328 PROGRAMMED DEATH 1 (PD-1) EXPRESSION OF PERIPHERAL CD4+ T LYMPHOCYTES IMPLICATES PROGRESSION OF MALNUTRITION AND HEPATIC CARCINOGENESIS IN PERSISTENT HEPATITIS C VIRAL INFECTION

Abstract

Background and Aims: Persistent HCV infection leads to liver fibrosis and carcinogenesis. Expression of PD-1, an inhibitory molecule, causes T cell exhaustion and failure of HCV eradication. Furthermore, degree of PD-1 expression defines the level of T cell dysfunction (Nakamoto N et al. Gastroenterology 2008. 134: p1927–37). However, little is known about how persistent T cell exhaustion influences clinically during HCV infection. Methods: Sixty patients of chronic hepatitis C were included. Peripheral blood mononuclear cells were taken after informed consent, and were analyzed by flow cytometry before intervention. Twenty-two patients (37%) were HCC-bearing cases. Clinical laboratory parameters including serum albumin, branch-chain amino acids (BCAA) to tyrosine ratio (BTR), cross-section area of visceral fat (by electrode impedance method), METAVIR staging of recent liver biopsy (available in 29 cases), and clinical staging of HCC were also analyzed. Results: PD-1 expression of peripheral CD4 T lymphocytes was significantly elevated in HCC-bearing cases (12.1% vs 7.4%, p < 0.0001), but that of peripheral CD8 T lymphocytes was not statistically significant. To further evaluate risk factors affecting hepatic carcinogenesis, we found that PD-1 expression of CD4 T lymphocytes had no statistical correlation to fibrosis stages of liver biopsy specimen (p =0.98). Elevated PD-1 expression of CD4 T lymphocytes significantly correlated to lower serum albumin (p < 0.0001, correlation coefficient c.c.= −0.49), lower BTR (excluding BCAA supplemented cases, p = 0.016, c.c.= −0.48), and higher crosssection area of visceral fat to body surface area (BSA) ratio (p = 0.0016, c.c.= 0.55), which suggested that T cell dysfunction significantly correlated to nutritional/metabolic derangements in chronic hepatitis C. PD-1 expression of CD4+ T lymphocytes also increased accordingly to the T factor of HCC (p =0.035), TNM staging (p = 0.015), and JIS scores (p = 0.013). Furthermore, PD-L2 levels expressed on plasmacytoid dendritic cells (pDCs) were significantly increased as PD-1 expression of CD4+ T lymphocytes elevated (p =0.002, c.c.= 0.61). Conclusions: These findings suggest that T cell exhaustion may play a pathological role in carcinogenesis and HCC progression in chronic HCV infection. Correlation of PD-1 expression of CD4+ T lymphocytes and nutritional/metabolic factors also suggests an immunological rationale for nutritional intervention in these patients.