The mechanisms underlying the profound modulation of parasite antigen-specific human T cell responses in lymphatic filariasis have been addressed by demonstrating the multiple pathways involved. By using live parasites and parasite antigen, we have demonstrated that both antigen presenting cell (APC) function in profoundly altered in fiarial infection and that at both the transcriptional and protein level, the T cells from patients with patent infection have induced pathsways (SOCS genes, ubiquin ligases, regulatory networks) that in concert prevent Th1-type T cell actiation. ? Moreover, the induction of apoptosis appears to be a common mechanism by which live filarial parasites influences the host response and does so in a TRAIL- and caspase 3-dependent mechansism. ? ? Because downregulatory mechanims are induced in chronic helminth infection, we have attempted to study the spillover effect of the this downregulation on responses and diseases that are non-parasitic. To this end, we have both clinical trials underway and in vitro models that have demostrated the influence of pre-existing chronic helminth infection on susceptibility to mycobacteria, on modulating the response to aeroallergens, and potentially to HIV. ? ? Because much of the pathology associated with filarial infections is related to lymphatic dysfunction, we have established a human in vitro model to examine parasite/lymphatic cell interaction. By purifying lymphatic endothelial cells (LEC) from blood vascular endothelial cells (BEC), we have been able to demostrate the presence of fialrial parasite molecules that induce lymphangiogenesis and abnormal vasculuar tube formation.
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