A project to examine microbial modulation of the immune system via regulatory cytokines is described. These studies are relevant to immunodeficiency diseases as well as how an immunosuppressed population may be predisposed to emerging zoonotics or novel pathogens. The prevention and treatment of infectious diseases fostered by compromised immunity will be impacted by these studies seeking disease intervention via targeted disruption of aberrant cytokine regulation. Pathogens that modulate T cell cytokines are directly addressed however, autoimmune disease pathologies may also be impacted by these studies.
The aims of this proposal address the hypothesis that, the nature as well as kinetics of adaptive responses are largely influenced by the type of antigen presenting cells involved and the cytokines present at the site of lymphocyte stimulation by antigen. The human pathogen T. b. rhodesiense (T.b.r) and the cytokine interferon-gamma (IFN- gamma), produced by CD8+ T cells, form the central aspects of the proposal. This organism provides a facile model to study how a pthogen can subvert immunity via the central regulatory actions of IFN-gamma on B cells and the production of other cytokines.
The Specific Aims addressing this hypothesis are: 1) to determine if the enhanced immune response to T.b.r observed in transgenic animals is due to an abrogationof T cell modulation and 2) to examine the role of IFN-gamma as a pathological immune modulator via regulation of cytokines and antigen presenting cells. The experimental design involves various strains of transgenic mice with enhanced or diminished immunity to T.b.r. to serve as donors or recipients of transplanted immune cells. Cell types able to """"""""invert"""""""" characteristic murine immune phenotypes during infection will be considered modulatory targets. Focus will also be upon assessment of cytokine production and """"""""polarization"""""""" by CD8+ T cells in strains with enhanced or diminished immunity. Understanding aberrant or microbial modulation of immune pathology is essential to prevention or intervention in infectious as well as emerging diseases.
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