Expressing Membrane Antibody Reporter in the Islet Cells of Nonobese Diabetic Mice to Noninvasive Image the Disease Progression of Autoimmune Diabetes and the Therapeutic Effects of Drugs or Transgenes

Expressing a reporter gene in the pancreatic islet of non-obese diabetic mice (NOD mice) allows researchers real-time monitoring the processes of islet loss by noninvasive imaging systems, overcoming the defect of traditional method in which researchers need to weekly sacrifice lots of NOD mice to observe the insulitis in pancreatic islet section. We have successfully developed a reporter system based on expressing a murine anti-polyethylene glycol antibody receptor (anti-PEG reporter) on cell surface to selectively trap PEG-labeled imaging probes (PEG-NIR797, PEG- 124I, PEG-SPIO) to assess the delivery of cells in vivo by different imaging systems (optical imaging, micro-PET, MRI). The endogenous anti-PEG reporter does not induce humoral or cellular immune responses in Balb/c mice. The anti-PEG reporter, which is highly specific, nonimmunogenic, and suitable to various imaging systems, is believably appropriate to be transgenically expressed in the pancreatic islet of NOD mice, assisting researchers in conveniently and accurately tracing the process of islet loss and further investigating the islet-protective effects of drugs and genes. Currently, we have successfully developed the NOD/pIns-αPEG mice which stably expressed the anti-PEG reporter in their pancreatic islets. The breeding program is well into the fifth generation. Importantly, the PEG-NIR797 fluorescent probe can specifically accumulate and be imaged in the pancreatic islet region of NOD/pIns-αPEG mice, but not control NOD mice, by an optical imaging system. Based on these promising results, this project has the following goals: (1) Noninvasively imaging the progression of autoimmune diabetes in NOD/pIns-αPEG mice. (2) Real-time imaging the islet-protective effect of the anti-CD3 antibody in NOD/pIns-αPEG mice. (3) Crossing the NOD/pIns-αPEG mice with the NOD mice which overexpressed DCR3 in pancreatic islets, and then noninvasively imaging the islet-protective effect of DCR3 in their offspring. We believe that successful development of the NOD/pIns-αPEG mice can help researchers easily tracing the disease progression of type1 diabetes by noninvasive imaging systems, further providing a valuable tool for worldwide pharmaceutical companies and drug research institutes to screen and evaluate the diabetes drugs.