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This thesis confirms the importance of Th2 responses in the development of protective and pathological responses to T. spiralis infection and shows that the role of IL-4 in the development of enteropathy depends on host mouse strain. Conversely a role in Th2 cytokine signalling to cells of the macrophage/neutrophil lineage in limiting enteropathy was also demonstrated. This thesis also demonstrated that co-stimulation via ICOS and OX40 can modulate the development of Th2 responses and the development of T. spiralis induced enteropathy and mastocytosis. The failure of TNFα/LTα -/- mice to expel T. spiralis from the small intestine despite developing a more severe enteropathy, this suggests that TNFα or LTα may play important protective roles in both expulsion and in limiting enteropathy. TNFα/LTα -/- mice also failed to develop mucosal mastocytosis suggesting that enteropathy in these mice is mast cell independent. It was also shown that signalling via the novel receptor PAR-2 plays a role in the development of enteropathy but not in the expulsion of T. spiralis, and was not required for the development of mucosal mastocytosis but enhanced mast cell degranulation. Thus, in conclusion this thesis provides further evidence that the expulsion of T. spiralis is not a direct result of the development of enteropathy and that different mechanisms are responsible for parasite expulsion and the development of enteropathy.

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Studies using the gastrointestinal nematode Trichuris muris typically focus on the E (Edinburgh) isolate. However, two other isolates exist: J (Japan) and S (Sobreda). Earlier experiments showed that following infection with the S isolate of T. muris the C57BL/6 mouse was susceptible and the worms survived, whereas the E and J isolates were expelled. The reason for the prolonged survival of the S isolate is unclear. The purpose of this study was to explore the immunological basis of S isolate survival. Overall, these data suggest that the S isolated has evolved immunomodulatory mechanisms to prolong its survival within the C57BL/6 host.

The host-parasite relationship of the hookworm Ancylostoma ceylanicum was explored in a hamster model system, focusing on intestinal mucosal responses to infection. Primary infection induced a rapid reduction in villous height culminating in excess of 75% reduction by day 35. Crypts of Lieberkuhn increased in depth achieving maximum depth by day 35. Mitotic figures in crypts and mast cells increased until day 28. Goblet cells increased continuously from background levels of 50 cell/mm² to exceed 300 cells/mm² by day 42. Paneth cell numbers declined in infected animals. Termination of infection by anthelmintic restored background values of intestinal architecture and goblet cell numbers within 7 days, but mast cells took longer and Paneth cell numbers increased beyond values in naïve controls. Mucosal changes are therefore dependent on the presence of worms, intensity of infection and change dramatically with time. Mucosal changes were studied in hamsters experiencing secondary infections following anthelmintic abbreviation of the immunizing infection, superimposed challenge infection and trickle infections. The kinetics of the responses were compared to animals experiencing primary infections and naive controls. Among the findings were: 1) continuous reduction in villous height and a marked increase in crypt depth from day 10 after challenge in abbreviated primary-challenged hamsters compared to little change in hamsters given superimposed challenge. 2) marked mast, goblet, and Paneth cell and eosinophil responses. 3) less intense mast cell responses in abbreviated primary-challenged compared to superimposed challenge animals 4) after a superimposed challenge poor goblet cell responses because levels were already high at the time of challenge, little change in Paneth cells but intense eosinophil responses 5) slower changes in mucosal architecture and mast cell responses in trickle-infected animals eventually exceeding those in primary infected animals. 6) less marked goblet and Paneth cell responses in trickle-infected groups but more intense, persistent increases in eosinophils Cyclosporin A's (CsA) usefulness as an immunosuppressive therapy for blocking T cell control of immunity was explored. However, CsA turned out to have marked anthelmintic properties and reductions in worm burden confounded the interpretation of mucosal changes.