Cryptococcosis is an often times fatal disease caused by a yeast-like organism, Cryptococcus neoformans. Patients with cryptococcosis frequently have high levels of cryptococcal antigen in their body fluids, and antigen levels directly correlate with the severity of disease. Using a murine model we have documented that animals with large numbers of cryptococci in their tissues have high cryptococcal antigen levels in their sera and minimal delayed-type hypersensitivity (DTH) responses to cryptococcal antigen. Furthermore, if cryptococcal antigen is injected into mice at concentrations similar to those found in human systemic cryptococcosis, a complex series of suppressor cells and factors is induced which specifically suppresses the DTH response and the T cells responsible for in vitro growth inhibition of cryptococci. Two sources of cryptococcal antigen have been shown to induce suppression. One is an in vitro prepared cryptococcal culture filtrate antigen (CneF), and the other is serum from C. neoformans infected mice having a high cryptococcal antigen titer. We feel there is now a sufficient understanding of the mechanisms which down-regulate the cryptococcal cell-mediated immune response, i.e. DTH, to achieve the following proposed specific aims. The first goal of these proposed studies is to determine the effects on clearance of C. neoformans from organs after mice have been suppressed by injecting tolerizing doses of CneF or cryptococcal specific first- (Tsl) or second-order (Ts2) suppressor cells. Furthermore, clearance of Listeria monocytogenes in mice treated with suppressive doses of CneF will be monitored to assess whether or not nonspecific effects on clearance are induced by CneF. The second objective in these studies is to establish which component(s) of the cryptococcal antigen is responsible for induction of suppression. This will be achieved by fractionating the antigen by conventional methods, and testing the antigen fractions for suppressive capabilities. And, third, we will assess changes occurring at the cellular level in lymph nodes and spleens during the induction of Tsl cells in contrast to changes occurring during the induction of DTH. Parameters to be monitored will be levels of Ia antigens on lymphoid cells, IL-1 and IL-2 production, and IL-2 receptors on cells. A greater understanding of the effects of suppression and the parameters involved in the induction of suppression will provide the rationale for future investigations on effective control of the protective immune mechanisms.
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