64 ANTIGEN-SPECIFIC REGULATORY T-CELLS IN AUTOIMMUNE HEPATITIS TYPE 2: CYTOKINE PROFILE AND EFFECT OF SEMI-MATURE DENDRITIC CELLS ON SUPPRESSOR FUNCTION

Primary Biliary Cirrhosis is an autoimmune liver disease that predominantly affects middle-aged women, characterized by lymphocytic infiltration in portal tracts and destruction of intrahepatic small bile ducts, causing liver fibrosis and eventually liver failure. The histopathology is presumably mediated by CD8 T cells. Here, we describe a novel mouse model which shows gender differences similar to the female predominance observed in PBC patients. Adoptive cell transfer experiments of OVA-specific CD8+ T cells into K14-Ovap transgenic mice were performed. K14-Ovap mice express the antigenic SINFEKL peptide (residues 257–264 of OVA) under the control of human keratinocyte-specific promoter which directs expression in biliary epithelial cells. OT1 CD8+ T cells were injected intraperitoneally in male and female mice and survival rate, serum transaminases and histologic sections of the liver were analysed. Serum transaminase levels were significantly increased in female recipient mice in comparison to PBS control animals after adoptive transfer of 4×106 OT1 CD8+ T cells (**p < 0.009). In contrast transaminase levels of male mice recipient did not increase even after transfer of 10×106 OT1 CD8+ T cells. After adoptive transfer of 4×106 OT1 CD8+ T cells, histopathologic examinations of female mice showed peribiliary lymphocytic infiltrates and granuloma like lesions, whereas in male mice no histological lesions were seen. On day 6 after adoptive transfer of 20×106 and 10×106 OT1 CD8+ T cells 100% of female recipient mice died. Survival rate increased with transfer of lower cells numbers (4×106 survival rate of 80%). Male mice which received the corresponding cell numbers survived. In previously described models of PBC the immunopathology develops equally in male and female mice, in contrast to the female predominance in humans. In our model female mice showed a higher susceptibility against OT1 CD8+ T cell mediated hepatobiliary injury. We here describe an inducible, gender affected, immune-mediated model of PBC which could serve as an important tool to study gender effects on early autoimmune liver injury.