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Published on: November 19, 2010
Anti-prion activity of cellulose ether is impaired in mice lacking pre T-cell antigen receptor α, T-cell receptor δ,
Kenta Teruya1, Ayumi Oguma1, Satoko Takahashi1
1Department of Neurochemistry, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.
Abstract:
The anti-prion activity of cellulose ether (CE) has been reported in rodents, but the mechanism of action is not well understood. As defects in early T-cell development have been reported in Tga20 mice which show only a slight effect of CE administration, we investigated the involvement of immune functions in the CE action. We confirmed an insertion of the prion protein transgene into the pre T-cell antigen receptor α gene of Tga20 mice, and its impaired expression in the thymus and other tissues. The influence of immune suppression on the CE effect was then examined in high CE-responder mice treated with immunosuppressive agents or neonatal thymectomy. As neonatal thymectomy significantly reduced the CE effect, we compared the influence of various T-cell defects in mice with similar genetic backgrounds. The CE effect was increased or unchanged in mice with defects in the αβ T-cell lineage, whereas it was abolished in T-cell receptor δ deficient mice. Further, when other immune defects were examined, the CE effect was reduced in mice with lysosomal trafficking dysfunction, but was unchanged in mice deficient in B-cell differentiation or toll-like receptor 4 signaling. These findings collectively suggest that the mechanism of CE action may involve γδ T cells and lytic granule function, as well as immune factors like natural killer T cells which are lacking in pre T-cell antigen receptor α deficient mice and neonatally thymectomized mice.
Insights
Cellulose ether (CE) shows anti-prion activity, potentially involving gamma delta T cells and lytic granule function. Further research is needed to fully understand its immune-mediated mechanism of action.
Area of Science:
- Immunology
- Neuroscience
- Biochemistry
Background:
- Cellulose ether (CE) exhibits anti-prion activity in rodents, but its mechanism remains unclear.
- Tga20 mice, with impaired T-cell development and slight CE response, prompted investigation into immune involvement.
- Prion protein transgene insertion into the pre T-cell antigen receptor α gene was confirmed in Tga20 mice.
Purpose of the Study:
- To elucidate the mechanism of cellulose ether's anti-prion activity by investigating the role of immune functions.
- To assess the impact of immune suppression and specific T-cell defects on CE efficacy.
- To identify key immune components involved in CE's therapeutic effects against prions.
Main Methods:
- Examined CE's effect in immunocompromised mice (immunosuppressive agents, neonatal thymectomy).
- Compared CE efficacy in mice with genetic defects in various T-cell lineages (αβ, γδ T cells).
- Investigated the influence of other immune deficiencies (lysosomal trafficking, B-cell differentiation, TLR4 signaling) on CE activity.
Main Results:
- Neonatal thymectomy significantly reduced the CE effect, highlighting the role of the thymus.
- CE efficacy was abolished in T-cell receptor δ deficient mice, implicating γδ T cells.
- The CE effect was reduced in mice with lysosomal trafficking dysfunction but unaffected by B-cell or TLR4 deficiencies.
Conclusions:
- Cellulose ether's anti-prion mechanism likely involves γδ T cells and lytic granule function.
- Natural killer T cells may also play a role, as they are absent in neonatally thymectomized and pre T-cell antigen receptor α deficient mice.
- Immune factors, particularly γδ T cells and lysosomal pathways, are critical for cellulose ether's anti-prion activity.
