In drug-induced, immune-mediated hepatitis, interleukin-33 reduces hepatitis and improves survival independently and as a consequence of FoxP3+ T-cell activity

Immune-mediated,drug-induced hepatitis is a rare complication of halogenated volatile anesthetic administration.IL-4-regulated Th2-polarized reactions initiate this type and other types of hepatitis,while the mechanisms that regulate the severity remain elusive.IL-33 is an innate,IL-4-inducing,Th2-polarizing cytokine that has been detected in patients with liver failure and has been associated with upregulated ST2+Foxp3+CD4+CD25+T cells;however,roles for IL-33 in drug-induced hepatitis are unclear.We investigated IL-33 in an anesthetic,immune-mediated hepatitis modeled in BALB/c,IL-33−/−and ST2−/−mice,as well as in patients with anesthetic hepatitis.The hepatic IL-33 and ST2 levels were elevated in BALB/c mice(p<0.05)with hepatitis,and anti-IL-33 diminished hepatitis(p<0.05)without reducing IL-33 levels.The complete absence of IL-33 reduced IL-10(p<0.05)and ST2+Foxp3+CD4+CD25+T cells(p<0.05),as well as reduced the overall survival(p<0.05),suggesting suppressive roles for IL-33 in anesthetic,immune-mediated hepatitis.All of the mice demonstrated similar levels of CD4+T-cell proliferation following direct Tcell receptor stimulation,but we detected splenic IL-33 and ST2-negative Foxp3+CD4+CD25+T cells in ST2−/−mice that developed less hepatitis than BALB/c mice(p<0.05),suggesting that ST2-negative Foxp3+CD4+CD25+T cells reduced hepatitis.In patients,serum IL-33 and IPEX levels were correlated in controls(r2=0.5,p<0.05),similar to the levels in mice,but not in anesthetic hepatitis patients(r2=0.01),who had elevated IL-33(p<0.001)and decreased IPEX(p<0.01).Our results suggest that,in anesthetic,immune-mediated hepatitis,IL-33 does not regulate the CD4+T-cell proliferation that initiates hepatitis,but IL-33,likely independent of ST2,reduces hepatitis via upregulation of Foxp3+CD4+CD25+T cells.Further studies are needed to translate the role of IL-33 to human liver disease.

Immune Checkpoint Inhibitor-induced Immune-mediated Hepatitis in A Lung Cancer Patient Undergoing Long-term Immunotherapy:A Case Report

Immune-mediated hepatitis(IMH)induced by immune checkpoint inhibitors(ICIs)is an immune-related adverse event(irAE).IMH usually occurs 8-12 weeks after the first dose of ICI therapy.We report an unusual case of a lung cancer patient who developed IMH 2 years after initial ICI treatment and relapsed during corticosteroid therapy.A 55-year-old male with stageⅣB lung cancer received ICIs(for over 2 years)and chemotherapy as a second-line therapy.Grade 4 IMH occurred 2 years after initial immunotherapy and was diagnosed as hepatitis via laboratory and imaging tests with the simultaneous exclusion of other causes.The patient responded well to the corticosteroids;however,he decided to discontinue treatment prematurely,meaning that the total treatment period was less than 4 weeks.This led to IMH reoccurrence and the need to readminister corticosteroids at a higher dose than before.Ultimately,the patient's IMH was controlled and did not reoccur.This case illustrates that immune-related toxicity needs to be monitored in patients undergoing long-term ICI therapy.Improving patient education is also essential for the management and treatment of irAEs.