Cytokine Control of the Granulomatous Response inSchistosoma mansoni-Infected Baboons: Role of Exposure and Treatment

Abstract

Variations in exposure and treatment may contribute to heterogeneity in immunity and granuloma-induced pathology in human schistosomiasis. To examine this hypothesis, olive baboons were either repeatedly infected with Schistosoma mansoni cercariae or received an equivalent dose in a single infection. They were then cured with praziquantel and reinfected with a single exposure. Serial liver biopsies were obtained throughout the course of the experiment, and cytokine responses by peripheral blood mononuclear cells were measured every 2 to 3 weeks. Reinfection after treatment resulted in a twofold-smaller granuloma size at 6 and 9 weeks after infection compared to the size for the same period after primary infection (P < 0.001) but had no effect at 16 or 19 weeks postinfection. The pattern of exposure did not influence granuloma size. During primary infection schistosome-soluble egg antigen (SEA)-induced cytokine production correlated with granulomatous inflammation. Cytokine levels peaked during the acute infection, declined with chronic infection, and became undetectable after treatment. Reinfection after treatment stimulated a two- to three-fold increase in SEA-specific interleukin-4 (IL-4), IL-5, IL-10, IL-2, and transforming growth factor β (TGF-β) production and a marked rise in SEA-specific immunoglobulin E (IgE) and IgG regardless of the type of exposure. Cytokine production was significantly greater in repeatedly exposed animals (P < 0.001). SEA-induced gamma interferon production, however, did not increase with reinfection after treatment. SEA-induced TGF-β was the only cytokine that remained elevated as the infection become chronic and correlated with diminished hepatic granuloma size, implying its participation in down-modulation. These studies demonstrate that baboons partially retain their ability to down-modulate the granulomatous response after treatment.

Resistance to re‐infection after exposure to normal and attenuated schistosome parasites in the baboon model

“…Treatment of infected baboons with praziquantel completely eliminates the infection as evidenced by absence of eggs in the faeces within 2 weeks of drug administration (7 ). Reinfection after chemotherapy leads to lower maturation of cercariae to adult worms.…”

“…In addition, hepatic granulomas are fewer and smaller after reinfection. For example, the acute phase hepatic granuloma diameter following secondary exposure was two fold less than in a primary infection of equal cercarial dose (7). The import of these findings is that mass chemotherapy is a useful and viable option for the control of schistosomiasis since it results in reduction of morbidity.…”

“…Reinfection after chemotherapy leads to lower maturation of cercariae to adult worms. In one of the studies, the cercarial maturation was as low as 16% for trickle re-infections (of 100 cercariae per week for 10 weeks) and 47% for a single dose (of 1000 cercariae) as compared to 76% in a primary infection (7).…”

“…More is known about the events in the baboon model downstream of the innate responses. Whereas in mouse models schistosomiasis shows a progressive switch from a Th1 to Th2 phenotype, as infection becomes chronic (14), the adaptive immune responses in baboons are typical of those observed in humans and are dominated by a mixed Th1/ Th2 phenotype (7,15). The first 4 weeks of infection are dominated by weak PBMC responses to larval parasite antigens (16), followed by dramatic Th2 egg-driven responses (7,16).…”

“…Whereas in mouse models schistosomiasis shows a progressive switch from a Th1 to Th2 phenotype, as infection becomes chronic (14), the adaptive immune responses in baboons are typical of those observed in humans and are dominated by a mixed Th1/ Th2 phenotype (7,15). The first 4 weeks of infection are dominated by weak PBMC responses to larval parasite antigens (16), followed by dramatic Th2 egg-driven responses (7,16). The development of acute disease and the rise in granuloma formation is dominated by anti-inflammatory Th2 cytokines, including interleukin-4 (IL-4), IL-5 and IL-10 (7,8,17), but the Th1 cytokine IFN-γ is also produced at this time point (7,8).…”