HEPATOCELLULAR CARCINOMA: CURRENT AND PROSPECTIVE IMMUNOTHERAPEUTIC STRATEGIES.

Hepatocellular carcinoma (HCC) is a highly lethal and the most common primary liver cancer with increasing worldwide incidence. Pathogenesis of HCC is immune mediated, however, not completely understood. Chronic low-grade inflammation alters both innate and adaptive immune responses. As a result tolerogenic environment is established in damaged organ. Up to date, incomplete understanding of HCC pathogenesis and the extend of biomarker variability among patients represent the major obstacle for early diagnosis and for the choice of effective treatment. Among current treatment options for HCC, thermal ablation strategy, which in addition to cancer eradication provides adjuvant/"danger"signal to the patient's immune cells, has demonstrated its active immunotherapeutic effect. In ongoing phase I/II clinical trials, tumor antigen loaded dendritic cell (DC)-based vaccines as well as tumor-specific cytotoxic T cells are being tested. Genetically redirected T cell therapy and more refined autologous vaccines are still awaiting approaches in HCC. The topic of this review focuses on current and bench-to-bedside immunotherapeutic strategies for HCC and discusses their advantages and limitations in clinic. We also weight up several prospective immunotherapeutic approaches which in theory have the potential for further implication in HCC. Combination of the induction of effective antitumor immunity with the inhibition of the mechanisms of tumor-induced immunosuppression ought to be a key objective in these future developments.

Cytokines and T regulatory cells in the pathogenesis of type 1 diabetes.

Type 1 diabetes (T1D) is an inflammatory disease of the pancreatic islet, in which insulin-producing ß-cells are preferentially destroyed to varying degrees by the concerted action of autoreactive T-cells and monocytic cells. Th1-type cytokines (IL-2 and IFN-γ) correlate with T1D, whereas Th2 (IL-4 and IL-10), Th3 (TGF-ß), and T regulatory cell-type cytokines (IL-10 and TGF-ß) correlate with protection from T1D. An altered balance between the proinflammatory and regulatory T-cell responses, in which T regulatory cells lose the battle, leads to T1D. The aim of current study was to determine the role of CD4+CD25+ regulatory T cells and cytokines: IFN-γ, IL-6, TNF-α, IL-10, IL-4, IL-17 in pathogenesis of T1D.The study was carried out on 71 patients suffering from T1D at the department of endocrinology, Tbilisi State Medical University and Diabetic Children Association. The circulating levels of (IFN-γ, IL-6, TNF-α, IL-10, IL-4, IL-17) were determined by ELISA according manufactures' protocol (R&D Systems Inc., USA). Tregs - CD4+CD25+ frequency was determined on cytofluorometer (BD FACSCalibur flow cytometer, USA). Statistical analysis was performed by using STATISTICA 8.0 for PC (Statsoft Inc., Minneapolis, USA) and Mann-Whitney U-test. Our study revealed significant decrease of IL-6, TNF-α, IL-10 and IL-4 plasma levels (1.197-, 1.188-, 1.504- and 1.840-times respectively) and increase of IL-17 plasma level (2.311-times) on the background of almost unchanged frequency of Tregs in patients with type 1 diabetes. In T1D patients CD4+CD25+ Tregs frequency did not correlate with diabetes duration and positivly correlated with age and IL-4. We supposed that decreased level of IL-4 and IL-10 reflects inhibited functional activity of these cells. We suggested that shifted balance of Th17/Tregs towards inflammatory IL-17 producing cells and decreased levels of suppressive cytokines IL-4 and IL-10 play crucial role in T1D. Future studies are needed to clarify changes in which subsets of heterogenous population of regulatory cells are associated with diabetes duration and how the therapy affects their frequency and function.