T Gondii - Antigenic Characterization and Immunology

Kasper, Lloyd

Abstract

The overall aim of this competing renewal is to further the understanding of the host immune response to Toxoplasma gondii, the principal central nervous system infection in those with AIDS. During the previous funding period key observations were made that establish the importance of the Th1 cytokine and CD8+ T cell response in protection against T. gondii infection.
The specific aims for this proposal are to characterize the early immune regulatory responses that occur during primary infection in the murine host. Delineation of these immunologic events will provide part of the framework toward understanding T. gondii infection in those with AIDS. Potential immunotherapy against this opportunistic pathogen will be further evaluated by the analysis of two important Th1 cytokines, IL-12 and IL-7, both of which are protective against acute infection. The first specific aim will be to evaluate the role of antigen presenting dendritic cells during primary infection. Cytokines produced by these important immune cells will be identified. The role of these cells in priming the host T cell response against T. gondii will be analyzed and the requirement for T cell co-stimulatory molecules assessed. Recent studies from this laboratory suggest that gamma delta T cells are involved in the early immune response to the parasite. The investigators will ascertain whether the dendritic cells are responsible for stimulating the proliferation of gamma delta T cells and whether this response can be enhanced by the administration of exogenous IL-7 or IL-12. The second specific aim will be to evaluate the role of intraepithelial lymphocytes (IEL) from the gut in host defense. Since Toxoplasma is an orally acquired pathogen, the first line of defense against the parasite may be the IEL. Recent evidence from this laboratory indicates that IEL are an important component of the host immunity against the parasite. The IEL cytolytic response against parasite infected target cells will be assayed and the cytolytic precursor frequency response established. The cytokine profile of the IEL cells will be determined and the effect of IL-7 or IL-12 on enhancing the response evaluated. Adoptive transfer of immune IEL into naive mice will be determined. A longitudinal analysis for phenotype and cytokine production using cells from various immune compartments will be done. The overall experimental approach should provide essential information to further the understanding of host immunity to Toxoplasma and the potential role for immunotherapy in those with AIDS.