Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.7.48 (transcriptase)
9,479 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The cytokine effector status of CD4+ T cells from lymph nodes (LN) and the central nervous system (CNS) of SJL/J mice immunized with autoantigen in adjuvant for the induction of experimental allergic encephalomyelitis (EAE) was compared. CD4+ T cells were FACS sorted based on the levels of expression of the activation marker CD45RB. Low levels of expression of this surface marker are induced by antigen recognition and are associated with 'effector' T cell function. Reverse transcriptase polymerase chain reaction (PCR) was used to analyze the expression of different T cell cytokine genes in the sorted populations. CD45RBlow cells constituted a minority of CD4+ cells in the LN and expressed elevated levels of IL-2, IFN-gamma, and IL-4 mRNA, whereas the CD45RBlow CD4+ population did not express detectable message for these cytokines under linear PCR conditions. By contrast to the LN, CD4+ cells from the CNS were predominantly CD45RBlow and expressed readily detectable levels of IL-2 and IFN-gamma mRNA, but almost no IL-4 transcription could be detected. IL-4 mRNA levels in CNS were 100- to 250-fold lower than in LN. Also, IL-4 message could not be detected in the CNS 1 week after remission. A cytokine-specific immunocytochemical single cell staining technique was used to enumerate cytokine-producing cells in LN cell populations and in CNS infiltrates. Between 1 and 5% cells in isolated LN cells produced detectable IL-2 and IFN-gamma. By contrast, the frequency of cytokine-producing cells stained in perivascular infiltrates in frozen sections from the brains of animals with active EAE was 10-fold higher.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Selective enrichment of Th1 CD45RBlow CD4+ T cells in autoimmune infiltrates in experimental allergic encephalomyelitis. 791 Apr 82

Rapid and severe rejection remains a major obstacle to successful clinical intestinal transplantation (IT). The aggressive nature of rejection in IT has been attributed to the increased massive immune stimulus provided by large numbers of resident lymphocytes, antigen presentation capacity of enterocytes, and graft damage mediated by luminal microflora. Early small bowel expression of proinflammatory cytokines, MHC class II, and adhesion molecules may also promote IT rejection, but the lack of a mouse model has hampered extensive studies of gene expression in IT. Using a recently developed surgical model, we examined the temporal pattern of gene expression in CB6F1 (H-2b/d) vascularized, heterotopic intestinal allografts transplanted into BALB/c (H-2d) mice. Although histological evidence of rejection was not present until day 7 in allografts, Northern blot analysis demonstrated increases in TNF alpha gene transcripts as early as day 3, followed by the expression of IL-1 beta, intercellular adhesion molecule-1, and MHC class II by day 5. Using reverse-transcriptase polymerase chain reaction, IFN-gamma was detected in allografts by day 3 and persisted to day 10. In contrast, IL-2, IL-4, IL-5, and IL-6 mRNA transcripts peaked by day 5 and then decreased, suggesting that both Th1 and Th2 subsets are involved in the rejection of unmodified small bowel allografts. The early and progressive expression of TNF alpha and IL-1 beta as well as IFN-gamma, intercellular adhesion molecule-1, and MHC class II in IT rejection may contribute to the difficulty in controlling IT rejection with present immunosuppression.
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PMID:Altered gene expression of cytokine, ICAM-1, and class II molecules precedes mouse intestinal allograft rejection. 794 Jul 16

