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)

To investigate how T cells are involved in hypersensitivity reactions to drugs that become immunogenic after metabolization, e.g., sulfonamides and antiepileptics, we analyzed in vitro the drug-induced activation of CD4+ and CD8+ T cell subsets, cytokine secretion, TCR V beta distribution, and proliferation of T cells from four drug-allergic individuals. In addition, the activation parameters CD25 and HLA-DR were analyzed in vivo on CD4+ and CD8+ T cells from five patients with acute drug allergies, some of them with anticonvulsant hypersensitivity syndrome with hepatitis. Our results show that, in vitro, drug-induced proliferation of PBMC from patients with allergy to sulfamethoxazole, phenytoin, or carbamazepine was specific and dose dependent. CD4+ as well as CD8+ T cells expressed elevated levels of CD25 and HLA-DR molecules after drug stimulation. Drug-activated lymphocytes secreted high amounts of IL-5 and normal or low levels of IL-2, IFN-gamma, IL-4, and TNF-alpha. An enhanced expansion of TCR V beta 17+ T cells 9 days after in vitro stimulation with sulfamethoxazole was observed in one patient with sulfamethoxazole allergy. The drug specificity of the in vitro-activated T cells was confirmed by generation of different sulfamethoxazole specific T cell lines and CD4+ and CD8+ T cell clones. T cell analysis of patients with acute drug allergy to carbamazepine, phenytoin, allopurinol, or paracetamol confirms the in vitro data, because all patients had activated CD4+ or CD8+ T cells in the circulation. Our data clearly show the involvement of drug-specific T cells in drug allergies.
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PMID:Activation of drug-specific CD4+ and CD8+ T cells in individuals allergic to sulfonamides, phenytoin, and carbamazepine. 760 18

The aim of the present study was to analyze on chronic alcoholic patients the effect of ethanol (EtOH) withdrawal on the immune system through the investigation of the distribution of PB lymphoid subsets, using multiple-stainings with monoclonal antibodies and flow cytometry. For this purpose a group of 20 patients with active alcoholism without liver disease, negative for hepatitis virus, and without malnutrition was analyzed and followed for 9 months after alcohol consumption had been discontinued. Twenty-five age- and sex-matched healthy volunteers were included in the study. The following panel of monoclonal antibodies combinations (FITC/PE/PerCP or PE-Cy5) was used: TCR alpha beta/CD3/HLA DR, CD25/CD56/CD3, TCR gamma delta/CD3/HLA DR, CD45RA/CD45R0/CD4, CD3/CD8, CD19/CD5, and CD3/CD11c. Analysis was performed on at least 1,500 events/tube at flow cytometry using the Lysys II software program. During the alcohol intake period, the most striking findings were a significant (P < 0.05) expansion of the CD8+ T-lymphocyte subset, which coexpresses the activation associated antigens HLA DR and CD11c, as well as a significant increase in both NK-cells (CD3-/CD56+) and the T-cell subset with NK activity coexpressing CD3 and CD56 (P < 0.05 and P < 0.01, respectively). In addition, a decrease in the CD5+ B-cells (P < 0.05), associated with reduced serum gamma-globulin levels, was also observed. During alcohol withdrawal, a rapid decrease towards normal values of activated CD8+/HLA DR+ and CD11c+ T-lymphocytes was observed as well as a normalization of CD19+/CD5+ B-cells and gamma-globulin serum levels; these changes might be directly related to EtOH suppression. Surprisingly, however, new immunological imbalances emerged in spite of the absence of alcohol intake. Thus, a progressive and significant expansion (P < 0.05) of CD4+ T-cells associated with an increased expression of the CD25 activation-related antigen and a preferential use of the CD45R0 isoform by CD4+ T-cells were observed. In parallel, there was an even more evident increase (P < 0.01) in the number of PB NK-cells. Our results show that EtOH consumption induces changes in the immune system, its effects persisting or even becoming more evident after suppression of EtOH intake for a 9 month period.
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PMID:Long lasting immunological effects of ethanol after withdrawal. 897 26

