Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019158 (hepatitis)
 30,205 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Murine intrahepatic lymphocytes (IHL) are dominated by invariant TCR alpha-chain expressing CD1d-reactive NKT cells, which can cause model hepatitis. Invariant NKT (CD56(+/-)CD161(+)) and recently identified noninvariant CD1d-reactive T cells rapidly produce large amounts of IL-4 and/or IFN-gamma and can regulate Th1/Th2 responses. Human liver contains large numbers of CD56(+) NKT cells but few invariant NKT. Compared with matched peripheral blood T cell lines, primary IHL lines from patients with chronic hepatitis C had high levels of CD161 and CD1d reactivity, but the invariant TCR was rare. CD1d-reactive IHL were strikingly Th1 biased. IHL also demonstrated CD1d-specific cytotoxic activity. Hepatocytes and other liver cells express CD1d. These results identify a novel population of human T cells that could contribute to destructive as well as protective immune responses in the liver. CD1d-reactive T cells may have distinct roles in different tissues.
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PMID:Cutting edge: Compartmentalization of Th1-like noninvariant CD1d-reactive T cells in hepatitis C virus-infected liver. 1182 74

Alfa-Galactosyl Ceramide was isolated from Ocean sponge which has antitumor effect against several tumors in in vivo animal model with no cytotoxicity. KRN7000(KRN) is the most potent alpha-Galactosyl Ceramide modified from the one isolated from Ocean sponge. KRN is also active against metastatic tumors through the activation ofanimal immune system. Research efforts in learning the mechanism of action, we found the important role of dendritic cells(DC) and NKT cells. NKT cells was first characterized in 1988 which is overlap some part with NK cells and T-Cells and majority is different from NK and T. KRN is active through the activation of DC and NKT in giving antigen specific immune stimulation in animal. This antigen specific stimulation is memorized by immune system and can reject second tumor challenge. KRN is not active in nude mice and NKT deficient animal. NKT cells level in blood is lower in patients with autoimmune disease, cancer, HIV positive or aplastic anemia. NKT rapidly releases IL-4 and IFN-gamma at high level when activated. NKT is CD1d and TCR restricted. NKT plays important role in autoimmune disease such as Type 1 Diabetes, Scleroderma and Systemic Lupus Erythematosus, infections such as Mycobacteria, Listeria and Malaria, GVHD control and tumor rejection. NKT acts as double edge sword, aggressive and suppressive ways. KRN can prevent the onset of Type 1 Diabetes, inhibit replication of hepatitis virus B in liver and suppress malaria replication in activating NKT cells. KRN can activate NKT through DC and activated NKT activates NK, T and macrophage. KRN also expands NKT cells and expanded NKT has full function. Although the exact role of DC and NKT is not clear, KRN clinical study results in conjunction with DC and NKT cell activation are expected.
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PMID:Role of NKT cells and alpha-galactosyl ceramide. 1243 Aug 64

Hepatitis C virus (HCV) infection induces an acute and chronic liver inflammation through an immune-mediated pathway that may lead to cirrhosis and liver failure. Indeed, HCV-related hepatitis is characterized by a dramatic lymphocyte infiltrate into the liver which is mainly composed by HCV non-specific cells. Several data indicated that interferon (IFN)-gamma secretion by intrahepatic lymphocytes (IHL) may drive non-specific cell homing to the liver, inducing interferon inducible protein-10 (IP-10) production. An interesting hallmark of these IHL is the recruitment of lymphocytes associated with mechanisms of innate immunity, such as natural killer (NK), natural killer T (NKT) and gamma delta T lymphocytes. CD81 triggering on NK cell surface by the HCV envelope glycoprotein E2 was recently shown to inhibit NK cell function in the liver of HCV-infected persons, resulting in a possible mechanism contributing to the lack of virus clearance and to the establishment of chronic infection. In contrast, intrahepatic NKT cells restricted to CD1d molecules expressed on the hepatocyte surface may contribute to a large extent to liver damage. Finally, an increased frequency of T cells expressing the gamma delta T cell receptor (TCR) was observed in HCV-infected liver and recent observations indicate that intrahepatic gamma delta T cell activation could be directly induced by the HCV/E2 particle through CD81 triggering. These cells are not HCV specific, are able to kill target cells including primary hepatocytes and their ability to produce T helper (Th)1 cytokines is associated with a higher degree of liver disease. Together, CD1d/NKT and/or E2/CD81 interactions may play a major role in the establishment of HCV immunopathogenesis. In the absence of virus clearance, the chemokine-driven recruitment of lymphocytes with an innate cytotoxic behavior in the liver of HCV-infected patients may boost itself, leading to necroinflammatory and fibrotic liver disease.
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PMID:Lymphocyte distribution and intrahepatic compartmentalization during HCV infection: a main role for MHC-unrestricted T cells. 1245 64

