IMMUNOPATHOGENESIS OF LYMPHATIC FILARIASIS

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In the proposed study we will examine the immunologic mechanisms by which T-lymphocytes activated by local contact with filarial antigen are responsible for initiating the local lymphatic damage that is the central pathological manifestation seen in individuals infected with Wuchereria bancrofti. The contributions to filarial immunopathology of receptors expressed on the surface of activated T-cells and of receptors induced by locally produced cytokines on the surface of endothelial cells will be assessed. Because there is no animal model of bancroftian filariasis, infected humans in an endemic area will be studied. By comparing and contrasting infected individuals with parasite induced lymphatic pathology to completely asymptomatic but equally heavily infected microfilaremic individuals, the role of specific immunologic adhesion receptors of the integrin and immunoglobulin superfamilies in mediating the destructive lymphatic pathology seen in W. bancrofti infections will be investigated. The specific experimental aims are: 1) to stage infected individuals into 2 clinical groups for in vitro immunological assays and to perform immunohistologic staining of inflamed superficial lymphatic vessels for in vivo correlation of the immunological findings; 2) to quantitate by a cell ELISA the ability of cytokines in patient derived PBMC culture supernatants to induce expression of MHC molecules and adhesion receptors on endothelial cells in an in vitro model system. Levels of specific cytokines will be correlated with receptor expression. The effect of receptor blockade will be assessed; 3) to examine, in an in vitro adhesion assay, the role of receptors on patient T-cells in mediating adherence to cultured endothelial cells that have been artificially stimulated with recombinant cytokines to induce maximal expression of known adhesion receptors; and 4) to examine T-cell adhesion to endothelial cells which have been activated by preassay incubation with patient cell derived cytokine supernatants, utilizing optimal experimental conditions for endothelial cell and T-cell receptor expression that had been defined separately in Specific Aims 2 and 3. Effects of mAb blockade of cell surface receptors will be examined. Adhesion receptors and ligands that are potential targets for immuno-therapeutic blockade with monoclonal antibodies, soluble receptor analogues, or blocking peptides will be identified, opening a possible new approach to disease control. Most importantly, further refinement of the in vitro model system will lead to the ability to screen defined recombinant filarial antigens, when they become available, for their immunopathogenic potential, leading to the identification of anti- pathology vaccine candidates.