The broad, long-term objective of this project is to determine the immunologic and inflammatory responses that have an impact on the progression and resistance to mycoplasma respiratory disease, and apply this information to development of effective immunotherapies against mycoplasma diseases.
The Specific Aims are to 1) Determine the role of CD4+ and CD8+ T cells in murine mycoplasma respiratory disease; 2) Examine the effects IFN-gamma and IL-4 in mycoplasma disease; and 3) Determine the role of T helper subset responses in generation of protective immunity against mycoplasma infection. Mycoplasma respiratory disease has a tremendous impact on health in the United States. There are 8 to 15 million cases in the United States annually. It is clear that immunologic responses have a major impact on the progression of mycoplasma respiratory disease. Immunity does play a role in resisting and recovery from disease, but a major component of mycoplasma respiratory diseases is immunopathologic. There is a critical need to understand the immunologic and inflammatory mechanisms that play a role in mycoplasma respiratory disease. Previous work suggests that T cells play a pivotal role in determining whether host responses are beneficial or detrimental. However, the role of the different T cell subsets is unclear. This information will provide important insights into the disease process and establish novel approaches for therapy and prevention of mycoplasma disease in humans. The experimental design is as follows: 1) Mice will be treated with monoclonal antibodies to deplete of CD4+ and/or CD8+ T cells and the severity of a murine model of mycoplasma respiratory disease, caused by Mycoplasma pulmonis, will be determined. Also, specific T cell subsets and B cells will be adoptively transferred into immunodeficient SCID mice, and disease severity will be determined; 2) IFN-gamma and IL-4 knockout mice will be infected with mycoplasma and disease severity and numbers of mycoplasma will be determined. Also, normal mice will be treated with monoclonal antibodies specific for those cytokines at different times after infection to determine the stage of disease that these cytokines play a role; and 3) Mice, treated with IFN-gamma or IL-4 specific monoclonal antibodies, will be immunized with mycoplasma antigens, and their subsequent resistance to mycoplasma disease will be determined. Also, mice will be immunized with mycoplasma antigen mixed with Th1 9IL-12) or Th2 (IL-4) promoting cytokines and protection from mycoplasma infection will be assessed. These results will allow further studies on pathogenesis and prevention of murine mycoplasma respiratory disease and provide insights for studies on human respiratory disease due to mycoplasma. Importantly, these studies will facilitate development of an innovative approach to combat mycoplasma diseases that relies on our understanding of the immunologic mechanisms of disease pathogenesis and the preferential activation of selected T helper cell subsets to maximize protection while minimizing disease and inflammatory reactions.
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