Effects Of Schistosoma Japonicum Infection On Host Helper T Cell Responses

Chronic Schistosomiasis japonicum is characterized by egg-induced granulomatous inflammation and further fibrosis in liver and intestinal tissues. The host immune response is involved in the disease pathological process. Elucidating the temporal pattern of immune dynamics would help further understanding the mechanism of immune regulation in response to the parasitic infection.Schistosoma japonicum infection still occurs in regions like China, Indonesia, and Philippines, and remains a major public health concern. Even though the currently available drugs for the parasite infection are safe and effective, massive chemotherapy can not prevent reinfection. In this case long-term protection strategies involving vaccination are demanded for disease prevention and control. Not one single vaccine that is satisfactory enough to apply to human has been developed yet despite of the huge amount of researches. The slow progress is probably due to the lack of knowledge on the host immune response mechanism. Immune mechanisms are not easily investigated in humans for ethical and practical reasons. As one of the reservoir hosts of S. japonicum, mice provide an applicable tool for this purpose.The aim of this research was to elucidate the kinetic T helper lymphocyte-mediated responses from several aspects and hepatic granuloma development during schistosomiasis japonicum systematically, and to evaluate the possible correlation between the Th responses and pathological liver injury. The study tried to demonstrate the immunological features at different stages of infection, and to explain the possible regulatory role of Th responses on the host hepatic damage and the mechanisms of host immune modulation and immunopathogenesis elicited by S. japonicum infection. The methods and results of the research were as follows:1. Disease manifestationsMurine models of schistosomiasis japonicum were developed and disease manifestations were examined every two weeks after infection. The infected mice did not gain weight as the controls, and their weights had been significantly lower than the controls since 2 weeks postinfection. At six weeks postinfection, the livers of the infected mice appeared dark and enlarged, with visible gray granulomas. Hepatic egg granulomas were detected in all the infected mice after week 6. When first formed the circumoval granulomas were mainly consisted of inflammatory cells, but at week 12 collagen was seen around the eggs. Both the size and the number of granulomas steadily increased throughout the experimental period.2. Dynamic of T helper subset during infectionThe IFN-?and IL-4 producing cells in host spleen were detected by intracellular cytokine staining and flow cytometry every two weeks during infection. The frequency of SEA specific Th1 cells (IFN-?producing cells) in splenic CD4+T cells increased at week 2 postinfection but declined quickly afterwords. In contrast, the frequency of SEA specific Th2 cells (IL-4 producing cells) did not rise unitl eight weeks postinfection, and had been significantly higher than the controls ever since. During week 8 to 12, after SEA stimulation the Th1/Th2 ratio of spleen cells from infected mice was much lower than the controls.3. Dynamic of cytokine profilesSera were assayed for IFN-?, IL-2, IL-4, IL-5, IL-10 and IL-13 levels every two weeks postinfection and comparison was performed between the two groups, so was the supernatant of splenic cell cultures. Th1 specific cytokines (IFN-?and IL-2) in sera from infected mice were elevated dramatically at two weeks postinfection, much higher than the control group; the levels peaked at week 4 and declined sharply after week 6. On the contrary, Th2 specific cytokines (IL-4, IL-5, IL-10 and IL-13) displayed no significant change during the first 4 weeks of infection. At week 6, an increase became apparent and peak was observed at week 8, after which the cytokines began to decline slowly, but remained significantly higher than controls at the end of 12-week infection.The dynamic pattern of cytokines in the unstimulated splenic cell cultures were similar to that observed in serum except that the elevation in IFN-?and IL-2 was not observed until 4 weeks postinfection, which was two weeks delayed compared with serum. The inducible cytokine pattern was also assessed by adding exogenous SEA into the cultures. After stimulation, the levels of IFN-?, IL-2 and IL-10 increased two weeks postinfection, a little ealierthan that in the unstimulated cultures.4. The overall dynamics of T helper immune responsesFactor analysis was employed to provide a more comprehensive demonstration of the Th1\Th2 imbalance. At 2 weeks postinfection a dramatic increase in Th1 response was already evident. The Th1 response demonstrated a clear prominence at week 4 and declined thereafter. In contrast, Th2 response was weak during the first 4 weeks of infection. However, at week 6 to 8 the Th2 response mounted remarkably and then started gradually decreasing after week 10. Week 6 clearly was the turning point for the shift from Th1 to Th2 polarization, which happened to be the onset of oviposition since granulomas first became notable at this time point. The correlation between the Th responses and the pathological hepatic damage was further assessed. The diameters of liver granulomas demonstrated a positive correlation with Th2 response at week 10, but a negative correlation with serum IL-13 at week 12.ConclusionsA generalized imbalance in Th1 and Th2 responses were developed during infection and the polarization of Th response changes as the infection progressed: Early contact with the parasite elicited an acute dominant Thl response, when the host was exposed to migrating immature schistosomula. However, as the infection progressed and the parasites mated and produced eggs at around week 6, there was a dramatic change in cytokine environment. The Th 1 response waned and a strong Th2 response emerged remarkably.The S. japonicum egg antigens probably played an important role in the conversion of Th 1 response to Th2 response. In turn, the imbalance of Th responses would also modify the host immunopathology and disease progression. As suggested in this research, Th2 response might promote the development of hepatic granulomas and IL-13 probably is a profibrotic agent.Elucidating the dynamics of Thl and Th2 response would contribute to the understanding of not only host immune response and regulation to 5". japonicum in particular, but also the immunopathology, host defense and Schistosoma immune evasion in general. Hopefully, the information provided in this study might facilitate the development of effective vaccines and new approaches for controlling or even reversing the liver fibrosis.