Sjogren's syndrome is an autoimmune disease affecting mainly the salivary and lacrimal glands. As a result of leukocyte infiltration and various immune reactions, the secretory function of the glands is impaired resulting in dry eyes and dry mouth. Systemic manifestation can be present and other exocrine glands can be affected. What triggers the leukocyte infiltration into the salivary and lacrimal glands remains unknown. It is nearly impossible to address this issue in humans because of the long lag time between the """"""""initial triggering event"""""""" and the eventual diagnosis of disease. Mouse models for Sjogren's syndrome have been valuable. However, each model studied so far seems to display unique characteristics reflecting only a particular aspect of the disease. In addition, the time for the development of disease remains relatively long. Thus, models in which the Sjogren's syndrome develops rapidly and models that are based on rational and fundamental concept are needed. Day 3 post-natal thymectomy induces sialoadenitis in a few strains studied, presumably by removing salivary gland antigen-specific regulatory T (Treg) cells. This report and the recent explosive advance of Treg cell study prompted us to hypothesize that Treg cell-deficient mice must display Sjogren's syndrome among the multiple organs affected. Indeed, we observed severe Sjogren's syndrome in interleukin-2 receptor alpha (IL-2Ralpha) knockout (KO) mice, IL-2 KO mice and scurfy mice all of them lack Treg cells. Remarkably, the development of Sjogren's syndrome is rapid (<1-4 months). Moreover, we developed adoptive transfer model in which the disease could be detected as early as 10 days after high dose leukocyte transfer. This application is based on these newly developed animal models to further advance the study of Sjogren's syndrome. We have 3 specific aims: (1) to establish that Treg cell-deficient mice truly express Sjogren's syndrome and these mice can be used as models for Sjogren's syndrome study; (2) to establish an accelerated model of Sjogren's syndrome using adoptive transfer approach and (3) to study the trigger of Sjogren's syndrome to understand the environment, self antigens, and pathogens in this process. This study should identify new and useful models for Sjogren's syndrome research. It should identify new mechanism(s) for the pathogenesis of the disease and provide potential treatment of the disease. ? ? ?
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