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Chronic, persistent infections have been difficult to diagnose and treat in domestic animal operations. This is true of prion diseases such as scrapie and Chronic Wasting Disease, viral diseases such as Bovine Viral Diarrhea Virus, and bacterial diseases such as Johne's disease. The immune system serves as the first and most effective line of defense against these pathogens, however in the case of persistent or chronic infections the cells of the immune system may fail to adequately recognize the infectious agent, or in fact participate in the disease process. Of all organs, the immune system is unique, in that it's component cells do not carry out their role solely within encapsulated, fixed lymphoid organs, but in fact continually recirculate between the blood and the lymph. Through this recirculation, immunological surveillance continually monitors all vascularized tissues for the presence of foreign antigen, and memory cells are disseminated throughout the tissues to protect against future disease. While this response is protective in most diseases, in the case of chronic or persistent infectious organisms it is clear that this migratory system also may serve to disseminate the infectious agent throughout the lymphoreticular system and beyond. While such dissemination clearly contributes to disease progression, a complete knowledge of the mechanisms responsible for antigen transport by migratory leukocytes may lead to novel therapeutics and diagnostic approaches. While small animal models may be used to gain interpolative knowledge on the distribution of infectious agents, large animal models offer advantages of scale, whereby leukocyte traffic may be directly and quantitatively monitored throughout the course of the disease process. Our lab has a focus on the role of the migratory immune system in the pathogenesis of persistent and chronic diseases of domestic animals, including prions and bovine viral diarrhea virus. It is our broad, long-term goal to define the role of migratory leukocytes in the pathogenesis of chronic diseases of domestic animals. It is the focus of this work to specifically define the lymphoid pathogenesis of prion agents and bovine viral diarrhea virus.
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To accomplish this goal, we have the following specific aims: <OL> <LI> To define the role(s) of regulatory T cells in the acute and chronic immune response to persistent diseases. <LI> To define the role(s) of migratory dendritic cells in the pathogenesis of persistent diseases. <LI> To map the mechanisms of Follicular Dendritic Cells in the maintenance of chronic diseases. <LI> To map the function of unique leukocyte subsets in domestic animals. </ol> Our laboratory is well-prepared to accomplish these, goals, with a proven track record in the study of lymphocyte recirculation. Furthermore, we have assembled a large number of reagents specific for sheep and cattle leukocyte subsets. Finally, we have established a network of collaborators with specific expertise in the pathogenesis of our target infectious agents.
NON-TECHNICAL SUMMARY: Chronic, persistent infections present a unique challenge to producers. These diseases frequently maintain a low-level infection within the herd, resulting in direct economic consequences through reduced gain, and indirect consequences as affected animals continue to infect cohorts. In both human and animal medicine, these infections pose a specific challenge to eradicate as they apparently evade and in some cases use the immune system throughout infection. We intend to capitalize on new knowledge in the field of immune regulation and new reagents available for study of these processes in domestic animals to directly examine the immune response to chronic diseases. As model diseases, we will capitalize on the existing strengths of SDSU research to examine both prion diseases (Chronic Wasting Disease and scrapie) and Bovine Viral Diarrhea Virus (BVDV). To accomplish this goal, we will employ the well-developed lymph cannulation model to sample lymph draining affected tissue, collect appropriate cells for both in vitro and in vitro experimentation, and define specific molecular mechanisms whereby these persistent infectious agents maintain infection in the presence of a functional immune system. The data obtained will be directly relevant to a greater understanding of how these agents evade the immune system, and provide new avenues to the development of therapeutic vaccines and diagnostic tests.
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APPROACH: To accomplish these objectives, we will employ a well-characterized combination of in vitro and in vivo experimental systems, taking advantage of new reagents to specifically identify individual subsets of leukocytes in domestic animal that were previously unavailable. These techniques will include: Objective #1: Direct cannulation of lymphatics will permit the analysis of normal and pathogenic migration patterns of suppressor/regulatory T cells, a population which may be critical to maintaining ongoing infection of these chronic infectious agents. The use of monoclonal antibodies which specifically identify these subsets is unique to our laboratory due to the large number of reagents developed over the past 5 years. Objective #2: Through the use of fluorescent tracking labels and in vitro assay, we will directly establish the role of migratory dendritic cells in the pathogenesis of these diseases. Direct cannulation methods will again permit analysis of the number, phenotype, and function of dendritic cells participating in the initial and chronic responses to these agents, thereby establish potential targets for therapeutic intervention and diagnostic tools. Objective #3: We will specifically use a combination of in vivo lymphatic cannulation and in vitro cell culture models to define the role of FDCs in the maintenance of prions, BVDV, and other chronic infectious agents. Over the past 5 years, we have developed a highly effective cell culture model to define the role of FDCs in germinal center function, which can now be applied to the study of chronic disease. Objective #4: Although a great deal of information on the normal function of the immune system has been established in murine and human systems, in some cases there are important differences in the ruminant immune system. A classic example of this is the development of gamma-delta T cells. In addition, we have identified two cell populations represented in peripheral blood and other tissues of cervids and sheep which appear to be absent from mice and other rodents. We will employ traditional in vivo analysis and in vitro functional analysis to define the role(s) of these unique cell populations in the ruminant immune system.