Cryptococcoses is an often fatal disease caused by a yeast-like organism, Cryptococcus neoformans. Cell-mediated immune (CMI) mechanisms are essential in host resistance against this organism as emphasized by the fact that individuals with reduced CD4 cell function, such as patients with the acquired immunodeficiency syndrome, (AIDS) are more susceptible to this organism than are normal individuals. For a number of years, we have been studying the anticryptococcal CMI response and its regulation and have found that the antigen shed by the C. neoformans cells is capable of inducing suppression of the anticryptococcal CMI response. Suppression is mediated by a complex circuit of cells and factors, beginning with first-order suppressor T (Ts1) cells induced by circulating cryptococcal antigen. The Ts1 cells, or a soluble factor therefrom, suppress the afferent limb of the CMI response and induce second-order suppressor T (Ts2) cells which, in conjunction with third-order suppressor T (Ts3) cells (induced by immunization with cryptococcal antigen), suppress the efferent limb of the CMI response. These cells and their soluble factors also reduce the animals' ability to clear the organism from infected tissues. Our long-range goals are to acquire a sufficient understanding of the protective CMI response against C. neoformans, the regulation of the response, and the antigenic components that stimulate and elicit the response, so that immunotherapeutic methods can be developed to effectively treat cryptococcoses in both normal and immunocomprised patients. In this application, our three goals for the next five years are focused on elucidating the cells, factors, lymphokines, antigenic determinants, and processes involved in the efferent limb of the anticryptococcal CMI response and the regulation of that response. We plan to further develop in vitro systems for analyzing the mechanisms which include the production and characterization of: i) anticryptococcal T cell clones that transfer delayed-type hypersensitivity (DTH) specifically for cryptococcal antigen and (ii) Ts2 and Ts3 cell hybridomas. We will characterize a recently identified cell that amplifies the anticryptococcal DTH response (Tamp cell) and define the Tamp cell's role in CMI resistance against C. neoformans. We will establish which component(s) in the cryptococcal antigen (CneF) elicits a DTH response and which suppresses that response. Achieving these goals will pave the way for designing immunotherapeutic protocols as well as provide a well-defined model which can serve as a basis for studying CMI responses and their regulation in other infectious diseases.
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