Type 1 diabetes results from autoimmune destruction of the insulin-producing p-cells of the pancreatic islets. Understanding the pathogenic process, as well as monitoring pre-diabetic individuals or people enrolled in clinical trials, has been hampered by the inability to access the target organ and to evaluate the true status of the autoimmune lesion. During the first 4 years of this program, we developed an imaging technique to visualize the changes associated with insulitis, based on the increased vascular leakage and phagocytic activity in infiltrated islets. These features can be detected by magnetic resonance imaging (MRI), via the local accumulation .of injected paramagnetic nanoparticles (MNP) that normally remain intravascular. Experiments in animal models were followed up by a pilot trial in which the technology to image the human pancreas was improved and was applied to patients with recent-onset diabetes. The trial is still ongoing, but preliminary results show pancreatic nanoparticle accumulation in most patients, comparable with that observed in affected mice. Most suggestively, the exceptions are individuals whose genetic alleles or immune markers make them unlikely to have true autoimmune diabetes. In the proposed work, we will: 1. Completethe optimization of the clinical MR imaging technique. Although the last funding cycle saw striking improvements in the application of MNP-MRI to visualizing pancreatic inflammation in human subjects, additional enhancements await exploration. We will optimize the technique to decrease respiratory artifact, increase spatial resolution and improve quantification through changes in pulse sequences and post- processing, which might also allow reliable measures of pancreatic blood volume. We will focus on protocol standardization, in order to make the technique exportable to other MRI groups for routine use. 2. Monitor the natural history of insulitis during the development of clinical diabetes. We will perform a """"""""natural history"""""""" study, tracking the evolution of pancreatic inflammation in at-risk individuals and in declared patients. These explorations should inform on the state of pancreatic inflammation in pre-diabetic individuals as a function of their risk status and eventual progression to diabetes. In patients with established diabetes, changes in inflammation will be correlated with rate of further p-cell loss. Aside from their mechanistic interest, these studies will lay the foundation for use in predicting disease or monitoring responses to therapy. 3. Image individuals with atypical disease features. Some diabetic patients show a very slow decline in p-cell function (LADA, individuals with very long-term C-peptide preservation). We will attempt to distinguish between a torpid inflammatory process, or an ability to vigorously regenerate p-cells, by imaging groups of such individuals. The ability to visualize and quantitate the degree of islet inflammation in diabetic or at-risk patients should provide important insights into the mechanisms that result in type 1 diabetes. It should also result in the validation of a diagnostic technique that would prove of great value in evaluating the actual risk inpre- diabetic patients, as well as the monitoring in real-time the effect of treatments in Type 1 diabetic patients.
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