Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0010346 (Crohn's disease)
 21,615 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Type 1, or cellular, immune response is characterized by overproduction of IL-1, IL-2, IFN-gamma and TNF-alpha and is the underlying immune mechanism of some autoimmune disorders such as psoriasis, alopecia areata, rheumatoid arthritis, Crohn's disease, multiple sclerosis, insulin-dependent diabetes mellitus and experimental autoimmune uveitis. Type 2 immune response is seen in allergic and antibody-mediated autoimmune diseases and is characterized by IL-4, IL-6 and IL-10 overproduction. Linoleic acid is a precursor of prostaglandin E2 (PGE2) and its intake results in tissue production of PGE2, especially in the absence of other polyunsaturated fatty acids (PUFAS) which inhibit this conversion. PGE2 decreases the production of IL-1, IL-2, IFN-gamma and TNF-alpha and proliferation of TH1 cells and increases the production of IL-4, leading to suppression of the type 1 immune response. Taken together, linoleic acid, the major PUFA of maize oil, could have therapeutic efficacy against cellular autoimmune disorders. On the other hand, excessive intake of linoleic acid may aggravate type 2 autoimmune disorders.
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PMID:The beneficial and detrimental effects of linoleic acid on autoimmune disorders. 1511 15

Atopic dermatitis has been characterized as an autoimmune or auto-allergic phenomenon in which environmental allergens resembling human proteins activate auto-reactive T-cells to release pro-inflammatory cytokines of the T-helper 2 (Th2) cytokine profile (IL-4, IL-5, IL-10, and IL-13). Infliximab is a chimeric IgG1 monoclonal antibody that blocks the effects of the inflammatory cytokine tumor necrosis factor (TNF)-alpha. Infliximab has been shown to benefit greatly patients suffering from diseases associated with a Th1 profile (IL-1, TNF-alpha, and IFN-mu), such as psoriasis, Crohn's disease and rheumatoid arthritis. Some researchers have suggested that disrupting the Th1-Th2 balance by downregulating Th1 cytokines may result in manifestations of Th2 disease. Consistent with this hypothesis, we present the cases of three patients who exhibited vivid manifestations of atopic dermatitis after the inception of infliximab induction therapy.
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PMID:Counter-regulatory balance: atopic dermatitis in patients undergoing infliximab infusion therapy. 1517 69

TNF can potentiate IFN-gamma production by activated T cells and other members of the TNF-superfamily play key roles in this effect. A newly discovered TNF-superfamily cytokine (TL1A) could also be involved in initiating or promoting the Th1 response by enhancing IFN-gamma production. The purpose of this study was to assess the role of recombinant TL1A on IFN-gamma production by cultured PBMC and lamina propria LPMC and to determine whether TL1A expression is altered in inflammatory bowel disease. IFN-gamma, but not IL-4 or IL-10 production by PBMC and LPL, was dose-dependently augmented by TL1A (or by activation of its receptor, death domain receptor 3 [DR3], with specific mAb) independently of, but in synergy with, IL-12 and IL-18. T cell activating stimuli induced expression of TL1A on the cell membrane (mb-TL1A) in a fraction of peripheral blood (PB) T cells. In the intestinal mucosa, a fraction of lamina propria (LP) T cells, especially CD4+ cells, constitutively expressed mb-TL1A, and the fraction increased in mucosal inflammation. A higher fraction of cells also express the TL1A receptor DR3 in ulcerative colitis and Crohn's disease. TL1A transcript was several times more abundant in RNA from mucosal biopsies taken from inflamed Crohn's disease lesions than in those taken from uninvolved areas. Expression of TL1A and its receptor DR3 by lamina propria mononuclear cells (LPMC) could have significant influence on the severity of mucosal inflammation.
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PMID:Potential role for TL1A, the new TNF-family member and potent costimulator of IFN-gamma, in mucosal inflammation. 1520 83

Mutations of the NOD2 gene have been associated with an increased susceptibility to Crohn's disease, but the pathogenetic mechanisms mediated by NOD2 remain elusive. In the present study, we demonstrate that the 3020insC frameshift-mutation in the NOD2 gene associated with Crohn's disease results in defective release of IL-10 from blood mononuclear cells after stimulation with the Toll-like receptor (TLR)2 ligands, peptidoglycan and Pam3Cys-KKKK, but not with bacterial LPS, a TLR4 ligand. The potential pathophysiological significance of this finding in patients with Crohn's disease and who are homozygous for this NOD2 mutation was substantiated by the finding of decreased anti-inflammatory cytokine release when cells from these patients were stimulated with different species of Bacteroides, an enteric microorganism implicated in the pathogenesis of Crohn's disease. In conclusion, defective NOD2 function results in a pro-inflammatory cytokine bias after stimulation of mononuclear cells with TLR2 stimuli, and this could contribute to the overwhelming inflammation seen in Crohn's disease.
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PMID:NOD2 mediates anti-inflammatory signals induced by TLR2 ligands: implications for Crohn's disease. 1521 53

