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

A 55-year-old-woman suffering from fluminant hepatitis owing to autoimmune hepatitis underwent ABO-incompatible liver transplantation (LRLD) of blood type A to B. In this study, we investigated whether a new immunosuppressive strategy by intraportal transfusion of donor-specific leukocytes (DSLT) separated from whole blood would yield immunological benefit in adult ABO-LRLD. The operative course was uneventful; she was discharged at 46 days postoperatively without humoral or cellular rejection. On immunologic analysis, 54.6% intrahepatic macrochimerism of donor type CD56+ T cells was recognized at 1 month after transplantation. The interleukin-10 Th2 cytokine level was increased on postoperative day 1. Adult ABO-incompatible liver transplantation can be performed with acceptable patient and graft survival rates with a low risk of antibody-mediated rejection with our strategy of immunosuppression by intraportal administration of DSLT. Donor type CD56+ NKT cells may induce tolerance by a veto mechanism and/or an anti-idiotype network. ABO-incompatible liver transplantation may be improved by this strategy.
 ...
PMID:Adult ABO-incompatible liver transplantation by intraportal transfusion of donor-specific antigen: a case report. 1892 67

Activation of invariant NKT (iNKT) cells in the liver is generally regarded as the critical step for Con A-induced hepatitis, and the role of NK cell receptors for iNKT cell activation is still controversial. In this study we show that blockade of the NKG2A-mediated inhibitory signal with antagonistic anti-NKG2A/C/E mAb (20d5) aggravated Con A-induced hepatitis in wild-type, Fas ligand (FasL)-mutant gld, and IL-4-deficient mice even with NK cell and CD8 T cell depletion, but not in perforin-, IFN-gamma-, or IFN-gamma- and perforin-deficient mice. Consistently, 20d5 pretreatment augmented serum IFN-gamma levels and perforin-dependent cytotoxicity of liver mononuclear cells following Con A injection, but not their FasL/Fas-dependent cytotoxicity. However, blockade of NKG2A-mediated signals during the cytotoxicity effector phase did not augment cytotoxic activity. Activated iNKT cells promptly disappeared after Con A injection, whereas NK1(-) iNKT cells, which preferentially expressed CD94/NKG2A, predominantly remained in the liver. Pretreatment with 20d5 appeared to facilitate disappearance of iNKT cells, particularly NK1(-) iNKT cells. Moreover, Con A-induced and alpha-galactosylceramide-induced hepatic injury was very severe in CD94/NKG2A-deficient DBA/2J mice compared with CD94/NKG2A-intact DBA/2JJcl mice. Overall, these results indicated that a NKG2A-mediated signal negatively regulates iNKT cell activation and hepatic injury.
 ...
PMID:NKG2A inhibits invariant NKT cell activation in hepatic injury. 1910 56

Concanavalin A (Con A) is known to induce acute hepatitis that is mediated by activation of NKT and T-cell and cytokine production in immunocompetent mice. The observation of Con A-induced autophagic cell death of hepatoma cells via a Bcl-2/adenovirus E1B 19 kDa-interacting protein 3 mediated autophagic pathway made us re-evaluate the effect of Con A-induced hepatitis in mice. Con A was administrated intravenously to BABL/c, SCID, or SCID/NOD mice at doses of 20, 30 or 40 mg/kg, respectively, to induce acute hepatitis. The levels of hepatitis and autophagy induction were both analyzed. We found that Con A can induce acute hepatitis in SCID or SCID/NOD mice with kinetics similar to that of BALB/c, but requiring a higher dose of Con A. No lymphocyte infiltrations were found in SCID or SCID/NOD mice, and the cytokine productions were different. An autophagy with microtubule-associated protein light chain 3-II conversion was demonstrated in the liver post-Con A injection in SCID/NOD mice. Due to the mannose/glucose-specific binding on cell membrane, Con A can induce a T-cell-independent acute hepatitis with autophagy in SCID/NOD mice.
 ...
PMID:Autophagy induction in T cell-independent acute hepatitis induced by concanavalin A in SCID/NOD mice. 1914 67