Reverse transcriptase-polymerase chain reaction showed that interleukin 3, IL-4, IL-5, IL-6, interferon-gamma and stem cell factor mRNA expression were higher in 15-deoxyspergualin-treated spleen cells than in control spleen cells. Increased IL-2 and IFN-gamma mRNA expression were observed in 15-deoxyspergualin-treated bone marrow cells. On the other hand, increased platelet counts in BALB/c-->C3H/He bone marrow chimeras were observed from days 20 to 33 in our previous work, when they were treated with 15-deoxyspergualin from days 14 to 25. In contrast, marked leukocytopenia and anemia were simultaneously observed, although a marked leukocytosis and a rapid recovery of anemia were observed on day 33 and thereafter. To analyze effects of 15-deoxyspergualin on hematopoiesis and the immune system, we examined mRNA expression in bone marrow and spleen cells from BALB/c-->C3H/He bone marrow chimeras treated with 15-deoxyspergualin from days 14 to 25. Reverse transcriptase-polymerase chain reaction showed that IL-3, IL-4, IL-6, stem cell factor, granulocyte colony-stimulating factor, and granulocyte/macrophage colony-stimulating factor mRNA expression were higher in 15-deoxyspergualin-treated chimeras than in control chimeras, indicating that these cytokines are responsible for an enhancement of hematopoiesis. It was conceivable that IL-6 supported thrombopoiesis in concert with other cytokines. On the contrary, increased IFN-gamma, IL-2, IL-3, IL-4, and IL-10 mRNA expression may play an immunosuppressive role in vivo.
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PMID:Effects of 15-deoxyspergualin in vitro and in vivo on cytokine gene expression. 797 17

Inflammatory cytokines, particularly those produced by Th1 type lymphocytes, are hypothesized to play a major role in the pathogenesis of autoimmune diseases. The present studies investigated this hypothesis in the BB rat. Diabetes-prone (DP) BB rats develop spontaneous hyperglycemia and thyroiditis. Coisogenic diabetes-resistant (DR) BB rats do not develop either disorder spontaneously, but both diseases are induced by depletion of RT6+ T cells. Reverse transcriptase-PCR was used to measure mRNA encoding type 1 and type 2 cytokines. In both DP and RT6-depleted DR rats, IFN-gamma mRNA was present in islets before and during disease onset. IL-2 and IL-4 mRNAs were minimal or undetectable in infiltrated islets but present in activated peripheral T cells. IL-10 mRNA was present at low abundance in infiltrating T cells. These observations suggested a Th1 type inflammatory response, and consistent with this interpretation, we observed that mRNA encoding the p40 chain of IL-12 was also present before and during disease onset. Similar cytokine mRNA profiles were observed in the thyroids of RT6-depleted DR rats and in the islets of DP rats treated with prophylactic parenteral insulin to prevent diabetes. We conclude that IFN-gamma and IL-12 may play a major role in the expression of insulitis and thyroiditis in the BB rat, that Th1 lymphocytes may predominate over Th2 lymphocytes in these inflammatory lesions, and that prevention of diabetes by insulin is not associated with an alteration in the cytokine gene profile of islet infiltrating cells.
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PMID:Cytokine gene expression in islets and thyroids of BB rats. IFN-gamma and IL-12p40 mRNA increase with age in both diabetic and insulin-treated nondiabetic BB rats. 855 12

Distinct cytokine-producing T cell subsets are well known to play a major role in IgE production and to be differentially regulated in allergic patients, although the characterization of the type 1/type 2 cytokine pattern in PBMC during allergic responses remains to be clearly defined. The aim of this study was to determine whether different cytokine profiles are observed directly in PBMC of atopic donors. We attempted to study several cytokines (IL-2, IFN-gamma, IL-4, IL-10 and IL-13) using not only ELISA but also polymerase chain reaction (PCR) techniques, because the frequency of cytokine-producing cells in peripheral blood is very low. All the patients were selected during their acute symptomatologic phase. Data showed a significantly higher production of IL-4 (P = 0.05) and IL-10 (P < 0.005) as determined by ELISA in phytohaemagglutinin (PHA)/phorbol myristate acetate (PMA)-stimulated mononuclear cells of atopic donors compared with controls, although spontaneous IL-4 production without stimulation was never detected within either atopic or control groups. The reverse-transcriptase (RT)-PCR technique appeared to be advantageous in that it allowed the detection of the spontaneous expression of cytokine mRNA in cells without stimulation. We found a clear expression of IL-4 mRNA spontaneously in all atopic patients, whereas normal donors in most cases did not show specific signals (P < 0.0001). Less differences between atopic subjects and controls were found in IL-10 mRNA expression. Although the technique of RT-PCR amplification used in this study is semiquantitative, a reproducible and significant (P < 0.001) enhancement of IL-10 mRNA expression was observed in atopic donors. A heterogeneous expression of IL-13 mRNA was observed in individuals from the two groups studied, although mean levels in atopic donors were slightly enhanced compared with controls (P = 0.02). Furthermore, we did not observe any alteration in the expression of the type 1-derived cytokines such as IFN-gamma and IL-2. In addition, we showed a lack of correlation between the expression of serum IgE (total or specific) and spontaneous IL-4 mRNA expression. This study showed a tendency of PBMC from atopic donors to express a type 2-like cytokine pattern, with IL-4 as the most discriminatory cytokine. Additionally, as the level of serum IgE has a low predictive value in allergic disease, and as the elevated expression of IL-4 that we found was not correlated with serum IgE, we could strongly suggest that the measurement of IL-4 in blood mononuclear cells may be of great value in the analysis of allergic responses in atopic donors.
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PMID:Differential spontaneous expression of mRNA for IL-4, IL-10, IL-13, IL-2 and interferon-gamma (IFN-gamma) in peripheral blood mononuclear cells (PBMC) from atopic patients. 856 69

