Role of the bacterial Cag-pathogenicity island on the H. pylori induced innate and adaptive immunity

Die Dissertation untersuchte molekulare und zelluläre Vermittler der durch H. pylori induzierten Immunantwort. Zunächst erfolgten eine umfassende immunhistochemische Charakterisierung leukozytärer Subpopulationen sowie die quantitative Analyse von Zytokinexpressionsprofilen in der Magenmukosa von 100 infizierten Patienten. Die anschließende bakterielle Genotypisierung konnte zeigen, dass der infizierende H. pylori Stammtyp die Entzündungsreaktion entscheidend beeinflusst. H. pylori-Stämme, welche die bakterielle cag-Pathogenitätsinsel besitzen, induzieren im Vergleich zur Infektion mit cagA-negativen Stämmen eine verstärkte Infiltration mit Granulozyten, Makrophagen, B-Lymphozyten und CD4+ T-Lymphozyten. Komparative Studien in H. pylori-infizierten Mäusen evaluierten schließlich die Vergleichbarkeit dieses Infektionsmodells mit der humanen Immunantwort.This dissertation investigated molecular an cellular mechanisms of the H. pylori induced immunity. Immunhistochemical charactarisation of the innate and adaptive immunity identifying cell subsets was preformed. Furthermore the role of the bacterial Cag-pathogenicity island on the innate and adaptive immunity was investigated. At last the human and murine immunresponse to H. pylori were compared

Role of the bacterial Cag-pathogenicity island on the H. pylori induced innate and adaptive immunity

Die Dissertation untersuchte molekulare und zelluläre Vermittler der durch H. pylori induzierten Immunantwort. Zunächst erfolgten eine umfassende immunhistochemische Charakterisierung leukozytärer Subpopulationen sowie die quantitative Analyse von Zytokinexpressionsprofilen in der Magenmukosa von 100 infizierten Patienten. Die anschließende bakterielle Genotypisierung konnte zeigen, dass der infizierende H. pylori Stammtyp die Entzündungsreaktion entscheidend beeinflusst. H. pylori-Stämme, welche die bakterielle cag-Pathogenitätsinsel besitzen, induzieren im Vergleich zur Infektion mit cagA-negativen Stämmen eine verstärkte Infiltration mit Granulozyten, Makrophagen, B-Lymphozyten und CD4+ T-Lymphozyten. Komparative Studien in H. pylori-infizierten Mäusen evaluierten schließlich die Vergleichbarkeit dieses Infektionsmodells mit der humanen Immunantwort.This dissertation investigated molecular an cellular mechanisms of the H. pylori induced immunity. Immunhistochemical charactarisation of the innate and adaptive immunity identifying cell subsets was preformed. Furthermore the role of the bacterial Cag-pathogenicity island on the innate and adaptive immunity was investigated. At last the human and murine immunresponse to H. pylori were compared

Role of the bacterial Cag-pathogenicity island on the H. pylori induced innate and adaptive immunity

Die Dissertation untersuchte molekulare und zelluläre Vermittler der durch H. pylori induzierten Immunantwort. Zunächst erfolgten eine umfassende immunhistochemische Charakterisierung leukozytärer Subpopulationen sowie die quantitative Analyse von Zytokinexpressionsprofilen in der Magenmukosa von 100 infizierten Patienten. Die anschließende bakterielle Genotypisierung konnte zeigen, dass der infizierende H. pylori Stammtyp die Entzündungsreaktion entscheidend beeinflusst. H. pylori-Stämme, welche die bakterielle cag-Pathogenitätsinsel besitzen, induzieren im Vergleich zur Infektion mit cagA-negativen Stämmen eine verstärkte Infiltration mit Granulozyten, Makrophagen, B-Lymphozyten und CD4+ T-Lymphozyten. Komparative Studien in H. pylori-infizierten Mäusen evaluierten schließlich die Vergleichbarkeit dieses Infektionsmodells mit der humanen Immunantwort.This dissertation investigated molecular an cellular mechanisms of the H. pylori induced immunity. Immunhistochemical charactarisation of the innate and adaptive immunity identifying cell subsets was preformed. Furthermore the role of the bacterial Cag-pathogenicity island on the innate and adaptive immunity was investigated. At last the human and murine immunresponse to H. pylori were compared

Improved Responses to Pegylated Interferon Alfa-2b and Ribavirin by Individualizing Treatment for 24-72 Weeks

BACKGROUND & AIMS: Guidelines recommend that patients with chronic hepatitis C virus (HCV) infection be treated with pegylated interferon and ribavirin for 24, 48, or 72 weeks, based on their virologic response to treatment. We investigated the effects of treating patients for individualized durations. METHODS: We treated 398 treatment-nave patients who had HCV genotype 1 infections with pegylated interferon alfa-2b and ribavirin for 24, 30, 36, 42, 48, 60, or 72 weeks (mean of 39 weeks, termed individualized therapy); the duration of therapy was determined based on baseline viral load and the time point at which HCV RNA levels became undetectable (measured at weeks 4, 6, 8, 12, 24, and 30). Results were compared with those of 225 patients who received standard treatment for 48 weeks (mean of 38 weeks). RESULTS: Rates of sustained virologic response (SVR) were 55% among patients who received individualized treatment and 48% among those who received standard treatment (P<.0001 for non-inferiority). SVR rates, according to the time point at which HCV RNA levels became undetectable, did not differ significantly between groups. Patients with a rapid virologic response (undetectable levels of HCV RNA at week 4) who were treated for 24 to 30 weeks achieved high rates of SVR (86%-88%). Rates of SVR increased among slow responders who first tested negative for HCV RNA at week 24 and were treated for 60 to 72 weeks compared with those treated for 48 weeks (60%-68% vs 43%-44%). The CC polymorphism at IL28B rs129797860 was associated with an increased rate of SVR compared with the CT/TT polymorphism (P<.0001) at baseline but not among patients who had undetectable levels of HCV RNA following treatment. CONCLUSIONS: Individualizing treatment of patients with chronic HCV genotype 1 infections for 24 to 72 weeks results in high rates of SVR among rapid responders and increases SVR among slow responders

