T Regulatory Cells in Hepatitis c Infected Patients

The ultimate outcome of hepatitis c viral infection is determined by the host immune response. Patients with acute hepatitis c viral infection who did not clear the virus developed chronicity. Persistant hepatitis c virus -specific cytotoxic T-cell responses in the liver have been associated with the development of hepatic inflammation which may ultimately lead to liver cirrhosis. One of the potential mechanisms that might modulate hepatitis c virus -specific immune responses is the inhibitory role of the regulatory T cells.

Regulatory T cells are a subtype of T-cells that play a fundamental role in maintaining immune homeostasis to balance between the tissue-damaging and protective effects of the immune response. Regulatory T cells are characterized by the expression of the Forkhead box protein P3 transcription factor in the nucleus and is generally accepted as the single best marker for regulatory Tcells. In cases of hepatitis c virus infection, the role of regulatory Tcells is still controversial and most of studies yielded conflicting reports. This conflict may be explained by the heterogeneity in the methods and sites of studying the frequency of regulatory T cells.

There are strong evidences that regulatory T cells and their cytokines may play an important role in the induction of tolerance in the liver.

Interleukin 35 is an immune-suppressive cytokine expressed in stimulated human regulatory Tcells during inflammatory responses and consists of Interlukin-12a ( Interleukin 12p35 subunit) and IL-27b chains, encoded by the Interleukin 12A and Epstien Bar I3 genes, respectively. It is a novel heterodimeric cytokine belonging to the Interleukin 12 family, and little is known about its receptor. Activated peripheral blood mononuclear cell (PBMC)- derived human regulatory T cells have been shown to express and secrete large amounts of Interleukin 35, which contributes significantly to the suppressive capacity of regulatory T cells in an Interlukin 35-dependent manner.

Additionally, human regulatory T cell -derived IL35 is required for the conversion of human conventional cluster of differentiation 4+Foxp3_ T cells into induced T regulatory 35 cells, which then promote the generation of more induced T regulatory 35 cells via Interleukin 35 secretion, resulting in infectious tolerance (18). In addition, Interleukin 35 has been shown to suppress the T helper (Th) cells Th1 and Th17.

In this study, investigators will evaluate the possible role of regulatory T cells and their cytokines in different groups of hepatitis c infected patients by investigating the frequency of regulatory T cells and serum level of IL35 and examining their relationship to the various patterns of hepatitis c viral persistence, hepatitis c virus pathogenesis, complications with cirrhosis and hepatocellular carcinoma in an attempt to estimate the future value of using anti IL35 and regulatory T cell depletion in those patients.