Several lines of evidence link inflammatory bowel diseases to modifications of intestinal microflora. Epidemiologic and clinical data suggest a triggering role for select agents in ulcerative colitis and in Crohn disease. Experimental evidence indicates that intestinal microorganisms are needed for developing intestinal inflammation in IL-10 knockout mice, and this is associated with an increased number of adherent clostridia and a decrease of lactobacilli and bifidobacteria. It may be hypothesized that a host-agent-specific relationship leads to an abnormal immune response, which may be genetically driven in select inflammatory bowel diseases. However, different from adults, the pattern of intestinal microflora undergoes profound changes during the early stage of life, contributing to the development of the immune system. A close relationship exists between microbiologic and immunologic imprinting. The microbiologic imprinting in neonates may be modified using bacterial probiotics that colonize the intestine, modify the immune response, and decrease the risk for atopy. Probiotics may decrease the recurrences of inflammatory bowel diseases. Preliminary evidence of intestinal antiinflammatory effects has been detected in children with cystic fibrosis. Overall these data provide the rationale to investigate the interaction between intestinal microflora and the local and general immune response in children with, or at risk for, inflammatory bowel diseases. This approach may be a key for understanding the pathophysiology of intestinal inflammation and may disclose novel strategies to educate better the immune system, particularly during its developmental stage.
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PMID:Microflora in inflammatory bowel diseases: a pediatric perspective. 1522 Jun 68

The mechanisms responsible for development of inflammatory bowel disease (IBD) have not been fully elucidated, although the main cause of disease pathology is attributed to up-regulated inflammatory processes. The aim of this study was to investigate frequencies of polymorphisms in genes encoding pro-inflammatory and anti-inflammatory markers in IBD patients and controls. We determined genotypes of patients with IBD (n= 172) and healthy controls (n= 389) for polymorphisms in genes encoding various cytokines (interleukin (IL)-1beta, IL-6, tumour necrosis factor (TNF), IL-10, IL-1 receptor antagonist). Association of these genotypes to disease incidence and pathophysiology was investigated. No strong association was found with occurrence of IBD. Variation was observed between the ulcerative colitis study group and the control population for the TNF-alpha-308 polymorphism (p= 0.0135). There was also variation in the frequency of IL-6-174 and TNF-alpha-308 genotypes in the ulcerative colitis group compared with the Crohn's disease group (p= 0.01). We concluded that polymorphisms in inflammatory genes are associated with variations in IBD phenotype and disease susceptibility. Whether the polymorphisms are directly involved in regulating cytokine production, and consequently pathophysiology of IBD, or serve merely as markers in linkage disequilibrium with susceptibility genes remains unclear.
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PMID:Inflammatory bowel disease: the role of inflammatory cytokine gene polymorphisms. 1522 9

SAMP1/YitFc mice develop discontinuous, transmural inflammatory lesions in the terminal ileum, similar to what is found in human Crohn disease. Compared with the mesenteric lymph nodes (MLNs) of AKR control mice, SAMP1/YitFc MLNs contain a 4.3-fold expansion in total B cell number and a 2.5-fold increased percentage of CD4(+) T cells expressing the alpha(E)beta(7) integrin. Although alpha(E)beta(7)(+)CD4(+) T cells possess a regulatory phenotype (CD25(+), L-selectin(lo), and CD45RB(lo)), express IL-10, and suppress effector T cell proliferation in vitro, they cannot prevent ileitis development in SCID mice adoptively transferred with effector CD4(+) T cells, although the CD4(+)CD25(+) subset, which overlaps with the alpha(E)beta(7)(+)CD4(+) subset, prevents colitis. The alpha(E)beta(7)(+)CD4(+) T cells express high levels of ICOS, a costimulatory molecule that augments B cell function, suggesting their involvement in the increase in B cells, IgA(+) cells, and soluble IgA found within the MLNs and ileum of SAMP1/YitFc mice. MLN B cell numbers correlate with ileitis severity in SAMP1/YitFc mice, and cotransfer of SAMP1/YitFc MLN B cells along with CD4(+) T cells increases ileitis severity in SCID mice compared with transfer of CD4(+) T cells alone. SAMP1/YitFc B cells prevent alpha(E)beta(7)(+)CD4(+) T cells from suppressing effector T cell proliferation. We conclude that SAMP1/YitFc MLN B cells contribute to the development of SAMP1/YitFc ileitis.
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PMID:Expanded B cell population blocks regulatory T cells and exacerbates ileitis in a murine model of Crohn disease. 1528 5

