Experience with lentivirus-mediated CD40 gene silencing in a mouse model of Graves' disease

Ye, Feng; Shi, Bingyin; Wu, Xiaoyan; Hou, Peng; Gao, Lei; Ma, Xiuling; Xu, Li; Wu, Liping

doi:10.1677/joe-10-0224

Cited by 4 publications

(6 citation statements)

References 31 publications

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“…In the present study, following four immunizations, 38 of 48 BALB/c mice (79.17%) developed hyperthyroidism, a percentage that is consistent with or greater than previous studies (20–23). All hyperthyroid mice demonstrated increased serum T 4 , TRAb N and C levels, and reduced TSH and weight levels.…”

Section: Discussionsupporting

confidence: 92%

An improved method for the establishment of a model of Graves' disease in BALB/c mice

Zheng

Wang

Tan

et al. 2017

Molecular Medicine Reports

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The present study aimed to develop a stable Graves' disease (GD) model in BALB/c mice by immunization and electroporation (EP). A total of 90 mice were divided into experimental (n=50), control (n=20) and blank (n=20) groups. The recombinant plasmid pcDNA3.1/thyroid-stimulating hormone (TSH) receptor 268 was constructed and injected into the bilateral gastrocnemius of experimental group mice at weeks 1, 4, 7 and 10. Equal volumes of saline were injected into the control and blank groups at the same time. The experimental and control groups were subjected to EP at the same time and location to enhance immunization. The levels of total serum thyroxine (T4) and serum TSH were examined by radioimmunoassay and immunoradiometric assay, respectively. The levels of serum thyrotropin receptor N-terminal (TRAb N) and C-terminal (TRAb C) antibodies were assessed by ELISA. Whole body pertechnetate (99mTcO4-) imaging was performed. Mouse weight and thyroid morphology and pathology were analyzed. The GD BALB/c mouse model was successfully established, with a positive rate of 79.17% (38/48). T4 levels increased from baseline levels of 12.05±4.23 to 52.51±23.58 ng/ml by week 12 (P<0.0001). TSH levels decreased from baseline levels of 5.53±2.78 to 1.43±0.89 µIU/ml by week 12 (P<0.0001). TRAb N antibody levels increased from baseline levels of 0.006±0.002 to 0.278±0.106 mIU/ml by week 12 (P<0.0001). TRAb C antibody levels increased from baseline levels of 11.111±2.808 to 46.701±26.436 arbitrary units/ml by week 12 (P<0.0001). At week 21, TSH levels remained reduced compared with pre-immunization levels (P<0.0001). Although T4, and TRAb N and C levels decreased, they remained increased compared with preimmunization levels (P<0.0001, P<0.0001, P=0.001). There were no significant alterations in antibody levels between the control and blank groups. Following four immunizations, the uptake of 99mTcO4- by the thyroid was significantly increased in the experimental group. The mean weight of the experimental mice was significantly reduced compared with the control and blank groups (all P<0.0001). Furthermore, the thyroid glands of the immunized mice were enlarged and exhibited lymphocyte infiltration, fewer colloid nodules and an increased height of epithelial cells. In conclusion, by injecting recombinant plasmid pcDNA3.1/TSHR268 and EP, a GD mouse model was successfully established.

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Section: Discussionsupporting

confidence: 92%

An improved method for the establishment of a model of Graves' disease in BALB/c mice

Zheng

Wang

Tan

et al. 2017

Molecular Medicine Reports

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“…However, despite successful lowering of CD40 expression, no effect on the rate of disease induction was observed [83]. …”

Section: Genes Predisposing To Gdmentioning

confidence: 99%

The Genetic Basis of Graves Disease

Płoski

Szymański²,

Bednarczuk

2011

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The presented comprehensive review of current knowledge about genetic factors predisposing to Graves’ disease (GD) put emphasis on functional significance of observed associations. In particular, we discuss recent efforts aimed at refining diseases associations found within the HLA complex and implicating HLA class I as well as HLA-DPB1 loci. We summarize data regarding non-HLA genes such as PTPN22, CTLA4, CD40, TSHR and TG which have been extensively studied in respect to their role in GD. We review recent findings implicating variants of FCRL3 (gene for FC receptor-like-3 protein), SCGB3A2 (gene for secretory uteroglobin-related protein 1- UGRP1) as well as other unverified possible candidate genes for GD selected through their documented association with type 1 diabetes mellitus: Tenr–IL2–IL21, CAPSL (encoding calcyphosine-like protein), IFIH1(gene for interferon-induced helicase C domain 1), AFF3, CD226 and PTPN2. We also review reports on association of skewed X chromosome inactivation and fetal microchimerism with GD. Finally we discuss issues of genotype-phenotype correlations in GD.