Con A-induced hepatic injury of mice accompanied by elevated transaminase was inhibited after in vivo depletion of liver NK cells and NK1+ T cells with intermediate TCR by anti-NK1 Ab or anti-IL-2Rbeta Ab. However, depletion of liver NK cells alone by anti-asialo-GM1 Ab did not inhibit hepatic injury. Although depletion of NK1+ T cells inhibited Con A-induced IL-2R expression of CD4+ high TCR (TCRhigh) cells and IL-4 mRNA expression of hepatic mononuclear cells, exogenous IL-4 engendered Con A-induced hepatic injury and endowed the expression of IL-2R of CD4+ TCRhigh cells. It was also found that in vivo treatment with anti-IL-4 Ab before Con A administration inhibited Con A-induced hepatic injury. In addition, although Con A did not induce hepatic injury in MHC class I-deficient mice, exogenous IL-4 again engendered severe hepatic injury in these mice. Further, while serum TNF-alpha levels induced by Con A were greatly decreased in NK1+ T cell-depleted mice and class I-deficient mice, TNF-alpha levels were recovered by exogenous IL-4. These findings reveal that although CD4+ TCRhigh cells in the liver and their production of TNF-alpha are the direct effectors of Con A-induced hepatic injury, liver NK1+ T cells also play an important role in this hepatitis model. Con A hepatitis may serve as an experimental model for human autoimmune hepatitis.
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PMID:Requirement of IL-4 and liver NK1+ T cells for concanavalin A-induced hepatic injury in mice. 923 53

Most old mice and human beings contain large clones of CD8+ alpha beta TCR+ T cells. In mice, clones bearing V beta 7 appear more frequently in animals infected with mouse hepatitis virus than in uninfected animals. This property is controlled by some non-MHC gene in the animals. The frequency of old mice containing such clones is affected by the origin of the animals. Although the clones are relatively anergic to acute stimuli in vitro, they can divide in vivo since in old animals they divide and turnover with about the same kinetics as other, non-clonally expanded CD8+ T cells. Moreover the clones expand slowly but inexorably after transfer into recipient animals. These data suggest that the CD8+ alpha beta TCR clones arise because they are specific for some exogenous or auto antigen to which the cells are continuously exposed in vivo.
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PMID:CD8+ T-cell clones in old mice. 947 72

We characterized liver-infiltrating leucocytes (LIL) from BALB/c and C57BL/6 mice 0-56 days after murine cytomegalovirus (MCMV) infection. Inflammation clears from C57BL/6 mice 4-5 weeks post infection (pi), but persists for several months in BALB/c mice. The LIL obtained were 60-80% Thy 1.2+ by flow cytometry. The percentage of CD8+ cells rose sharply in all mice 7 days pi, with little decrease in BALB/c mice by day 56. CD4-CD8-Thy 1.2+/TCR alpha beta + cells were more prevalent in LIL than lymph node cells (LNC) irrespective of MCMV infection, whilst infection increased the proportion of CD8+ L-selectin- LIL (but not LNC). LIL from both mouse strains demonstrated cytotoxic activity against YAC-1 cells, but only LIL from BALB/c mice proliferated spontaneously ex vivo 21 days pi, as measured by tritiated thymidine incorporation. BALB/c LIL produced IFN gamma and IgG2a 7-21 days pi, whilst IL-10 secretion was similar in both strains. Thus, persistent hepatitis in BALB/c mice is associated with activation and proliferation of intrahepatic leucocytes with some bias towards a Th1 response.
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PMID:Contrasting phenotypes of liver-infiltrating leucocytes isolated from MCMV-infected BALB/c and C57BL/6 mice. 961 48

The relationships between T cell populations during primary viral infection and persistence are poorly understood. Mice infected with the neurotropic JHMV strain of mouse hepatitis virus mount potent regional CTL responses that effectively reduce infectious virus; nevertheless, viral RNA persists in the central nervous system (CNS). To evaluate whether persistence influences Ag-specific CD8+ T cells, functional TCR diversity was studied in spleen and CNS-derived CTL populations based on differential recognition of variant peptides for the dominant nucleocapsid epitope. Increased specificity of peripheral CTL from persistently infected mice for the index epitope compared with immunized mice suggested T cell selection during persistence. This was confirmed with CD8+ T cell clones derived from the CNS of either acutely (CTLac) or persistently (CTLper) infected mice. Whereas CTLac clones recognized a broad diversity of amino acid substitutions, CTLper clones exhibited exquisite specificity for the wild-type sequence. Highly focused specificity was CD8 independent but correlated with longer complementarity-determining regions 3 characteristic of CTLper clonotypes despite limited TCR alpha/beta-chain heterogeneity. Direct ex vivo analysis of CNS-derived mononuclear cells by IFN-gamma enzyme-linked immunospot assay confirmed the selection of T cells with narrow Ag specificity during persistence at the population level. These data suggest that broadly reactive CTL during primary infection are capable of controlling potentially emerging mutations. By contrast, the predominance of CD8+ T cells with dramatically focused specificity during persistence at the site of infection and in the periphery supports selective pressure driven by persisting Ag.
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PMID:Selection of CD8+ T cells with highly focused specificity during viral persistence in the central nervous system. 1020 9