Increasing evidence suggests that TLRs are involved in the pathogenesis of liver diseases; however, the underlying mechanisms remain obscure. In this study, we found that treatment with CpG-oligodeoxynucleotide (ODN) promoted the accumulation and activation of murine hepatic NKT cells. Additional experiments showed that CpG-ODN preferred to act on CD4(+) NKT cells, while having less effect on CD4(-) NKT cells. The effect of CpG-ODN on liver NKT cells depended on the presence of Kupffer cells and IL-12. Meanwhile, CpG-ODN pretreatment aggravated liver injury and promoted the production of inflammatory cytokines in a Con A-induced fulminant hepatitis model via TLR9 activation. Collectively, our data demonstrate that TLR9 stimulation prefers to promote the accumulation and activation of hepatic CD4(+) NKT cells and suggest that TLR9 signaling might be involved in the pathogenesis of human hepatitis.
 ...
PMID:TLR-9 activation aggravates concanavalin A-induced hepatitis via promoting accumulation and activation of liver CD4+ NKT cells. 1926 55

Coinhibitors and costimulators control intrahepatic T cell responses that trigger acute hepatitis. We used the ConA-induced hepatitis model in the mouse to test if the coinhibitor herpes virus entry mediator (HVEM) modulates hepatitis-inducing T cell responses. Compared with ConA-injected, wild-type (wt) C57BL/6 (B6) mice, HVEM-deficient (HVEM(-/-)) B6 mice showed lower serum transaminase levels and lower proinflammatory IFN-gamma, but higher protective IL-22 serum levels and an attenuated liver histopathology. The liver type I invariant NKT cell population that initiates acute hepatitis in this model was reduced in HVEM(-/-) mice but their surface phenotype was similar to that of untreated or ConA-treated wt controls. In response to mitogen injection, liver invariant NKT cells from HVEM(-/-) B6 mice produced in vivo more IL-22 but lower amounts of IFN-gamma and IL-4 than wt controls. Bone marrow chimeras showed that HVEM deficiency of the liver nonparenchymal cell population, but not of the parenchymal cell population, mediated the attenuated course of the dendritic cell- and T cell-dependent ConA hepatitis. IL-22 is produced more efficiently by liver NKT cells from HVEM(-/-) than from wt mice, and its Ab-mediated neutralization of IL-22 aggravated the course of hepatitis in wt and HVEM(-/-) mice. Hence, HVEM expression promotes pathogenic, proinflammatory Th1 responses but down-modulates protective IL-22 responses of T cells in this model of acute hepatitis.
 ...
PMID:IL-22-dependent attenuation of T cell-dependent (ConA) hepatitis in herpes virus entry mediator deficiency. 1934 25

The glycosphingolipid sulfatide (SO(3)-3Galbeta1Cer) is a demonstrated ligand for a subset of CD1d-restricted NKT cells, which could regulate experimental autoimmune encephalomyelitis, a murine model for multiple sclerosis, as well as tumor immunity and experimental hepatitis. Native sulfatide is a mixture of sulfatide isoforms, i.e. sulfatide molecules with different long-chain bases and fatty acid chain lengths and saturation. Here, we demonstrate that sulfatide-specific CD1d-restricted murine NKT hybridomas recognized several different sulfatide isoforms. These included the physiologically relevant isoforms C24:1 and C24:0, major constituents of the myelin sheet of the nervous system, and C16:0, prominent in the pancreatic islet beta-cells. The most potent sulfatide isoform was lysosulfatide (lacking a fatty acid). Shortened fatty acid chain length (C24:1 versus C18:1), or saturation of the long fatty acid (C24:0), resulted in reduced stimulatory capacity, and fatty acid hydroxylation abolished the response. Moreover, sulfatide was not responsible for the natural autoreactivity toward splenocytes by XV19 T hybridoma cells. Our results reveal a promiscuity in the recognition of sulfatide isoforms by a CD1d-restricted NKT-cell clone, and suggest that sulfatide, a major component of the myelin sheet and pancreatic beta-cells, is one of several natural ligands for type II CD1d-restricted NKT cells.
 ...
PMID:Multiple tissue-specific isoforms of sulfatide activate CD1d-restricted type II NKT cells. 1958 39

An intravenous injection of Concanavalin A (Con A) elevated the serum level of alanine aminotransferase (ALT) activity, a marker for liver damage, and an oral administration of PDE7A inhibitor SUN11817 suppressed the increase of ALT activity in a dose-dependent manner. Histological analysis revealed that Con A injection caused extensive liver damage, and that the SUN11817 treatment improved the degenerative change in the liver. In addition, SUN11817 inhibited not only the production of IL-4 and TNF-alpha in the Con A-induced hepatitis model but also that in vitro by murine splenocytes stimulated with alpha-galactosylceramide, an activator specific for NKT cells. The Con A injection to mice also induced expression of Fas ligand (FasL) on NKT cells, which was significantly prevented by SUN11817. As NKT cells are known to contribute to the pathogenesis in Con A-induced hepatitis by producing cytokines such as IL-4 and TNF-alpha and inducing FasL-mediated hepatocyte injury, it is thought that PDE7A inhibitor SUN11817 improves liver injury in the Con A model by blocking cytokine production and FasL expression in NKT cells. PDE7A might be a novel pharmaceutical target for hepatitis.
 ...
PMID:Inhibition of phosphodiesterase 7A ameliorates Concanavalin A-induced hepatitis in mice. 1967 49