Immune system is a major determinant of pathophysiology of inflammatory bowel disease (IBD), and cytokines are well known mediators of immune system. Recently, informations on pro-inflammatory cytokines and their role in IBD have led to development of potential therapeutic approach to manipulate these cytokines and there by inhibiting inflammation in IBD. These therapeutic approaches include inhibitors of the tumour necrosis factor (TNF)-alpha lymphocyte trafficking, type 1 T helper (Th1) cell polarization and nuclear factor type beta; immunoregulatory cytokines and various growth factors. Studies on these therapies have documented variable results and the outcomes of many clinical trials are awaited. However, these potential therapies, if become real may revolutionise approach in patients with IBD. Analysis of the inflammed mucosa from patients with Crohn disease (CD) and ulcerative colitis (UC) have shown increased expression of certain proinflammatory cytokines such as interleukin-1 (IL-1), interleukin 6 (IL-6) and TNF-alpha. The latter is important in the recruitment of neutrophils into inflammed tissue, a process which results from three physiological steps: (i) rolling, (ii) adhesion, and (iii) transendothelial migration. Understanding of the biology of chronic inflammation has expanded the therapies available for IBD and particularly CD. At present, the biological therapies that are being used in clinical practice or investigated for the treatment of IBD are predominantly proteins, usually delivered intravenously or subcutaneously. The therapies used include: 1. TNF-alpha inhibitors: infliximab, CDP 571, etanercept, onercept, CNI- 1493 and thalidomide. 2. Inhibitors of lymphocyte trafficking: natalizumab, LPD-02 and ICAM-1. 3. Inhibitors of Th1 polarization: monoclonal antibodies for IL-12, interferon (IFN)-gamma and anti IFN-gamma. 4. Immunoregulatory cytokines: IL-10 and IL-11. 5. Inhibitors of nuclear factor kappa (beta NF-kbeta.) 6. Growth factors: epidermal growth factor (EGF) and Keratinocyte growth factor (KGF).
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PMID:Recent advances in biological therapy for inflammatory bowel disease. 1530 63

The transfer of genes encoding immunoregulatory proteins is a promising new strategy in the treatment of intestinal inflammation. Previous work has demonstrated that daily systemic interleukin (IL)-10 therapy is able to prevent disease onset in animal models of colitis but is not sufficient to treat established disease. This study investigates the therapeutic efficacy of an adenovirus encoding IL-10 (AdvmuIL-10) in the treatment of experimental colitis. Colitis was induced in BALB/c mice by the addition of dextran sodium sulfate to the drinking water for 7 days. A single systemic injection of AdvmuIL-10, empty cassette vector (Adv0), or saline vehicle was administered on day 4 after the onset of colitis. The addition of DSS to the drinking water led to an acute, dose-dependent colitis. A single injection of AdvmuIL-10 led to a marked reduction in both stool markers of inflammation (IL-1beta, IL-6, and TNFRII) and serum IL-6. Furthermore, the histological colitis score was significantly reduced in mice receiving AdvmuIL-10 compared to controls (4.9 +/- 1.1 Vs 9.1 +/- 1.2, respectively; P < 0.05). A single systemic injection of AdvmuIL-10 is therapeutic in mice with established DSS colitis. Gene therapy strategies using adenoviral vectors encoding IL-10 may prove to be a potent therapy for chronic inflammation of the colon such as Crohn's disease.
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PMID:IL-10 gene therapy is therapeutic for dextran sodium sulfate-induced murine colitis. 1538 64

T-helper-1 (Th1) cytokines play an important role in Crohn's disease, and interleukin-12 (IL-12), which is composed of two subunits, p40 and p35, drives Th1 differentiation. In previous reports, IL-12 p40 was shown to prevent IL-12 from binding to the receptor. We demonstrate here the effect of IL-12 p40 overexpression in intestinal epithelia on enterocolitis mediated by Th1 cells in IL-10-deficient (IL-10(-/-)) mice on a C57BL/6J background. IL-10 deficient (IL-10(-/-))/T3b-IL-12 p40+ (IL-12 p40+) mice and IL-10(-/-)/T3b-IL-12 p40- (IL-12 p40-) mice were generated by crossing T3b-IL-12 p40 transgenic mice and IL-10(-/-) mice. At 8 weeks of age, IL-12 p40+ mice did not show any clinical manifestations of colitis. The colon length of IL-12 p40- mice became shorter than that of IL-12 p40+ mice. The histological score of IL-12 p40+ mice was lower. Interferon-gamma (IFN-gamma) production was suppressed in both the mesenteric lymph node cell culture and colon tissue culture of IL-12 p40+ mice. There was no significant difference in IL-4 production and tumor necrosis factor-alpha (TNF-alpha) production between the two groups. These results show that overexpression of IL-12 p40 in intestinal epithelia prevents enterocolitis in IL-10(-/-) mice by suppressing IFN-gamma production, and suggest a potential clinical application of IL-12 p40 for Crohn's disease. Furthermore, these results also suggest that local gene transduction in the intestinal epithelium may be a potent therapeutic approach for Crohn's disease.
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PMID:IL-12 p40 prevents the development of chronic enterocolitis in IL-10-deficient mice. 1544 6


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