Coccidioidomycosis is a mycotic disease characterized by depressed cellular immune reactivity which, in most patients, is specific for Coccidioides immitis antigens. A long term goal of our studies has been to define the basis for depressed T cell function and to determine if immunosuppression is the cause or the effect of the disease. Using a murine model, we have established that intravenous injection of C. immitis antigen or intranasal instillation of viable arthroconidia into BALB/c mice induces a suppressor cell(s) that inhibits the induction (or expression) of delayed-type hypersensitivity (DTH) to C. immitis. Adoptive transfer of spleen cells from antigen-treated donors or spleen cell lysates from infected BALB/c mice to normal, syngeneic mice suppresses the response of recipients to immunization with coccidioidal antigen. Hence, suppression is mediated via a spleen cell population(s). Suppression is antigen specific as evidenced by the ability of Coccidioides-suppressed mice to respond to immunization with tuberculin. The activation of a suppressor cell circuit(s) in BALB/c mice precedes and may contribute to progressive coccidioidal disease. This hypothesis is based upon the finding that BALB/c mice are highly susceptible to pulmonary infection and, although the mice mount a significant level of DTH early during the course of disease, they become anergic and succumb to the disease within 22 days. In contrast, DBA/2 mice are resistant to pulmonary infection and maintain strong DTH reactivity throughout a 30-day period postinfection. On the basis of these data, we propose a four-year study to: (i) characterize the splenic cell population(s) responsible for suppression of DTH to C. immitis by fractionation of spleen cells on nylon wool and by depletion of specific cell populations with cytolytic antibodies plus complement prior to assays for a suppressor activity; (ii) determine if suppressor cells are preferentially activated in the susceptible BALB/cf mouse strain as compared to resistant DBA/2 and (BALB/c X DBA/2)F1 mouse strains; and (iii) determine if suppressor activity adversely modulates the course of coccidioidomycosis by inducing or adoptively transferring suppressor activity prior to or at the time of pulmonary infection with C. immitis arthroconidia.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Microbial Physiology and Genetics Subcommittee 2 (MBC)
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Texas Center for Infectious Disease
San Antonio
United States
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