Study On New CD4~+ Helper T Cells And Effect Cytokines In The Development Of Drug Induced Liver Injury And The Correlation With Liver Disease Prognosis

Background and AimsDrug-induced liver injury (DILI) has seriously threatened the clinical drug safe administration. DILI is the most common cause of acute liver failure. The mechanism of the immune-mediated drug reaction may involve a hapten-like action, resulting in auto immunity against hepatocellular components.CD4+ helper T cells (Th cells) are implicated in the adaptive immune. In the development of DILI, cytokines, such as IL-6、TNF、IL-4、IL-10、IL-17、IL-13、IL-1β、 IFN-y, implicated the activation of immune system and the adaptive immune. IL-17-producing CD4+ T (Th17) cells are implicated in the pathogenesis of DILI, with elevated IL-17 levels observed in DILI. Furthermore, increased Th17 cell is detected in DILI onset, suggesting a correlation between the level of IL-17 and the severity of liver inflammation.Th22 cells, secreting IL-22 but not IL-17 and IFN-y, are involved in the pathogenesis of inflammation and auto-immune diseases. IL-22 is secreted mainly by Th22, Th17 and Thl cells in human. Our previous report suggests that IL-22 was hepto-protective in chronic hepatitis B patients, but others found IL-22 was pro-inflammatory in chronic liver diseases. The relationship between DILI and Th22/Th17 remains to be explored. So far, no perfect animal model could precisely mimics human DILI. The precise underlying mechanism is currently being determined. Comprehensive, detailed, and excellent clinical study are needed to illuminating the immunity response in DILI. The distribution of immune cells in liver of DILI patients and the role of helper T cells in DILI were unkown. In this study, DILI patients were enrolled strictly, liver tissue and plasma were collected to explore the express of immune cells in DILI. The role of the CD4+ helper T cells and the effect cytokines in the development of DILI and the relationship with the prognosis of DILI were also observed.MethodsIdentified the express of immune cells in DILI liver; The frequencies of peripheral immune cells producing IL-22 (Th22/Th17/Thl cells) and intrahepatic IL-22/IL-17 production from DILI, non-DILI liver diseases, and healthy control were examined. Plasma IL-22/IL-17 and the related cytokines were determined in DILI patients at week 0 (defined as the occurrence of liver injury within 7 days),4 and 24. Multivariable stepwise logistic regression was applied to explore the associations between various factors and recovery of DILI.ResultsImmune cells (leukomonocyte, plasma cells and eosinophil granulocyte) were observed in DILI liver. The frequencies of Th22/Th17 cells were significantly higher from DILI onset patients than HC. Significant increase of Th22 cells and the related cytokines levels were observed in DILI with hepatocellular injury type. There was a positive correlation between intrahepatic IL-22 level and liver regeneration. Multivariable analysis showed that the odds ratio (OR) of plasma IL-22 at 4 weeks was 1.054 [95% confidence interval (CI),1.012,1.124].ConclusionImmune cells are involved the development of DILI. Th22 and its related cytokines might be hepato-protective, which might provide new perspective for understanding the immunopathogenesis of DILI. Plasma IL-22 might be a reliable indicator to evaluate the prognosis of DILI and provide a novel therapeutic target for DILI treatment.