeks after infection, mice that eventually will become MSS develop T cell-stimulatory, cross-reactive idiotypes (CRI) while HSS mice never produce CRI. Because presence of CRI is useful to predict degree of chronic pathology, we used this measure to investigate what other early immunological events occurred in animals destined to develop severe morbidity. At 8 weeks of infection, there was a strong inverse correlation between CRI and splenomegaly, egg counts, and liver hydroxyproline. Similarly, phorbol myristate acetate (PMA)- and ionomycin-stimulated intracellular cytokine expression of IL-4, IL-5, and GM-CSF in splenic CD4(+) T cells was inversely correlated with serum CRI and directly correlated with spleen size. In contrast, spleen cell intracellular TNF-alpha and peritoneal cell production of nitric oxide demonstrated positive correlations with CRI and inverse correlations with measures of morbidity. Surprisingly, IL-10 and IFN-gamma were not correlated with CRI levels. These studies link chronic pathology to certain immunological responses during the acute phase of schistosomiasis.
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PMID:Early responses associated with chronic pathology in murine schistosomiasis. 1743 May 47


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