Immunopathogenesis of schistosomiasis mansoni : Immunity and pathology in a primary and a secondary infection following chemotherapy in the mouse and the baboo models

Sammanfattning: This thesis describes a series of experiments aimed at elucidating the mechanisms ofimmunity and pathology elicited by both a primary infection and a reinfection exposure toSchistosoma mansoni following chemotherapy. The effects of a single large cercarial doseand a cumulatively equivalent dose, administered as multiple small doses are compared. Inaddition, the suitability of two animal models, a murine (BALB/c mice) and a non-humanprimate (Olive baboons, Papio cynocephalus anubis) for this purpose is evaluated. Duringthe primary infection, single-dose infected (SI) baboons developed more severe clinicaldisease than the multiple-dose infected (MI) group. Hepatic granulomata developed morerapidly and modulated more slowly in the SI group than in the MI group. Intestinal lesions inthe infected baboons included smooth muscle hypertrophy, villous atrophy and goblet cellhyperplasia, which were all less severe in baboons previously immunised with irradiatedcercariae. High tissue eosinophilia and recruitment of giant cells was observed in modulatingbaboon granulomata. By contrast, fibroblasts and collagen around the schistosome eggs werethe features of modulating mouse granulomata. In both animal models, reinfection followingchemotherapy resulted in reduced morbidity compared to a primary infection and a primaryMI dose elicited a T helper (Th) 2 cell associated immune response on reinfection. A primarySI dose in mice, however, led to a dominant Th1 response. Baboons exposed to multipleinfections, both prior to and following chemotherapy, developed peri-portal fibrosis. Insummary, i) variation in cercarial exposure contributes to the heterogeneity of the immuneresponse and morbidity ii) although the consequences of reinfection exposures are milder, they may be associated with increased risk for the development of hepatic fibrosis and iii)regarding the pathogenesis of natural schistosome infections, particularly repeated infections,the baboon is a better model than the mouse.