ROLE OF T REGULATORY CELLS IN CHRONIC HCV INFECTED EGYPTIAN PATIENTS AND THEIR IMPACT ON THE RESPONSE TO PEGYLATED INTERFERON THERAPY.

Treatment of patients with chronic hepatitis C with the current standard pegylated interferon (PEG-IFN) and ribavirin achieves overall response (SVR) rates of ~55%. A role of CD4+ CD25+ regulatory T cells (Treg cells) has been proposed as they can suppress HCV-specific T cells in HCV-infected patients. Patients with chronic HCV legible for PEG-IFN plus ribavirin treatment, were classified according to their response to treatment into two groups (responders and non-responders, 32 and 27 patients respectively). Blood and plasma samples were collected at the start of treatment and at 12 and 24 weeks during treatment. Immunophenotyping by flow cytometry for Treg cells, the FOXP-3 expression using real-time PCR and measurement of IL-10, TGF-ß CXCL-9 and CXCL-10 were performed. Increased expression of Treg cells was detected in patients who didn't respond to treatment before and during treatment. Also, the levels of IL-10, TGF-ß, CXCL-9 and CXCL-10 revealed significant increase.in non-responders all through compared to responders group. Evaluation of Treg cells, cytokines (IL-10 & TGF-ß) and chemokines (CXCL-9 & CXCL-10) before starting the treatment could be a predictor of response to treatment with PEG-IFN plus ribavirin. The optimum levels which would differentiate between responders and non-responders are needed to be defined before-hand.

Serum Markers of Epithelial Mesenchymal Transition as Predictors of HCV-induced Liver Fibrosis, Cirrhosis and Hepatocellular Carcinoma.

INTRODUCTION: Hepatitis C virus (HCV) is a major cause of chronic liver disease in Egypt, leading to hepatic fibrosis, liver cirrhosis (LC), and hepatocellular carcinoma (HCC). Liver fibrosis is characterized by excessive deposition of extracellular matrix (ECM). Newly-recognized pathogenic mechanisms point to the epithelial-mesenchymal transition (EMT) of hepatocytes to matrix synthesizing (myo-) fibroblasts. Transforming growth factor-beta (TGF-ß1), bone morphogenic protein (BMP)-7, and connective tissue growth factor (CTGF) are biomarkers reflecting the EMT process. YKL-40 is a glycoprotein member of ECM and plays a role in cancer cell proliferation. The purpose of this study was to determine the serum biomarkers of EMT and its impact on the fibrogenic process and tumorigenesis in HCV-genotype 4 patients. METHODS: In this case-control study that was conducted in 2013-2014, 97 HCV-infected patients were subjected to clinical examination, laboratory investigations, and liver biopsy. According to the histopathologic examination, they were classified to F0 (14 cases), F1 (17 cases), F2 (15 cases), F3 (18 cases), F4 (22 cases), and HCC (11 cases). Fifteen age- and gender-matched subjects were included as normal controls. Serum levels of TGF-ß1, BMP-7, CTGF, YKL-40 were assessed, and the TGF-ß1/BMP-7 ratios were calculated. The data were analyzed by plotting the receiver operating characteristic curve (ROC), Pearson product-moment correlation coefficient, and Spearman's rank correlation coefficient (Spearman's rho). RESULTS: Serum levels of TGF-ß1, BMP-7, CTGF, and YKL-40 were significantly increased in all patient groups compared to controls (p < 0.001). LC exhibited the highest CTGF level and YKL-40 was highest in HCC. The TGF-ß1/ BMP-7 ratios reflected the progression of EMT from CHC to LC, however, there was no significant difference between LC and HCC. TGF-ß1/ BMP-7 ratio is considered to reflect positive correlation with CTGF in LC group (r = 0.629; p < 0.03) and YKL-40 in HCC group (r = 0.504; p < 0.04). CONCLUSION: Increased TGF-ß1/BMP-7 ratio and CTGF levels reflect the rate of EMT and provide information about fibrogenic activity. Also, this ratio, in association with YKL-40, can be used to predict malignant transformation in HCV-genotype 4 Egyptian patients.