The patient was a 50-year-old woman who presented intermittent mild fever with elevated liver enzymes for 12 years. The liver biopsy showed diffuse portal and sinusoidal involvement of lymphoid cells with minimal atypia and epithelioid histiocytic granuloma formation. Subsequent bone marrow biopsy showed lymphomatous involvement. The lymphocytes infiltrating the liver were reactive for T-cell marker and showed TCR gamma gene rearrangement. The patient was diagnosed as primary peripheral T-cell lymphoma of the liver. Indolent clinical course and resemblance with hepatitis were considered to be a rare and unique feature of this case.
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PMID:A case report of primary T-cell lymphoma of the liver. 1080 5

To study peripheral tolerance of CD8 T cells to a classically MHC-restricted peptide Ag expressed in hepatocytes, ALB1 transgenic (tg) mice expressing the CTL epitope GP33 of the lymphocytic choriomeningitis virus glycoprotein under control of the mouse albumin promoter were generated. ALB1 mice exclusively expressed the GP33 transgene in the liver and, at a 100- to 1000-fold lower level, in the thymus. TCR-tg mice specific for the GP33 epitope were used to directly follow GP33-specific T cells in vivo. These experiments revealed that 1) thymic expression of the GP33 transgene led to incomplete central deletion of TCR-tg cells; and 2) peripheral TCR-tg cells in ALB1 mice ignored the GP33 transgene expressed in hepatocytes. Ignorance of adoptively transferred TCR-tg cells in ALB1 mice was broken by infection with lymphocytic choriomeningitis virus, leading to induction of hepatitis in ALB1, but not in control, mice. Taken together, we have established a novel model of virus-induced CD8 T cell-mediated autoimmune hepatitis in mice and demonstrate that naive CD8 T cells may ignore Ags expressed in the liver.
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PMID:Break of T cell ignorance to a viral antigen in the liver induces hepatitis. 1094 66

Mouse hepatitis virus (MHV) provides an excellent animal model for the study of the immunopathological mechanisms involved in hepatic viral diseases. We previously generated an attenuated viral variant, YAC-MHV3, which induces a subclinical disease and recovery within 15 days. In contrast, the L2-MHV3 strain induces the development of a fulminant hepatitis, leading to death within 3 days. In this paper, we document intrahepatic and splenic T cell subpopulations involved in the hepatitis process and viral elimination identified in attenuated or pathogenic MHV3-infected C57BL/6 mice. Percentages of intrahepatic CD4(+) cells decreased in attenuated YAC-MHV3-infected mice, while they increased in mice infected with pathogenic L2-MHV3, compared with uninfected animals. Moreover, in YAC-MHV3-infected mice, the percentages of intrahepatic CD8(+) cells slightly decreased at 24 h pi, then increased until 15 days pi. In contrast, the CD4/CD8 ratios of splenic lymphoid subpopulations increased in the first days of infection and returned to normal values at 15 days pi. Intrahepatic NK1.1(+)alphabeta - TCR(inter) cells decreased in both virally infected groups of mice, while CD4(+)alphabeta - TCR(inter) LFA-1(high) cells increased in L2-MHV3-infected mice, in contrast with what was seen in YAC-MHV3-infected mice. However, these cells became anergic following Con A or PHA stimulation. Ex vivo studies showed that only the intrahepatic CD8(+) cells that were increased in YAC-MHV3-infected mice could be stimulated by lectins. In addition, in vitro viral infections revealed that L2-MHV3 viral infection led to an increase of intrahepatic CD4(+)alphabeta - TCR(inter) cells in the absence of CD8(+) cells only. These results indicate that the attenuated phenotype of the YAC-MHV3 virus is related to two different mechanisms: the first involves no increase of intrahepatic CD4(+)alphabeta - TCR(inter) or NK-T cells, while the second favors the recruitment and activation of CD8(+) cells in liver. The results are discussed in relation to the integrity of intrahepatic immune tolerance mechanisms and immune-mediated viral elimination.
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PMID:Recovery from mouse hepatitis virus infection depends on recruitment of CD8(+) cells rather than activation of intrahepatic CD4(+)alphabeta(-)TCR(inter) or NK-T cells. 1172 27

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


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