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)

The relationships between metabolic alterations and tissue-specific gene expression of tumor necrosis factor-alpha (TNF-alpha), interleukin 6 (IL-6), gamma-interferon (gamma-IFN), and interleukin 1 and serum levels of TNF-alpha and IL-6 before and after a live Escherichia coli septic challenge to rats were examined. From 0 to 2 h, serum glucose significantly decreased while plasma glucagon increased. By 8 h, plasma glucagon, serum insulin, and glucose appearance were significantly elevated. Gene expression of phosphoenolpyruvate carboxykinase increased 1 h after E. coli but by 4 h was significantly decreased. TNF-alpha mRNA (liver and spleen) and serum peptide levels peaked 1-2 h after the septic challenge and then decreased substantially by 6-8 h. Spleen IL-6 and gamma-IFN mRNA expression reached a maximum 4 h after E. coli challenge, whereas serum IL-6 levels were elevated by 2 h after injection of the bacteria. The increase in TNF-alpha mRNA and serum peptide levels correlated with the early fall in serum glucose and rise in plasma glucagon. Alterations in the rate of glucose appearance and plasma glucagon were observed later and coincided with the increased mRNA expression of IL-6 and gamma-IFN. Thus the metabolic alterations observed in the septic rat are associated with a complex cascade of several cytokines.
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PMID:Sepsis-induced cascade of cytokine mRNA expression: correlation with metabolic changes. 159 Mar 83

Multiple low doses of streptozotocin are known to induce immune-mediated insulin deficient diabetes and depression of immune reactivity. We show here that immune depression by streptozotocin is not general but that some parts of the immune system are stimulated. Spleen cells from streptozotocin-treated mice showed enhanced cytotoxicity against syngeneic islet cells and various tumour cells including insulinoma cells. Several cell types served as effector cells, including macrophages, asialo GM1+ and Lyt-2+ lymphocytes. The increased cytotoxic activity towards islet cells was mostly due to macrophages and to non-asialo GM1+ and non-Lyt-2+ lymphocytes. A higher activation state of macrophages in low dose streptozotocin-treated mice was demonstrated by measurements of superoxide anion release. We conclude that multiple low doses of streptozotocin stimulate 'natural cytotoxicity', i.e. the non-MHC restricted cytotoxic activity of macrophages, T cells and natural killer lymphocytes.
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PMID:Low dose streptozotocin causes stimulation of the immune system and of anti-islet cytotoxicity in mice. 165 63

To evaluate the effects of a gonadotropin-releasing hormone agonist on non-reproductive systems, we administered [D-Leu6,Des-gly10]-GnRH ethylamide (leuprolide; 5 micrograms/day) for 21 days to female Sprague-Dawley rats. In Experiment 1, continuous infusion (Alzet minipumps sc) was compared to injection. Increased thymus and body weights and decreased estradiol and uterine weights were noted for both administration methods. Spleen weight increased only in rats treated by continuous infusion. Ovary, kidney and liver weights did not change. Only leuprolide-injected rats had elevated LH with decreased corticosterone and ACTH levels, possibly related to the injection process. Glucose, insulin, progesterone, FSH and corticosterone/ACTH were not different. In Experiment 2, intact and ovariectomized rats were implanted with minipumps delivering leuprolide or 0.9% NaCl. Body and thymus weights increased, whereas uterine weight and estradiol declined in both leuprolide-treated and ovariectomized rats. No synergism between leuprolide and ovariectomy was noted. Thymosin alpha 1, but not thymosin beta 4, increased in leuprolide-treated ovariectomized rats. Peripheral white blood cell count was elevated in leuprolide-treated intact rats and ovariectomized rats. In bone marrow, non-nucleated cell count declined in leuprolide-treated intact rats, contributing to the decreased total cell count in this group. Nucleated cell count was unaffected. Therefore, thymus weight gain was accompanied only in some cases by functional changes. Our results demonstrate that leuprolide affects non-reproductive systems, in a similar manner to ovariectomy. We suggest that such alterations may be due to the hypoestrogenic environment produced by leuprolide.
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PMID:The gonadotropin-releasing hormone agonist leuprolide affects the thymus and other non-reproductive systems of female rats. 166 99

