Lymphatic filariasis in humans is characterised by a profound bias in the immune response. Parasite specific Th1 responses, including proliferation, are dramatically impaired while Th2 responses predominate. In this study, a mouse model of filariasis was used to investigate the role of the infective form (the third stage larvae, L3) and the blood stage form (the microfilariae, mf) in modulating the immune response. Sub-cutaneous infection of BALB/c mice with L3 and mf of <I>Brugia pahangi</I> has a profound and contrasting effect on Th cell function, that appears to replicate, at least in part, the two striking aspects of the human immune response. A Th2 response predominated and polyclonal Th1 responses and antigen-specific proliferation are down-regulated in L3-infected mice. Surprisingly, antigen-specific proliferation was absent in mf-infected mice in which a Th1-biased response dominated. Furthermore, after four days of culture in the presence of antigen spleen cells from mf-infected mice, but not L3-infected mice or uninfected controls, displayed a S.I.<1. These data would suggest that spleen cells primed by infection with mf are undergoing accelerated death in culture. The remaining part of the study was focused on examining the mechanisms underlying the skewed responses in both L3- and mf-infected animals that may suggest some novel pathways operating in the infected human. Treatment of spleen cells from L3-infected mice with neutralising anti-IL-4, anti-IL-10 or rIL-2 resulted in a dramatic increase in ConA-driven proliferation, IL-2 and IFN-γ production. Interestingly, removal of the residuent spleen APC population and replacement with APC from uninfected animals also restored the defective mitogen-driven Th1 responses. Furthermore, replacing the APC population or neutralising IL-10, but not IL-4, resulted in antigen-specific IL-2 and IFN-γ indicating that <I>B. pahangi</I>-primed Th1 cells do exist in L3-infected mice but appear to be unable to respond in the presence of IL-10 perhaps operating via its effect on APC function.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:337528 |
| Date | January 1997 |
| Creators | Osborne, Julie |
| Publisher | University of Glasgow |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://theses.gla.ac.uk/6492/ |
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