CTLA4Ig, a fusion protein that blocks CD28-B7 costimulation, was studied in a LEW to F344 rat model of chronic cardiac rejection. In rats treated with a single dose of CTLA4Ig (0.5 mg intraperitoneally) 2 d after transplantation, allografts survived significantly longer ( > 70 d in 64%) than in untreated controls or rats treated with control Ig (all rejected within 25 d). Only 25% of grafts from rats treated with a single, high dose of cyclosporine A (25 mg/kg, 2 d after transplantation) survived longer than 70 d. Reverse transcriptase PCR and immunostaining analyses of tissue from 75-d, CTLA4Ig-treated allografts showed reduced expression of the T cell factor IFN-gamma and macrophage activation factors monocyte chemoattractant protein-1, inducible nitric oxide synthase, and galactose/N-acetylgalactosamine macrophage lectin, as well as TGF-beta. Grafts from longterm survivors ( > 120 d) treated with CTLA4Ig showed significant reductions in the frequency and severity of arteriosclerosis in comparison with cyclosporine A-treated rats. Thus, T cell activation is a proximal event in the cascade that culminates in the arteriosclerosis of chronic rejection. Strategies for blocking T cell costimulation may help prevent chronic rejection in clinical transplantation.
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PMID:Chronic cardiac rejection in the LEW to F344 rat model. Blockade of CD28-B7 costimulation by CTLA4Ig modulates T cell and macrophage activation and attenuates arteriosclerosis. 860 41

We report that I-Ab-restricted T cell clones, elicited by influenza infection of C57BL/10 mice and specific for the hemagglutinin peptide HA1 186-205, express class II. They respond to peptide stimulation by IL release (IL-3 or IFN-gamma) without a requirement for APC but do not proliferate. Moreover, surface expression of class II requires de novo synthesis in the presence of the stimulatory peptide and is inhibited by coculture with TCR-specific Ab, or brefeldin A or cycloheximide. Clonotypic specificity of peptide induction was confirmed by failure of other allele specific peptides to enhance class II expression. Addition of the viral peptide to T cells induced homotypic adhesion, which provides a physical basis for stabilization of class II-peptide complexes at the cell surface. Extinction of class II expression was evident in the corresponding T cell hybridomas, which might account for the failure to report class II expression by murine T cells. Control studies indicated that class II was not passively acquired from APC by demonstrating 1) failure of processed Ag to induce class II expression, 2) allo-class II (Ak) was not acquired by coculture with peptide and semisyngeneic (H-2 b/k) APC, 3) absence of class II expression by a NP peptide-specific Th2 clone under identical culture conditions, and most significantly, 4) reverse-transcriptase PCR amplification and surface expression of class II using highly purified preparations of FACS-selected CD4+ class II- cells cocultured with the stimulatory peptide.
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PMID:Viral peptide specific induction of MHC class II expression by murine T cell clones. 880 37