Chemically induced autoimmunity is a recently recognized environmental hazard that may affect individuals genetically predisposed to autoimmune disease and chronically exposed to certain chemicals. For example, moderate concentrations of mercury may lead to renal autoimmune disease in a small but significant percentage of the exposed population. Mercury also induces autoimmune glomerulonephritis in susceptible Brown Norway (BN) and MAXX inbred strain rats. Autoimmune responses, directed to epitopes of the renal glomerular basement membrane (GBM), are rapid in onset and have a self-limiting course in mercury-treated rats. Both regulatory T cells and idiotype-anti-idiotype network have been implicated in the resolution of this autoimmune process. In our investigations of immune regulation of mercury-induced autoimmune glomerulonephritis, we have used flow cytometry to quantitate lymphocyte subpopulations in the spleen and lymph nodes of mercury-treated and control BN rats. Of particular interest was the RT6+ T cell subset, that appears to have important immunoregulatory properties in a rat model of autoimmune insulin-dependent diabetes mellitus. Spleen and lymph nodes from control BN rats contained 22 and 52%, respectively, RT6+ cells. Spleens from mercury-treated animals contained 21% RT6+ cells on Day 10 of treatment, 13% on Day 17, 16% on Day 24 and 20% on Day 30. Lymph nodes from the same rats had 36% RT6+ cells on Day 10, 23% on Day 17, 29% on Day 24, and 28% on Day 30. The decrease in RT6+ cells correlated inversely with autoimmune responses to GBM, which peaked on Days 17-24 and declined by Day 30. Moreover, autoimmune responses were also associated with elevated RT6-:RT6+ T cell ratios. Similar results were obtained in two additional groups of BN rats, comprising both younger and older animals, sacrificed at Day 18 of mercury treatment. Analysis of other lymphocyte subpopulations demonstrated a decrease of CD4+ and CD5+ cells, whereas B cells as well as CD8+, IL-2 receptor+, and MHC class II+ subsets showed no consistent correlation with the onset or resolution of the autoimmune process. These findings suggest that mercury-induced changes in RT6+ T lymphocytes may be related to the development of renal autoimmune disease in genetically predisposed BN rats.
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PMID:Reduction of the RT6.2+ subset of T lymphocytes in brown Norway rats with mercury-induced renal autoimmunity. 201 77

Novel islet cell, duct cell, and acinar cell markers have been identified by monoclonal autoantibodies (Maab) derived from prediabetic BB rats. Spleen cells from two rats that both developed diabetes after splenectomy were fused with mouse myeloma cells. A cellular immunoradiometric assay for differential reactivity toward the surface of two closely related, insulin- and non-insulin-producing rat islet tumor cell lines was used to select and clone several IgM-producing hybridomas. The supernatants were finally characterized by two-color immunofluorescence with islet hormone antisera on frozen sections of human, monkey, and rat pancreas. Maab EB52 stained PP cells, but also few A cells on rat pancreas. Maab CA812 identified a subpopulation of islet D cells on rat, human and monkey pancreas. Although the CA812-reactive antigen and somatostatin were coexpressed in most D cells in adult rat pancreas, only a few islet D cells were stained in the newborn pancreas. The CA812-reactive antigen was not detected in somatostatin-producing cells in the duct epithelium. Maab H37 and IF5 selectively stained acinar cells in rat, human, and monkey pancreas, whereas Maab DA39 identified the rat ductal epithelium including the scattered endocrine cells of the ducts. In summary, B lymphocytes producing autoantibodies to pancreatic endocrine, exocrine, and ductal markers are present in prediabetic BB rats and can be detected by use of transformed pluripotent islet cells as target. Such B lymphocytes can be immortalized to produce monoclonal antibodies to study their role in insulin-dependent diabetes mellitus pathogenesis and to clarify the development of the pancreas.
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PMID:Novel islet, duct, and acinar cell markers defined by monoclonal autoantibodies from prediabetic BB rats. 212 46

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

A recombinant plasmid encoding for rat preproinsulin I was encapsulated in large liposomes and injected intravenously into rats. Glycemia and blood, splenic and hepatic insulin were assayed from 6 h after inoculation. Control animals received (1) empty liposomes, (2) liposomes carrying the E. coli pBR322 plasmid, (3) the free rat insulin I gene, or (4) no injection. All controls showed unchanged glucose and insulin levels. Six hours after inoculation, the treated rats had 72 +/- 6 mg glucose per 100 ml of blood, compared with 107 +/- 2 mg for controls. Radioimmunoassay of blood insulin gave 61 +/- 8 microU/ml (43 +/- 5 microU/Ml for controls). Spleen and liver values were 242 +/- 20 and 205 +/- 22 microU/g of tissue, respectively (112 +/- 20 and 87 +/- 15 microU/g in controls). The kinetics and extent of uptake of liposomes by spleen and liver were studied by external gamma-camera imaging after injection of 111In-labeled liposomes. The results paralleled insulin synthesis in the two organs. The insulin gene was localized in liver cells after the injection of liposomes containing the plasmid encoding insulin. Livers were processed 4 h after inoculation for isolation of hepatocytes, Kupffer cells, and endothelial cells. DNA was purified and exogenous DNA detected by Southern blotting. Kupffer cells were the primary targets for gene incorporation with liposomes consisting of phospholipids and cholesterol. Targeting of liposomes to other liver cells was attempted by including lactosylceramide in the liposomes. This increased the amount of exogenous gene in hepatocytes and particularly in endothelial cells. Detailed electron microscopy and biochemical studies were performed in order to follow the liposome-encapsulated DNA from the moment of i.v. injection to its entering the nucleus of different liver cells. Interactions of liposomes taken up in vivo by the liver cells with subcellular organelles were studied as well. The mechanism of DNA transport by liposomes in vivo and its potential are discussed.
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PMID:Liposomes as carriers of DNA. 269 45

