Autoimmune diseases are a major health problem, and their frequency in most developed countries is on the rise. Despite energetic research efforts, our understanding of the immunological mechanisms responsible for these disorders remains too meager to permit rational preventive or therapeutic intervention in most cases. This ignorance is largely due to their mechanistic complexity, with the implication of a multiplicity of genetic and environmental factors, networks of-interacting immune system players and sophisticated, multiplex effector mechanisms. Additional complications arise from the fact that many of these diseases seem to be heterogeneous disorders, and that often they can only be diagnosed rather late in their course, after significant tissue destruction has already occurred. These problems seem more tractable in light of the impressive advances in imaging technology that have taken place over the past several years -- it is now possible to visualize cells or even molecules in vivo in real time by a variety of modalities in both rodents and humans. The overall objectives of this proposed program are to develop novel imaging methodologies for visualizing inflammatory processes during the unfolding of autoimmune disease, and to exploit these methods to answer a defined set of questions currently being posed about type-1 diabetes and inflammatory (rheumatoid) arthritis in rodent models and human patients. These goals will be achieved in the context of four highly interactive projects and one core. Project 1 will focus on the development of novel imaging methodologies (including magnetic resonance, fluorescence, and bioluminescence modalities) and establishment of proof-of-principle for their biological application. Proiect 2 will apply these novel methods to issues concerning type-1 diabetes in murine models -- for example, how pancreatic islet p-cell mass/activity evolves during disease progression or how regulatory T cells traffic to and are maintained in the insulitic lesion. Project 3, in parallel, will apply such methods to arthritis questions in murine models asking, for example, whether early microvascutar changes predicate the heterogeneity of joint involvement or how mast cells migrate through the arthritic lesion. Project 4 will apply one of the new imaging methods, magnetic resonance visualization of MION distribution within the microvasculature, to a small number of type-1 diabetes patients and their at-risk relatives to test its potential in disease diagnosis, staging and stratification. Finally, Core A will provide required technology to all of the projects, primarily image acquisition and data analysis; this core also has a development component, aiming to push the technology to its limits. Some major strengths of this program are that it attacks a critical issue, mobilizes a distinguished group of principal investigators, is unusually interactive, and opens a vista of exciting future perspectives. Its uniqueness resides in certain of its resources (probes, models, patient collections) and in the multiple axes of interaction: imagers/immunologists, physical/chemical/biological inputs, diabetes/arthritis models, basic/clinical research, The resulting cross-fertilization is sure to result in novel solutions to the difficult and multitudinous problems posed by autoimmunity.
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