Severe hepatic injury is induced by Concanavalin A (Con A) administration in mice, the major effector cells being CD4(+) T cells, NKT cells and macrophages. Since autologous lymphocyte subsets are associated with tissue damage, Con A-induced hepatic injury is considered to be autoimmune hepatitis. However, it has remained to be investigated how autoantibodies and B-1 cells are responsible for this phenomenon. In this study, it was demonstrated that autoantibodies which were detected using Hep-2 cells in immunofluorescence tests and using double-strand (ds) DNA in the ELISA method, appeared after Con A administration (a peak at day 14). Moreover, autoantibody-producing B220(low) cells (i.e., B-1 cells) also appeared at this time. Purified B220(low) cells were found to have a potential to produce autoantibodies. These results suggest that Con A-induced hepatic injury indeed includes the mechanism of autoimmune hepatitis.
 ...
PMID:Co-appearance of autoantibody-producing B220(low) B cells with NKT cells in the course of hepatic injury. 1985 63

Immune-mediated liver diseases including autoimmune and viral hepatitis are a major health problem worldwide. In this study, we report that activation of the farnesoid X receptor (FXR), a member of the ligand-activated nuclear receptor superfamily and bile sensor highly expressed in the liver, attenuates liver injury in a model of autoimmune hepatitis induced by Con A. We found that FXR gene ablation results in a time-dependent increase of liver expression (up to 20-fold in a 9-mo-old mouse) of osteopontin, a NKT cell-derived extracellular matrix protein and immunoregulatory cytokine. In comparison to wild-type, FXR(-/-) mice are more susceptible to Con A-induced hepatitis and react to Con A administration by an unregulated production of osteopontin. Administering wild-type mice with a synthetic FXR agonist attenuated Con A-induced liver damage and liver expression of the osteopontin gene. By in vitro studies, we found that FXR is expressed by primarily isolated NKT cells and its ablation favors ostepontin production in response to Con A. Chromatin immunoprecipitation assay and coimmunoprecipitation experiments demonstrate that the short heterodimer partner (SHP), a nuclear receptor and FXR target, was expressed by NKT cell hybridomas and increased in response to FXR activation. FXR activates SHP that interacts with and inhibits c-Jun binding to the osteopontin promoter. These data indicate that in NKT cells, FXR activation causes a SHP-mediated inhibition of osteopontin production. These data support the notion that the bile acid sensor FXR regulates the activation of liver NKT cells.
 ...
PMID:The bile acid sensor farnesoid X receptor is a modulator of liver immunity in a rodent model of acute hepatitis. 1988 Apr 46

Although there is growing evidence that NKT cells play an important role in various immune responses through the invariant T cell receptor, other cell surface molecules responsible for their function are not fully understood. Here we study the role of ICOS, the third member of the CD28 family of costimulatory receptors, in in vivo and in vitro NKT cell responses. To establish its in vivo role in systems dependent on NKT cells, we examined the development of Con A-induced hepatitis in ICOS knockout (ICOS(-/-)) mice. We demonstrated that hepatic injury in ICOS(-/-) mice was greatly suppressed as evidenced by the reduced elevation of serum transaminases, reduced apoptosis of hepatocytes and mild histopathological changes. In investigating the cause of this defect, we first found that the NKT cell population is significantly reduced in the liver and spleen of ICOS(-/-) mice. We made and analyzed mixed bone marrow chimera mice with bone marrow cells from ICOS(+/+) and ICOS(-/-) mice, and demonstrated that the defect in ICOS-mediated costimulation results in a significant defect in the development of NKT cells, especially of Valpha14i NKT cells, in the thymus. When we examined the function of residual NKT cells in ICOS(-/-) mice, we found that their cytokine production following stimulation with alpha-galactosylceramide (alpha-GalCer) was strongly impaired. Based on these findings, we propose that ICOS-mediated costimulation may play a critical role in both the development and the optimal function of NKT cells, and that defective ICOS-mediated costimulation may result in impaired Con A-induced hepatitis in ICOS(-/-) mice.
 ...
PMID:Suppression of Con A-induced hepatitis induction in ICOS-deficient mice. 1991 90


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>