Spleen cells from non-obese diabetic mice were found to generate low interleukin 2 production and cell proliferation in response to concanavalin A. However, some of non-obese diabetic mice maintained in the same environment preserved their responsiveness to this T cell mitogen. Non-obese diabetic mice at every age had a higher percentage of Thyl.2, L3T4, and Lyt2-positive spleen cells than did control mice, suggesting that the dysfunction of spleen cells did not depend on the number of T cells or the ratio of these subpopulations. Evidence for macrophage-mediated suppression participating in the deficient function of splenic lymphocytes in this mouse model of insulin-dependent diabetes includes: 1) the restoration of mitogen-induced interleukin 2 production after the macrophages have been depleted by silica absorption form spleen cells; 2) the complete suppression of the cell proliferation by thioglycollate-stimulated peritoneal exudate cells from non-obese diabetic and control mice, and the partial suppression by spleen macrophages from non-obese diabetic mice; 3) the reversal of the suppression of interleukin 2 production by the prostaglandin synthetase inhibitor indomethacin (0.1-1 microgram/ml); 4) the partial suppression of interleukin 2 production, conversely, by the exogenous prostaglandins E1 and E2 (2.5 x 10(-6) mol/l). These results indicate that the activated macrophages existing among the spleen cells suppress the response of splenic T cells to concanavalin A. This impairment may contribute to the pathogenesis of insulin-dependent diabetes in non-obese diabetic mice.
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PMID:Suppression of concanavalin A-induced responses in splenic lymphocytes by activated macrophages in the non-obese diabetic mouse. 278 66

The non-specific activation of the immune system by administration of complete Freund's adjuvant (CFA) was examined in two congenic Lewis rat strains LEW. 1A (RT1a) and LEW. 1W (RT1u) as a possible mean of amplification of the specific immune response, directed to pancreatic beta cells induced by multiple non-diabetogenic injections of streptozotocin (STZ). Rats were given intraperitoneally 0.5 ml CFA and 1 day later 25 mg/kg body weight STZ. This combined treatment was repeated twice at weekly intervals. Control groups received vehicle, STZ or CFA only with the same doses and at the same times. Only CFA/STZ-treated rats developed a persisting hyperglycaemia (greater than 15 mmol/l glucose) namely 3/18 (17%) LEW. 1W and 47/76 (62%) LEW. 1A rats. The pancreatic insulin content in these hyperglycaemic rats was reduced by 96.6% in LEW. 1A rats and by 93% in LEW. 1W rats measured 8 weeks after the last CFA/STZ treatment. The response to CFA indicated by an increase of number of peripheral leucocytes and relative spleen weight gain at 7 days after CFA administration, was higher in LEW. 1A rats compared with those of LEW. 1W rats. Spleen cells harvested 72 h/48 h after the first and second CFA/STZ administration showed a cytotoxic reaction to isolated syngeneic islets as measured by 51Cr-release in vitro. Control rats receiving vehicle, STZ or CFA only showed no cellular anti-islet cytotoxicity. The anti-islet cytotoxicity of spleen cells was only transient and disappeared after the third CFA/STZ administration. Anti-islet cytotoxic antibodies were not detectable in this short-term study.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Genetic control of diabetes induction by complete Freund's adjuvant combined with subdiabetogenic doses of streptozotocin in Lewis rats--evidence for transient cytotoxicity against beta cells. 295 92

In the NOD mouse, an autoimmune process beginning by 5 weeks of age with lymphocyte infiltration and destruction of insulin-secreting beta cells leads to overt diabetes which begins to appear by 11 weeks of age. Although there is a high incidence of insulitis by 10 weeks of age (greater than 80%) in both males and females, by 30 weeks of age diabetic symptoms have occurred in 53-80% of females and in 12-40% of males. Intraperitoneal injection of a high dose (200 mg/kg) of cyclophosphamide (CY) consistently induces the onset of diabetes in male and female NOD mice at an age when spontaneous diabetes rarely occurs. Spleen T cells from CY-induced diabetic mice are capable of transferring the disease into irradiated nondiabetic syngeneic recipients. This indicates that the diabetogenic effect of CY is not mediated by direct toxicity on pancreatic beta cells but is mediated by abrogation of a suppressor mechanism which may prevent activation of T cells responsible for the development of diabetes in the NOD mouse. Additionally, CY is only effective in NOD mice and not in F1 hybrids between NOD and other strains of mice. Thus, the potential beta cell aggressor mechanism is not present in these hybrids as it is in homozygous mice, which indicates that it is not under the control of dominant genes.
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PMID:Anti-suppressor effect of cyclophosphamide on the development of spontaneous diabetes in NOD mice. 296 52


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