IFN-gamma is critical for prevention of development of toxoplasmic encephalitis (TE). Since IL-4 down-regulates production of IFN-gamma, we examined its role in the pathogenesis of TE in IL-4-targeted mutant (IL-4-/-) mice. IL-4-/- mice all died from 6 to 20 wk after peroral infection with cysts of the ME49 strain of Toxoplasma gondii; control mice survived. At 4 and 8 wk after infection, significantly greater numbers of T. gondii cysts and foci of acute inflammation, and greater amounts of tachyzoite-specific mRNA (by reverse-transcriptase PCR) were in brains of IL-4-/- mice than controls. Toxoplasma IgG2b and IgG3 Ab levels were slightly but significantly higher in sera of IL-4-/- than control mice, whereas IgM and IgG2a levels did not differ between these mice. Toxoplasma IgG1 and IgE Abs were not detected in sera of either strain. Amounts of IFN-gamma, TNF-alpha, IL-6, and IL-10 mRNA detected by reverse-transcriptase PCR did not differ between brains of infected IL-4-/- and controls, although brains of the former mice had greater numbers of inflammatory mononuclear cell infiltrates. IL-4 mRNA was detected only in infected control mice. Spleen cells of control mice at 8 wk after infection produced significantly greater amounts of IFN-gamma following stimulation in vitro with soluble T. gondii Ags than did those from IL-4-/- mice. These results indicate that IL-4 is protective against development of TE by preventing formation of T. gondii cysts and proliferation of tachyzoites in the brain. The impaired ability of IL-4-/- mice in the late stage of T. gondii infection to produce IFN-gamma most likely contributes to their susceptibility for development of severe TE.
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PMID:IL-4 is protective against development of toxoplasmic encephalitis. 880 58

SJL mice immunized with proteolipid protein (PLP) develop relapsing experimental autoimmune encephalomyelitis (R-EAE). R-EAE is a CD4+, Th1 cell-mediated demyelinating disease of the central nervous system (CNS) that is used as a model for the human disease multiple sclerosis (MS). Previous studies showed that young (< 8 weeks) male SJL mice were resistant to active induction of EAE with CNS homogenate, while female mice were susceptible. We have recently observed that young male SJL mice immunized with a major encephalitogenic peptide of myelin, PLP 139-151, developed initial clinical and histological symptoms of EAE with a severity similar to age-matched females; however, unlike females, male mice did not relapse. Significant T cell proliferation to PLP 139-151, but not to other PLP and myelin basic protein (MBP) epitopes, was observed in both males and females during the initial episode, recovery, and first relapse of clinical disease. Reverse transcriptase-polymerase chain reaction (RT-PCR) analysis of lymphokine mRNA revealed differences in IFN-gamma and IL-4 synthesis consistent with the hypothesis that Th2 T cells develop in young male SJL mice that regulate the relapsing phase of the disease. These data suggest that immunization of young male SJL mice with PLP 139-151 overrides a defect in antigen presentation responsible for the previously observed resistance to EAE, and that natural processing and presentation of neuroantigens during the course of acute EAE induces Th2 cells that prevent the relapse of disease.
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PMID:Male SJL mice do not relapse after induction of EAE with PLP 139-151. 889 79

Reverse transcriptase-polymerase chain reaction (RT-PCR) was used to identify intrarenal expression of cytotoxic attack molecules (granzyme B and perforin) and immunoregulatory cytokines (IL-2, IL-4, IL-10, IFN-gamma, and TGF-beta 1) in 127 human renal allograft biopsies. The biopsies were classified using the Banff criteria, and intrarenal gene expression was correlated with the histological diagnosis. Molecular analyses revealed that intragraft display of mRNA encoding granzyme B, IL-10 or IL-2 is a correlate of acute rejection, and intrarenal expression of TGF beta 1 mRNA, of chronic rejection. These data, in addition to demonstrating differential and highly selective intragraft gene expression during rejection, suggest that therapeutic strategies directed at the molecular correlates of rejection might refine existing anti-rejection strategies.
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PMID:Molecular analyses of human renal allografts: differential intragraft gene expression during rejection. 906 37


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