EL-3：Transgenic Studies for dissecting immunopathogenic mechanisms and developing novel therapeutic approaches in non-obese diabetic mice

Huey-Kang Sytwu, MD, PhD

Department of Microbiology and Immunology

National Defense Medical Center, Taipei, Taiwan

Phone: 886-2-87923100, ext. 18540

Fax: 886-2-87921774

Email: Sytwu@ndmctsgh.edu.tw

Insulin-dependent diabetes mellitus (IDDM) is caused by a progressive autoimmune destruction of the insulin-producing cells in the pancreatic islets of Langerhans. A widely used animal model for dissecting immunopathological mechanisms in IDDM and for developing preventive and/or therapeutic strategies is the non-obese diabetic (NOD) mouse, an inbred strain that spontaneously develops an autoimmune diabetes resembling human IDDM. To dissect the immunopathogenic mechanisms of IDDM and develop potential therapeutic strategy for this disease, several novel transgenic NOD mice have already been established by our lab. The first one is the Th1 and Th2 doubly transgenic NOD mouse which provides the best in vivo model to study the pathogenic nature and the differentiation of helper T cell subsets during the diabetogenic process in IDDM. To further delineate the protective roles of some novel immune modulatory molecules, such as soluble decoy receptor 3 (DcR3), cytotoxic T lymphocyte antigen 4 (CTLA4), program death ligand 1 and 2 (PD-L1 and 2), heme oxygenase 1 (HO-1), in the autoimmune process and search for potential preventive and/or therapeutic targets in this disease, we generated (a) insulin promoter (pIns)-sDcR3 transgenic NOD mice, (b) pIns-single chain anti-CTLA4 transgenic NOD mice, (c) pIns-single chain anti-4-1BB transgenic NOD mice, (d) pIns-PD-L1 transgenic NOD mice (e) pIns-PD-L2 transgenic NOD mice (f) pIns-HO-1 transgenic NOD mice. Making full use of these unique mouse strains, we are quantitatively and qualitatively investigating the immunopathogenic mechanisms of autoimmune diabetes and provide valuable information for the development of novel immunotherapies. Finally, by using the established lenti-viral system in our lab, we are currently transducing various immunomodulatory genes into islets and investigating the function and survival of these genetically modified graft islets. This may provide tremendous help for successful islet transplantation in the future.