Schistosomiasis continues to be one of the most prevalent parasitie infections in the world. In schistosomiasis mansoni, helminth parasite eggs preeipitate an intrahepatic granulomatous and fibrosing inflammatory process, which is mediated by, and dependent on, MHC class lI-restricted CD4+T helper lymphoeytes specific for schistosome egg antigens (SEA). In the mouse model of the disease, CBA mice develop high pathology characterized by large granulomas and strong eggantigen- speeifie T cell responses whereas C57BL/6 (BL/6) mice develop low pathology with significantly smaller granulomas and a more attenuated T cell response to the SEA. While in the acute phase of the disease both strains develop a Thl type cytokine response, during the chronic phase CBA mice exhibit a Thl/Th2 type response whereas BL/6 mice bias their cytokine response to a Th2 phenotype. The following experiments were undertaken to further investigate how the prevailing cytokine environment, CD4+ T cell apoptosis and T cell costimulatory pathways influence the development of the egg-induced immunopathology in the experimental murine schistosome infection and the outcome of the disease: l. An artificial model of high pathology by immunization of BL/6 mice with SEA in complete Freund’s adjuvant (CFA) was used to study the role of Thl vs. Th2 cytokine responses in the development of egg-induced immunopathology. The results showed that the immunization with SEA/CFA induced a Thl shift in the cytokine production by a numerically stable population of SEA-specifie CD4+ T cells that correlated with a severe exacerbation of the immunopathology and death of these otherwise low pathology mice. 2. The role of CD4+T cell apoptosis in the egg-induced immunopathology, and the possible underlying mechanisms that account for this type of cell death, were studied by comparing several immune parameters related to CD4+ T cells between the two polar strains of mice, CBA and BL/6. The results demonstrated that CD4+ T cell apoptosis of granuloma and mesenteric lymph node cells was higher in the low pathology BL/6 strain than in the high pathology CBA strain as a result of IL-2 deprivation. The in vivo treatment of BL/6 mice with recombinant IL-2 resulted in increased hepatic pathology and decreased CD4+ T cell apoptosis. 3. Finally, the role of the ICOS-B7RP-l (inducible costimulatory molecule-B7-related protein-l) costimulatory pathway on the development of egg-induced immunopathology was examined by treating infected BL/6 mice with a blocking mAb against ICOS. The results showed that the ICOS-B7RP-l costimulatory pathway serves primarily to control IFN-γ production by SEA-specific T lymphocytes, thereby promoting a Th2 cytokine environment conducive to limited hepatic damage in the low pathology BL/6 strain. These findings contribute to our knowledge on the mechanisms that regulate the immune response in murine schistosomiasis. They provide new insights on how CD4+ T lymphoeytes regulate immunopathology; confirm that the establishment of a Th2 cytokine environment correlates with host protection in this helminth infection and demonstrate that apoptosis represents a significant means of controlling the CD4+ T cells that mediate the immunopathology. The results presented in this thesis may serve to devise and implement strategies for amelioration of the immunopathology in this disease.
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