DESCRIPTION (provided by applicant): Primary biliary cirrhosis is considered a model autoimmune disease because of the clinical homogeneity between patients and the highly specific and highly directed nature of the hallmark of this disease, sera antimitochondrial antibodies. Considerable data from our laboratory suggests that a multi-lineage response to pyruvate dehydrogenase (PDC-E2), the major mitochondrial autoantigen, is the pathogenic effector mechanism responsible for the destruction of small biliary epithelial cells (BECs). Our laboratory has considerable experience in defining the immunobiology of this immune response in humans and recently has developed a unique murine system in which a PBC-like disease is induced following chemical xenobiotic immunization. Our goal is to take advantage of these data and develop specific immunotherapy that we hypothesize will down-regulate the immune response to PDC-E2 and modify the autoimmune response. We will construct an AAV8 vector containing the ApoE/hAAT enhancer/promoter to drive PDC-E2 expression with or without four consecutive miR-155 target sites in the 3'untranslated region. Two AAV constructs will be designed. One will be confined to PDC-E2 expression on hepatocytes and the other will be a plasma membrane-anchored PDC-E2. Control vectors will similarly be produced and transduction rates and duration of transgene expression will be monitored by real time expression using an optical imaging system. Further, four perfectly complementary targets of microRNA 155 (miR-155), expression of which is found only in mature APCs, will be inserted into the 3'untranslated region of the PDC-E2 cDNA to prevent APC activation. We will apply combinatorial testing of both of these constructs in the presence or absence of miR-155 to determine whether we can inhibit anti-PDC-E2 responses in mice immunized with PDC-E2 and similarly we will determine whether specific tolerance can be reintroduced against PDC-E2 in mice with a previously established anti-PDC-E2 response. Finally, we will take advantage of our xenobiotic model of autoimmune cholangitis and the identical vectors with and without miR-155 to either prevent or modify clinical disease. In this model we can address the titer immunoglobulin subclass and affinity of the antimitochondrial response as well as examine extensive tissue histopathology and finally immunochemical characterization of liver specific infiltrates. PUBLIC HEALTH RELEVANCE: Primary biliary cirrhosis (PBC) is an orphan autoimmune disease that has been relatively ignored by the large pharmaceutical companies. There have not been recent advances in the treatment of PBC. Our goal is to take advantage of our data on the immune response in patients with PBC, our recently developed animal model of PBC and our expertise in gene therapy, to develop novel treatments that we believe will down-regulate/modulate the autoimmune response in PBC and lead to therapeutic improvement.
|Effective start/end date||6/1/10 → 5/31/13|
- National Institutes of Health: $181,940.00
- National Institutes of Health: $230,894.00
- Immunology and Microbiology(all)
Explore the research topics touched on by this project. These labels are generated based on the underlying awards/grants. Together they form a unique fingerprint.