Cytochrome P450IID6-specific CD8 T cell immune responses mirror disease activity in autoimmune hepatitis type 2.
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)-gamma 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-gamma were used for HLA-A2 tetramer construction. Frequency, IFN-gamma 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.


CONCLUSIONS
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.).
Longhi
Maria Serena
MS
Institute of Liver Studies, King's College London School of Medicine at King's College Hospital, Denmark Hill, London, UK.
Hussain
Munther J
MJ
Bogdanos
Dimitrios P
DP
Quaglia
Alberto
A
Mieli-Vergani
Giorgina
G
Ma
Yun
Y
Vergani
Diego
D
D000293:Adolescent; D000328:Adult; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002648:Child; D002675:Child, Preschool; D019389:Cytochrome P-450 CYP2D6 / Q000276:immunology*; D003602:Cytotoxicity, Immunologic; D005260:Female; D015789:HLA-A2 Antigen / Q000032:analysis / Q000276:immunology; D019693:Hepatitis, Autoimmune / Q000276:immunology*; D006801:Humans; D007150:Immunohistochemistry; D007371:Interferon-gamma / Q000096:biosynthesis; D008297:Male
D015789:HLA-A2 Antigen; D007371:Interferon-gamma; D019389:Cytochrome P-450 CYP2D6