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Published on: August 29, 2012
Experience with lentivirus-mediated CD40 gene silencing in a mouse model of Graves' disease
Feng Ye1, Bingyin Shi, Xiaoyan Wu
1Department of Endocrinology, First Affiliated Hospital of Xi'an Jiaotong University School of Medicine, Xi'an, People's Republic of China.
Abstract:
CD40 plays an important role in the pathogenesis of Graves' disease (GD). Inhibition of CD40 expression may be a promising treatment for GD. In this study, we used an animal model to investigate whether lentivirus expressing siRNA for CD40 (LV-CD40-siRNA) could be useful for the therapy of GD. BALB/c mice were injected with PBS alone (PBS group), negative lentivirus (control siRNA group), or LV-CD40-siRNA (CD40 siRNA group), 3 days before being treated with adenovirus expressing human TSHR A subunit (Ad-TSHR289) three times at 3-week intervals to induce GD model. Sera thyroxine (T(4)) levels were assayed by RIA. The expression of CD40 was detected at the mRNA level by real-time PCR and protein level by flow cytometry. The expression of CD40, CD80, and CD86 was significantly decreased in the CD40 siRNA group (P<0.05), while FOXP3 expression was increased compared to the control siRNA group (P=0.05). Mean T(4) levels were decreased 14% in the CD40 siRNA group compared to the control siRNA group. The rate of disease induction was similar among the three groups injected with Ad-TSHR289. LV-CD40-siRNA is a useful tool to inhibit the expression of CD40 in vivo, but it cannot decrease the incidence of hyperthyroidism in a limited period of time.
Insights
Inhibition of CD40 using lentivirus-delivered siRNA (LV-CD40-siRNA) effectively reduced CD40 expression in a Graves' disease mouse model. However, this approach did not decrease hyperthyroidism incidence within the study
Area of Science:
- Immunology
- Endocrinology
- Gene Therapy
Background:
- Graves' disease (GD) pathogenesis involves CD40.
- Inhibiting CD40 shows therapeutic potential for GD.
Purpose of the Study:
- To evaluate lentivirus-mediated CD40 siRNA (LV-CD40-siRNA) efficacy in a GD animal model.
- To assess the impact of CD40 inhibition on GD markers and hyperthyroidism.
Main Methods:
- Induced GD in BALB/c mice using adenovirus expressing human TSHR A subunit.
- Administered LV-CD40-siRNA or control lentivirus.
- Measured serum thyroxine (T4), CD40, CD80, CD86, and FOXP3 expression.
Main Results:
- LV-CD40-siRNA significantly decreased CD40, CD80, and CD86 mRNA and protein levels.
- FOXP3 expression was elevated in the CD40 siRNA group.
- Mean T4 levels decreased by 14% in the CD40 siRNA group compared to controls.
Conclusions:
- LV-CD40-siRNA is effective for in vivo CD40 expression inhibition.
- LV-CD40-siRNA did not reduce hyperthyroidism incidence within the observed timeframe.
