The helminth parasite Schistosoma mansoni is long lived, causing chronic infections in its natural human and experimental mouse hosts. It has been long-recognized that during schistosomiasis the parasite-induced Th response, as measured by in vitro antigen-stimulated T cell proliferation or cytokine secretion assays, peaks early and then declines despite ongoing infection, a process that has been termed """"""""immunomodulation"""""""". The size of granulomatous lesions around parasite eggs trapped in host tissues mirrors the rise and fall of the Th response. Immunomodulation in schistosomiasis appears to play a vital role in minimizing immunopathology in a setting where the immune system is incapable of eliminating the pathogen. We are interested in how immune responses during chronic schistosomiasis are regulated to favor host survival. This area was once a major focus of immunological research on schistosomiasis, but in the more recent past has received comparatively little attention. However, the development of new tools (such as IL-4 reporter mice) and the discovery of new immunoregulatory pathways (such as those mediated by regulatory T cells), have provided an exciting new framework for re-addressing the important question of immunomodulation in schistosomiasis.
The specific aims of our proposal are: 1) To use IL-4 reporter mice to characterize Th2 cells throughout infection. 2) To establish whether Th2 cells from chronically infected mice are irreversibly dysfunctional or whether environmental signals are required to maintain them in this state, and 3) To identify the mechanisms responsible for immunomodulation during chronic infection. The ability to use IL-4 reporter mice to specifically identify cells that have committed to Th2 differentiation as a result of infection allows powerful experiments in which the function of sorted Th2 cells following transfer to acutely infected or naive mice, or in vitro, can be followed. Our studies will incorporate cellular and molecular analyses of dysfunctional Th2 cells from chronically infected mice in comparison with functional Th2 cells from acutely infected mice. Together, our studies are likely to generate new insights into the processes that allow the regulation of Th2 responses during chronic schistosomiasis, and have the potential to identify targets for intervention in important diseases of the developed world, such as asthma, that are mediated by chronic, poorly controlled Th2 responses.
Showing the most recent 10 out of 18 publications