CD1d is a major histocompatibility complex (MHC) class I-related molecule that functions in glycolipid antigen presentation to distinct subsets of T cells that express natural killer receptors and an invariant T-cell receptor-alpha chain (invariant NKT cells). The acquisition of glycolipid antigens by CD1d occurs, in part, in endosomes through the function of resident lipid transfer proteins, namely saposins. Here we show that microsomal triglyceride transfer protein (MTP), a protein that resides in the endoplasmic reticulum of hepatocytes and intestinal epithelial cells (IECs) and is essential for lipidation of apolipoprotein B, associates with CD1d in hepatocytes. Hepatocytes from animals in which Mttp (the gene encoding MTP) has been conditionally deleted, and IECs in which Mttp gene products have been silenced, are unable to activate invariant NKT cells. Conditional deletion of the Mttp gene in hepatocytes is associated with a redistribution of CD1d expression, and Mttp-deleted mice are resistant to immunopathologies associated with invariant NKT cell-mediated hepatitis and colitis. These studies indicate that the CD1d-regulating function of MTP in the endoplasmic reticulum is complementary to that of the saposins in endosomes in vivo.
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PMID:CD1d function is regulated by microsomal triglyceride transfer protein. 1510 43

A subset of CD161(+)CD56(+/-) NKT cells can recognize glycolipids presented by CD1d and positively or negatively regulate inflammatory responses, including those implicated in several models of hepatitis. CD1d is expressed at very low levels in the healthy liver, but there is a large fraction of CD161(+)CD56(+) NKT cells. There are high levels of nonclassical proinflammatory hepatic CD1d-reactive T cells in hepatitis C virus (HCV) infection. Hepatic inflammatory cells and biliary cells adjacent to portal tract fibrotic areas of HCV-infected donors specifically up-regulated CD1d. A hepatocyte cell line expressing minimal CD1d was efficiently recognized by hepatic CD1d-reactive T cells, suggesting a role for these cells in disease. Hepatic CD1d-reactive T cells from HCV-positive as well as negative donors produced large amounts of IFN-gamma with some IL-13, but only rarely detectable IL-4. We confirmed large numbers of hepatic CD161(+) T cells, lower levels of CD56(+) T cells, and small numbers of classic invariant NKT cells. However, hepatic CD1d-reactivity was not restricted to any of these populations. We suggest virally infected hepatic cells can process potent CD1d-presented liver Ag(s), for surveillance by resident Th1 hepatic CD1d-reactive T cells. This process may be beneficial in acute viral clearance, but in chronic infection could contribute to liver injury.
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PMID:Hepatic CD1d expression in hepatitis C virus infection and recognition by resident proinflammatory CD1d-reactive T cells. 1526 53

Wilson disease (WD) is an autosomal recessive disorder of copper transport, resulting in copper accumulation and toxicity to the liver and brain. There is no evidence that the WD patient's immune system attacks copper accumulated hepatocytes. Here we describe that the frequency and absolute number of Valpha24+Vbeta11+ natural killer T (NKT) cells were significantly increased in 3 cases of WD, whereas those of CD3+CD161+ NKT cells were within the normal range. Patients no. 1 and 2 had a presymptomatic form of WD. Their tissue specimens showed pathological changes of mild degeneration of hepatocytes with a few infiltrating mononuclear cells and a low degree of fatty change. Patient no. 3 displayed fulminant hepatitis with Coombs-negative haemolytic anaemia. The tissue specimens of patient no. 3 showed macronodular cirrhosis with thick fibrosis, inflammatory infiltrates and spotty necrosis. Human Valpha24+Vbeta11+ NKT cells are almost equal to CD1d-restricted NKT cells. Therefore we investigated CD1d-restricted NKT cells in the LEC rat as an animal model of WD. In LEC rats before hepatitis onset, the number and phenotype of liver NKT cells were normal. At about 4 months of age all LEC rats developed acute hepatitis accompanied by acute jaundice, and CD161high NKT cells developed in their livers. CD161highalphabetaTCRbright NKT cells developed in some of them. Their hepatitis was severe. CD161highalphabetaTCRbright NKT cells expressed an invariant rat Valpha14-Jalpha281 chain, which is CD1d-restricted. Furthermore, liver lymphocytes in the acute jaundiced LEC rats with CD161highalphabetaTCRbright NKT cells had significant and CD1d-specific cytotoxic activity.
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PMID:Contribution of Va24Vb11 natural killer T cells in Wilsonian hepatitis. 1560 25