Vitamin D levels vary during antiviral treatment but are unable to predict treatment outcome in HCV genotype 1 infected patients

Background: Different parameters have been determined for prediction of treatment outcome in hepatitis c virus genotype 1 infected patients undergoing pegylated interferon, ribavirin combination therapy. Results on the importance of vitamin D levels are conflicting. In the present study, a comprehensive analysis of vitamin D levels before and during therapy together with single nucleotide polymorphisms involved in vitamin D metabolism in the context of other known treatment predictors has been performed. Methods: In a well characterized prospective cohort of 398 genotype 1 infected patients treated with pegylated interferon-α and ribavirin for 24–72 weeks (INDIV-2 study) 25-OH-vitamin D levels and different single nucleotide polymorphisms were analyzed together with known biochemical parameters for a correlation with virologic treatment outcome. Results: Fluctuations of more than 5 (10) ng/ml in 25-OH-vitamin D-levels have been observed in 66 (39) % of patients during the course of antiviral therapy and neither pretreatment nor under treatment 25-OH-vitamin D-levels were associated with treatment outcome. The DHCR7-TT-polymorphism within the 7-dehydrocholesterol-reductase showed a significant association (P = 0.031) to sustained viral response in univariate analysis. Among numerous further parameters analyzed we found that age (OR = 1.028, CI = 1.002–1.056, P = 0.035), cholesterol (OR = 0.983, CI = 0.975–0.991, P<0.001), ferritin (OR = 1.002, CI = 1.000–1.004, P = 0.033), gGT (OR = 1.467, CI = 1.073–2.006, P = 0.016) and IL28B-genotype (OR = 2.442, CI = 1.271–4.695, P = 0.007) constituted the strongest predictors of treatment response. Conclusions: While 25-OH-vitamin D-levels levels show considerable variations during the long-lasting course of antiviral therapy they do not show any significant association to treatment outcome in genotype 1 infected patients

The <i>DHCR7-TT-</i>genotype of the <i>rs12785878</i> SNP shows a significant association to stage of fibrosis.

<p>The <i>DHCR7-TT-</i>genotype of the <i>rs12785878</i> SNP shows a significant association to stage of fibrosis.</p

Patient demographic, biochemical and genetic characteristics.

<p>A VitD deficiency (<20 ng/ml) was observed in 251 (64,1%) out of 391patients. A liver fibrosis stage of 0–2 was observed in 321 (84,9%) out of 378 patients, while 57 (15%) out of 378 patients showed a liver fibrosis stage of 3–4.</p><p><i>Abbreviations</i>: BMI: body-mass-index, ALT: alanine aminotransferase, AST: aspartate aminotransferase, gGT: gamma-glutamyl-transferase, HOMA: homeostatic model assessment of insulin resistance, AP: alkaline phosphatase, TSH: thyroid stimulating hormone, IP10: interferon-γ-inducible-protein-10, HCV: hepatitis C virus.</p><p><i>Missing data</i>: Cholesterol levels were missing in 14 patients, Baseline Vitamin D levels were missing in 7 patients, Baseline IP10 levels were missing in 7 patients, Baseline viral load values were missing in 16 patients, Liver biopsy status was missing in 20 patients. HOMA-index values were missing in 74 patients, Triglyceride levels were missing in 15 patients, AP levels were missing in 4 patients, Ferritin levels were missing in 10 patients, Vitamin D levels on week 24 were missing in 69 patients, IP10 levels on week 1 were missing in 23 patients, IP10 levels on week 4 were missing in 42 patients, TSH values were missing in 6 patients, Genotype of the <i>IL28B</i>-gene was missing in 31 patients, Genotype of the <i>CYP27B1</i>-gene was missing in 32 patients, Genotype of the <i>CYP2R1</i>-gene was missing in 32 patients, Genotype of the <i>DHCR7</i>-genes was missing in 24 patients, Genotype of the <i>CYP24A1</i>-gene was missing in 24 patients, Genotype of the <i>DBP</i>-genes was missing in 24 patients.</p

VitD concentrations vary dependent on the month of sample obtainment (1A), whereas fluctuations between baseline-VitD and TW24-VitD-values (ΔVitd) are observed as well (1B).

<p>VitD concentrations vary dependent on the month of sample obtainment (1A), whereas fluctuations between baseline-VitD and TW24-VitD-values (ΔVitd) are observed as well (1B).</p

Uni- and multivariate analysis of predictors of SVR to antiviral therapy.

<p>Only patients with complete data for the remaining covariates (277 out of 398) and with significant variations in the univariate analysis were included in multivariate analyses. Missing data and abbreviations are illustrated in the legend of <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0087974#pone-0087974-t001" target="_blank">Table 1</a>. A VitD deficiency (<20 ng/ml) was observed in 251 (64,1%) out of 391patients. A liver fibrosis stage of 0–2 was observed in 321 (84,9%) out of 378 patients, while 57 (15%) out of 378 patients showed a liver fibrosis stage of 3–4.</p