The current immunological paradigms surrounding filarial inflammation have evolved almost exclusively from studies of peripheral immune responses. In humans, examination of tissue at the actual site of disease activity, such as we now shown to be feasible for the study of filariasis, provides an unusual opportunity to examine pathogenetic mechanisms of the immune response to a human helminthic pathogen. Because there is no adequate animal model of bancroftian filariasis, biopsy tissue and peripheral blood from infected humans in a W. bancrofti endemic area of Brazil will be simultaneously studied. Patients will be initially classified into 3 groups based on clinical and current infections in order to carry out the following 3 specific experimental aims: 1) Determine the T-cell Receptor (TCR) repertoire at the site of disease by comparing TCR Vb repertoires in infected tissue and in blood of the same individual; 2) Determine the cytokines relevent to local disease by comparing levels of cytokines relevent to local disease by comparing levels of cytokine mRNA from biopsies in the different clinical groups; and 3) Examine the effect of total body worm burden from study subject with a clearing dose of macrofilaricide. Based on our substanstial published preliminary data, we believe that all W. bancrofti infected patients have disease irrespective of the presence of any overt clinical manifestations. Thus, the current polar polar classification of filariasis patients according to clinical or microfilaria status may not be appropriate for understanding local immunopathologic events in tissue. We hope, as a result of the proposed work, to be able to provide a relevent framework for staging and classifying disease in order to be able to develop targetted strategies for immunotherapeutic intervention. Moreover, the findings may be broadly applicable to local tissue reactions in other human helminths.
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