Title

Interleukin-4 mediated host protection against Brugian filariasis

Date of Completion

January 2002

Keywords

Health Sciences, Pathology|Health Sciences, Immunology

Degree

Ph.D.

Abstract

Lymphatic filariasis (LF), caused by the filarial nematodes Wuchereria bancrofti, Brugia malayi and B. timori, is a debilitating disease affecting over 120 million people worldwide. Biochemical approaches have resulted in our current treatment protocols, which involve poorly understood pharmacological intervention, and have been partially successful at the community level, but have proven inadequate on an individual level. In light of these inadequacies, our laboratory, as well as many others, have begun to adopt an immunological approach to the treatment of LF. Preliminary data from our laboratory indicate a role for IL-4 in murine host protection against infection with Brugian parasites, a finding with significant implications in the determination of an appropriate vaccine-induced immune response. These findings are in apparent contrast to previously published reports. The primary purpose of this thesis is to demonstrate, through infection of IL-4−/− mice on various genetic backgrounds, that IL-4 does play an integral part in the anti-parasitic response. Further, we will establish that Stat6 activation downstream of IL-4 receptor signaling is required and provide, as a foundation for future studies, a phenotypic analysis of various IL-4 mutants with respect to the humoral immune response and cellular influx into the site of infection following exposure to B. malayi. Building upon these initial observations, we provide evidence that IL-4-mediated effector functions such as B cell IgG1 production, eosinophil recruitment and macrophage differentiation along the “alternative” pathway are important components of the anti-parasite response. Surprisingly, we also demonstrate that T cell production of IL-4 and expression of the IL-4 receptor enhance host protection, but are not essential. In addition we analyze the immune response generated upon re-exposure to the parasite in light of the IL-4-mediated mechanisms alluded to above, and suggest a unique role for IL-13 in accelerated clearance of the challenge infection. Finally, we have utilized IL-4−/− mice as a model to investigate current issues of stage-specific immunity and sexual dimorphism in mammalian host protection. Importantly, these studies have demonstrated the existence, in an immunocompetent animal, of concomitant immunity following a secondary parasitic exposure. ^