Preventive CTLA-4-Ig Treatment Reduces Hepatic Egg Load and Hepatic Fibrosis inSchistosoma mansoni-Infected Mice

Abstract

Background. Hepatic fibrosis and granuloma formation as a consequence of tissue entrapped eggs produced by female schistosomes characterize the pathology of Schistosoma mansoni infection. We have previously shown that single-sex infection with female schistosomes mitigates hepatic fibrosis after secondary infection. This was associated with an increased expression of cytotoxic T-lymphocyte-associated protein-4 (CTLA-4), known as a negative regulator of T cell activation. Based on these findings, we hypothesized that administration of agonistic CTLA-4-Ig (Belatacept) is capable to prevent and/or treat hepatic fibrosis during schistosomiasis. Methods. Mice were infected with 50 S. mansoni cercariae and CTLA-4-Ig, or appropriated control-Ig was administered for 4 weeks. Preventive treatment started 4 weeks after infection, before onset of egg production, and therapeutic treatment started 8 weeks after infection when hepatic fibrosis was already established. Results. When given early after infection, livers of CTLA-4-Ig-treated mice showed significantly reduced collagen deposition and decreased expression of profibrotic genes in comparison to controls. In addition, administration of CTLA-4-Ig suppressed the inflammatory T cell response in infected mice. If therapy was started at a later time point when fibrogenesis was initiated, CTLA-4-Ig had no impact on hepatic fibrosis. Conclusion. We could demonstrate that an early preventive administration of CTLA-4-Ig suppresses effector T cell function and therefore ameliorates liver fibrosis. CTLA-4-Ig administration after onset of egg production fails to treat hepatic fibrosis.

A one-year unisexual Schistosoma mansoni infection causes pathologic organ alterations and persistent non-polarized T cell-mediated inflammation in mice

“…In another study by our research group, the suppression by female schistosomes of the host immune response was studied in more depth using the “air pouch model”. It was shown that the number of recruited inflammatory cells was significantly lower in the group pre-infected with female schistosomes than in the group pre-infected with male schistosomes, as were cytokine and chemokine levels ( 18 , 20 , 21 ).…”

Unisexual infection with Schistosoma mansoni in mice has the potential to boost the immune response against eggs after challenge infection

“…Male worms had no anti-fibrotic or CTLA-4 inducing effect in this setting. Belatacept, a CTLA-4 immunoglobulin, also showed antifibrotic effects in a subsequent study when applied before the onset of egg deposition (29). This study suggests that an anti-fibrotic effect can be achieved when T effector cell inhibition occurs and that female worms can induce this effect with an 11-week interval to reinfection.…”

Single-sex schistosomiasis: a mini review

“…Besides, the lack of relatively high production of Th1 cells implies that Th1 and Th2 responses might be regulated independently ( 75 ). Subsequent experiments indicated that Ctla4 had a preventive effect against schistosome-induced hepatic fibrosis ( 77 ).…”