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

Abstract EN

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.