Study On The Antigen-specific T Lymphocytes In Patients With Primary Biliary Cirrhosis

It has been hypothesized that destruction of biliary tract in primary biliary cirrhosis (PBC) would be mediated by autoreactive liver-infiltrating T cells through either cytotoxicity or lymphokine production. The aims of this study were to investigate the pathogenesis from T cells level through analysis of HLA alleles polymorphism in Chinese PBC patients, to indentify epitopes of PDC-E2 specific CTL, to quantitate and functionally analyze antigen specific CTL in peripheral blood. In addition, we expected to find a new immunotherapeutic method to antagonize effector function of PDC-E2 specific CTL and to provide important clues for therapy of PBC by screening of analogue peptides. Susceptibility to primary biliary cirrhosis in Chinese individuals is associated with DRBl*0701 allele but the association is not restricted to any particular subgroup of patients, and valine at position 78 of HLA DR(31 may play an important role in the pathogenesis of primary biliary cirrhosis. Peptides of KLSEGDLLA(159¹67aa) and LLAEIETDKA(165¹74aa) located in the inner lipoyl domain of PDC-E2 are HLA-A*0201 restricted CD8⁺ CTL immunodominant epitopes in PBC. The frequencies of PDC-E2₁65-174 specific CTL are similar to that of PDC-E2₁59₁67 in peripheral blood of PBC patients, both of which play important roles in the development of PBC. An alanine substitution at position 5 (I5A, LLAEAETDKA) of PDC-E2₁65-174 significantly reduced peptide induced effector functions of PDC-E2₁65-174 specific CTL, which indicate I5A peptide can be utilized to manipulate the CD8⁺ T cell responses against PDC-E2₁65-174.