CD1d-restricted natural killer T (NKT) cells are involved in the regulation of various immune responses, and have been shown to inhibit viral replication in animal hepatitis models when activated by the glycolipid alpha-galactosylceramide (alpha-GalCer, KRN7000). Previous studies have indicated that alpha-GalCer-induced activation of the immune system requires both CD1d expression by antigen-presenting cells as well as (normal) numbers of NKT cells. Discrepancies exist over circulating numbers of human invariant Valpha24+Vbeta11+ NKT cells during hepatitis C virus (HCV) infection. Here, by cross-sectional analysis and longitudinal analysis of patients undergoing effective combination antiviral therapy, we demonstrate that circulating Valpha24+Vbeta11+ NKT cell numbers are not decreased during active HCV infection. Importantly, as we also show that CD1d is expressed at comparable levels by peripheral blood monocytes and CD1c+ myeloid dendritic cells (DC) of healthy individuals and HCV-infected patients, these data indicate that all ingredients for evaluating the antiviral effects of the Valpha24+Vbeta11+ NKT cell ligand alpha-GalCer in HCV-infected patients are present.
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PMID:Circulating Valpha24+Vbeta11+ NKT cell numbers and dendritic cell CD1d expression in hepatitis C virus infected patients. 1563 52

We examined the in vivo behavior of liver natural killer T cells (NKT cells) by intravital fluorescence microscopic imaging of mice in which a green fluorescent protein cDNA was used to replace the gene encoding the chemokine receptor CXCR6. NKT cells, which account for most CXCR6(+) cells in liver, were found to crawl within hepatic sinusoids at 10-20 microm/min and to stop upon T cell antigen receptor activation. CXCR6-deficient mice exhibited a selective and severe reduction of CD1d-reactive NKT cells in the liver and decreased susceptibility to T-cell-dependent hepatitis. CXCL16, the cell surface ligand for CXCR6, is expressed on sinusoidal endothelial cells, and CXCR6 deficiency resulted in reduced survival, but not in altered speed or pattern of patrolling of NKT cells. Thus, NKT cells patrol liver sinusoids to provide intravascular immune surveillance, and CXCR6 contributes to liver-based immune responses by regulating their abundance.
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PMID:Intravascular immune surveillance by CXCR6+ NKT cells patrolling liver sinusoids. 1579 95

Leukocyte trafficking to the central nervous system (CNS), regulated in part by chemokines, determines severity of the demyelinating diseases multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE). To examine chemokine receptor CX3CR1 in EAE, we studied CX3CR1(GFP/GFP) mice, in which CX3CR1 targeting by insertion of Green Fluorescent Protein (GFP) allowed tracking of CX3CR1+ cells in CX3CR1(+/GFP) animals and cells destined to express CX3CR1 in CX3CR1(GFP/GFP) knockouts. NK cells were markedly reduced in the inflamed CNS of CX3CR1-deficient mice with EAE, whereas recruitment of T cells, NKT cells and monocyte/macrophages to the CNS during EAE did not require CX3CR1. Impaired recruitment of NK cells in CX3CR1(GFP/GFP) mice was associated with increased EAE-related mortality, nonremitting spastic paraplegia and hemorrhagic inflammatory lesions. The absence of CD1d did not affect the severity of EAE in CX3CR1(GFP/GFP) mice, arguing against a role for NKT cells. Accumulation of NK cells in livers of wild-type (WT) and CX3CR1(GFP/GFP) mice with cytomegalovirus hepatitis was equivalent, indicating that CX3CL1 mediated chemoattraction of NK cells was relatively specific for the CNS. These results are the first to define a chemokine that governs NK cell migration to the CNS, and the findings suggest novel therapeutic manipulation of CX3CR1+ NK cells.
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PMID:The neuronal chemokine CX3CL1/fractalkine selectively recruits NK cells that modify experimental autoimmune encephalomyelitis within the central nervous system. 1667 47

Administration of concanavalin A (Con A) induces a rapid and severe liver injury in mice. Natural killer T (NKT) cells are recognized to be the key effector cells, and a variety of cytokines [e.g., interleukin 4 (IL-4), IL-5, interferon gamma (IFN-gamma), and tumor necrosis factor alpha (TNF-alpha)] have been shown to play vital roles in Con A-induced liver injury, whereas the role of IL-15, a critical cytokine in the development and homeostasis of NKT cells, remains obscure. In this study, pretreatment with IL-15 prevented mice from Con A-induced mortality, elevation of serum transaminase, liver necrosis, and hepatocyte apoptosis. Depletion of NKT cells abolished Con A-induced liver injury, which could be restored by adoptive transfer of purified NKT cells but not by that of in vivo or in vitro IL-15-treated hepatic NKT cells. Furthermore, transfer of wild-type NKT cells to CD1d-/- mice restored liver injury, whereas transfer of IL-15-treated NKT cells did not. IL-15 pretreatment decreased the NKT-derived IL-4, IL-5, and TNF-alpha production, thereby resulting in less infiltration of eosinophils, which play a critical role in Con A-induced liver injury. In conclusion, IL-15 protects against Con A-induced liver injury via an NKT cell-dependent mechanism by reducing their production of IL-4, IL-5, and infiltration of eosinophils. These findings suggest that IL-15 may be of therapeutic relevance in human autoimmune-related hepatitis.
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PMID:Interleukin-15 prevents concanavalin A-induced liver injury in mice via NKT cell-dependent mechanism. 1672 7


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