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.
Highlights
Schistosomiasis is a debilitating tropical disease caused by infection with trematode worms of the genus Schistosoma spp
To investigate whether cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) impacts the development of hepatic fibrosis during Schistosomiasis, we treated S. mansoni-infected mice with CTLA-4-Ig or appropriate control antibodies for 4 weeks starting at 4 weeks p.i. or 8 weeks p.i. (Figure 1(a))
We previously demonstrated that the antifibrotic effect of single-sex infection with female schistosomes is associated with increased CTLA-4 expression in livers of these mice [15]
Summary
Schistosomiasis is a debilitating tropical disease caused by infection with trematode worms of the genus Schistosoma spp. The larvae of Schistosoma (S.) mansoni, one of the most common Schistosoma species besides S. haematobium, penetrate the skin of their hosts and migrate via the blood circulation, transiting the lungs to reside as adults in the mesenteric veins, where they mate and lay eggs around 5 weeks after infection Parts of these eggs enter the portal circulation and are entrapped within the small liver sinusoids. 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. CTLA-4-Ig administration after onset of egg production fails to treat hepatic fibrosis
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
