Cytochrome P450IID6-specific CD8 T cell immune responses mirror disease activity in autoimmune hepatitis type 2

Abstract

Autoimmune hepatitis type 2 (AIH‐2) is a severe organ‐specific disorder characterized by liver kidney microsomal antibody type 1 targeting cytochrome P4502D6 (CYP2D6). Growing evidence implicates the involvement of CD8 T cell immune responses in its pathogenesis. We investigated CYP2D6‐specific CD8 T cell human leukocyte antigen (HLA)‐A2 restricted responses in AIH‐2 (20 patients, 11 HLA‐A2+). Binding affinity of CYP2D6 peptides to HLA‐A2 was predicted by the algorithm SYFPEITHI and assessed in vivo by T2 cell assays. CD8 T cell interferon (IFN)‐γ production was assessed via intracellular cytokine staining, cytotoxicity via chromium release assay, and frequency of circulating and intrahepatic CYP2D6‐specific CD8 T cells via tetramer staining. CYP2D6‐specific CD8 T cell reactivity was tested at diagnosis and during treatment and correlated with indices of disease activity. Seven CYP2D6 peptides with high HLA‐A2 binding affinity colocalizing with known B cell or CD4 T cell epitopes were selected. Five sequences inducing high levels of IFN‐γ were used for HLA‐A2 tetramer construction. Frequency, IFN‐γ production, and cytotoxicity of CYP2D6‐specific CD8 T cells were higher at diagnosis than during treatment. Intensity of CYP2D6‐specific CD8 T cell responses correlated with disease activity. Immune responses to CYP2D6_245‐254 were the strongest both at diagnosis and during treatment. Conclusion: HLA‐A2–restricted, CYP2D6‐specific CD8 T cell immune responses vary according to disease stage and correlate with hepatocyte damage. CD8 T cell targets on CYP2D6—in particular CYP2D6_245‐254—may be the focus of novel immune intervention in AIH‐2. (HEPATOLOGY 2007.)