The role of CD4+ T cells in the gastrointestinal (GI) immune system in vivo was studied in mice selectively depleted of this subset by treatment with monoclonal anti-L3T4 (GK1.5) mAb. Treatment of young BALB/c mice with weekly injections of anti-L3T4 mAb resulted in a selective depletion of CD4+ T cells in both IgA effector (lamina propria regions of the intestine; LP) and inductive (Peyer's patch; PP) sites. However, levels of CD3+CD4-CD8+ and CD4-CD8- (double negative) T cells remained constant or increased. When sections of small intestine were assessed for the isotype of Ig-containing cells, normal mice contained predominantly IgA plasma cells with small numbers of IgM and IgG plasma cells while anti-L3T4 treatment dramatically reduced the numbers of IgA plasma cells. When numbers of IgA-producing cells were assessed by the isotype-specific ELISPOT assay, the LPL of anti-L3T4 mAb-treated mice showed an 80% reduction in the number of IgA spot-forming cells. The effect of anti-L3T4 mAb treatment on IgA inductive sites was also studied and this treatment reduced the overall size of PP as well as the germinal centers in this tissue. Although anti-L3T4 treatment depleted CD3+CD4+ T cells in PP, the relative frequency of surface IgA-positive (slgA+) B cells in this tissue did not change. These results show that repeated injection of anti-L3T4 mAb results in a CD4+ T cell deficiency in both IgA inductive (PP) and effector (LP) sites. The depletion of CD4+ T cells resulted in reductions in the numbers of mature IgA plasma cells present in the LP of gut-associated tissues, and reduced the overall size of PP including germinal centers, but did not affect the frequency of sIgA+ B cells in this IgA inductive site.
Results Natural killer cell cytotoxicity, in the absence of IL-2 stimulation, was no different between the groups. With IL-2 stimulation, EU demonstrated significantly higher cytotoxicity compared to cHCV (32.864.4% vs 17.663.2%, p¼0.023), with similar levels to SR (27.769.9%, p¼0.50 Introduction Liver related outcomes (LRO) represent a meaningful end-point for future anti-fibrotic therapies. Staging of liver fibrosis on histology is a surrogate for these outcomes but may not be an ideal tool. Aim Our initial aim was to determine liver related outcomes and survival from the individual stages of significant fibrosis. Our second aim was to assess the value of morphometric collagen quantification within cirrhosis to predict clinical outcomes. Method The study cohort was selected from a single centre within the Trent HCV study, a prospective cohort which began in 1991 to address the natural history of chronic hepatitis C. Inclusion criteria for this study were the presence of significant fibrosis (at least Ishak Stage (IS) three on biopsy) and at least 3-year follow-up post biopsy. LRO was defined as decompensation (variceal bleeding, ascites, encephalopathy), HCC, liver transplant and liver-related death. Automated morphometry was performed to measure the Collagen Area Fraction (CAF). Survival at 3, 5 and 7 years respectively was evaluated. Results The study cohort comprised 155 patients (70% male; mean age 49 years). The median follow-up time was 78 months. A LRO occurred in 48 patients (31.0%, estimated annual incidence 5.2%). HCC developed in 16 patients (10.6%, estimated annual incidence 1.6%) liver-related death occurred in 34 patients (21.9%, estimated annual incidence 3.3%); clinical decompensation developed in 20 patients (13.3%, estimated annual incidence 2.1%). See Abstract P46 table 1. CAF was measured in a subgroup of 89 patients. The median CAF was calculated for each Ishak stage and increased progressively towards the more advanced stages. (IS 3: median CAF 3.7%, IQR 1.5e5.1; IS 4: median CAF 5.2%, IQR 2.8e7.4; IS 5: median CAF 6.8%, IQR 3.4e9.5; IS 6: median CAF 9.9%, IQR 6.2e15.7). Within Ishak stage 6 the median CAF scores predicting LRO were higher (13.89, 12.48 and 12.69%) compared to median CAF scores in patients with no outcomes (8.59, 8.32 and 8.10%) at years 3, 5 and 7 respectively. Conclusion Clinical outcomes represent realistic and meaningful end-points for future trials evaluating anti-fibrotic agents once advanced fibrosis has developed. Further development and validation of morphometry within advanced fibrosis could enable better identification of patients at risk of more rapid progression of liver disease than Ishak stage alone. were split into three groups according therapy regimen: LAM+ADV (n¼192, 78% males, median age 40 y, 35% HBeAg+, 34% cirrhosis, median duration 36 months), ETV (n¼154, 79% males, median age 42 y, 31% HBeAg+, 34% cirrhosis, median duration 28 months) and TDF (n¼60, 50% males, median age 40 y, 23%HBeAg+, 25% cirrhosis, median duration 9 months). HBV DNA viral load...
Graft-versus-host reaction (GvHR) was induced in neonatal mice to produce crypt hyperplasia with and without stunted villi. Lactase activity was measured along individual villi of control and GvHR mice using quantitative cytochemistry. Lactase activity increased in control mice as enterocytes migrated over the lower part of the villus. This increase was followed by a period when lactase activity remained approximately constant. Effects produced by GvHR on this normal profile of development included an extension of the distance on the villus over which enterocytes could continue to increase lactase activity, a reduction in the time needed for an enterocyte to express lactase activity at maximal rate, and an overall decrease in the maximal lactase activity expressed by mature enterocytes. These effects have been quantified by fitting logistic curves to the experimental data. Parallel biochemical analyses of intestinal homogenates showed sucrase, isomaltase, trehalase and maltase activities to increase markedly 7-8 days after the injection of parental spleen cells. Attention is drawn to similarities between these results and steroid induced precocious development of intestinal function in neonatal mice.
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