Candida albicans causes a variety of infectious problems for dental patients. Denture stomatitis and oroesophageal candidiasis are also major problems for AIDS patients. The applicant's recent research on cadidiasis in immunocompetent and immunodeficient gnotobiotic mice has produced new and important findings on the role of thymus-matured and non-thymus-matured T cells and phagocytic cells in resistance to lethal oroesophageal and systemic candidiasis. Their data demonstrates that immunocompetent and some immunodeficient mice manifest resistance to lethal oroesophageal candidiasis. Multiple immune defects (innate and T-cell-mediated) appear to be required for mice to show enhanced susceptibility to lethal oroesophageal candidiasis. The natural susceptibility of these gnotobiotic murine models will help elucidate the cellular basis for resistance to candidiasis at all mucosal surfaces; the model is especially good for studies on oroesophageal candidiasis that minics the disease seen in many dental and AIDS patients. The applicants have demonstrated that CD4epsilon and CD8+ (alphabeta and gammadelta T-cell receptor) T cells, as well as phagocytic cells, play unique roles in resistance to candidiasis at different mucosal sites. This research project will clarify the role that thymus-matured and non-thymus-matured T cells (and their products) and phagocytic cells play in resistance to candidiasis. The applicants will identify the lymphocytes involved in resistance, assess their capacity to restore resistance to oroesophageal candidiasis, and ascertain if therapy with cytokines, produced by immune lymphocytes, can enhance resistance to lethal oroesophageal candidiasis and systemic candidiasis of endogenous origin. This research will not only clarify the role of lymphocytes (and their products) and phagocytic cells in resistance to candidiasis, but it will also provide a rational basis for innovative immunotherapy that will enhance resistance to oroesophageal and systemic candidiasis in patients. This study is also important for the development of safe and effective vaccines that may protect immunocompetent, but not immunodeficient hosts. Restoration and enhancement of immune function may be critical for the effectiveness of anti-Candida vaccines that are now under development.
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