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“…CD40/CD40L signaling has an important function in humoral and cellular immunity. 36) CD40 was originally identified as a B-cell receptor, which delivers contact-dependent T helper signals to B-cells through interaction with CD40L. Dysregulation in the CD40-CD40L co-stimulation pathway is a prominent feature in human diseases, ranging from inflammatory conditions to systemic autoimmunity and tissue-specific autoimmune diseases.…”

Section: Discussionmentioning

confidence: 99%

“…Dysregulation in the CD40-CD40L co-stimulation pathway is a prominent feature in human diseases, ranging from inflammatory conditions to systemic autoimmunity and tissue-specific autoimmune diseases. 37) There have already been reports on the successful treatment of different diseases by means of CD40 inhibition, 36,38,39) and RNA interference has become a promising tool for treating various diseases. In this study, we have demonstrated that administration of CD40-targeting siRNA could impede the in vivo development of EAM.…”

Section: Discussionmentioning

confidence: 99%

Attenuation of Experimental Autoimmune Myocarditis by si-RNA Mediated CD40 Silencing

Gong

Han

Zou³

et al. 2014

Int. Heart J.

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SummaryCD40 plays an important role in the pathogenesis of myocarditis, and inhibition of CD40 expression could be a promising treatment for myocarditis. In this study, we used an animal model, experimental autoimmune myocarditis (EAM), to investigate whether CD40 siRNA could be exploited for myocarditis therapy.Lewis rats were immunized with purified porcine cardiac myosin to induce EAM or were injected with phosphatebuffered saline (PBS) alone (PBS group), scrambled small interfering RNA (siRNA) (negative control group), or CD40-siRNA (CD40 siRNA group).CD40 siRNA treatment suppressed the increase in heart weight/body weight ratio, and attenuated the severity of myocardial lesions. Cytokine production, including Th1-type cytokines, was significantly suppressed in rats with myocarditis after CD40 siRNA treatment; however, production of Th2-type cytokines was higher. Specific knockdown of CD40 in EAM rats resulted in increased FOXP3 gene expression and the CD25+ CD4+ subpopulation of T cells but also a decrease in CD80 and CD86 expression. Lymphocyte (T and B cell) proliferation in response to myosin stimulation was significantly inhibited by CD40 silencing.CD40-siRNA is a useful tool for inhibiting in vivo CD40 expression, and it could have therapeutic potential in the prevention and treatment of myocarditis in humans. (Int Heart J 2014; 55: 539-545) Key words: RNA interference, Lymphocyte M yocarditis, an inflammatory heart muscle disease associated with cardiac dysfunction, can be caused by many agents, such as viruses and drugs, and is a potentially lethal disease, which can cause sudden death. 1,2)The disease has acute and chronic phases. Patients with myocarditis may develop dilated cardiomyopathy, which represents the chronic phase of the disease that leads to heart failure. 3)While there is still no effective therapy for myocarditis, recent studies have shown that autoimmunity plays an important role in the pathogenesis and development of myocarditis. 4) Experimental autoimmune myocarditis (EAM) is a model of post-infectious myocarditis, and can be induced by severe myocardial damage, including infiltration of mononuclear cells into the myocardium and activation of dendritic cells (DCs), with the subsequent activation of autoreactive T-cells, along with the secreted cytokines. 5-7)RNA interference is a post-transcriptional mechanism of gene silencing in which siRNA can lead to specific endonucleolytic cleavage of mRNA.8) RNA interference with siRNA is a specific, long-lasting, and straightforward approach for blocking the expression of specific genes.9) The therapeutic use of siRNA is promising, due to sequence-specific gene silencing, and has been successfully used in several animal models of diseases and clinical trials. 10)CD40 is a member of the TNF receptor superfamily and, as a co-stimulatory molecule, it plays critical roles in T cell activation and differentiation.11,12) CD40 expression can stimulate Th1 activation, 13,14) and the CD40/CD40 ligand (CD40L) interaction has been demonstrated to e...

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Experience with lentivirus-mediated CD40 gene silencing in a mouse model of Graves' disease

Cited by 4 publications

References 31 publications

An improved method for the establishment of a model of Graves' disease in BALB/c mice

An improved method for the establishment of a model of Graves' disease in BALB/c mice

The Genetic Basis of Graves Disease

Attenuation of Experimental Autoimmune Myocarditis by si-RNA Mediated CD40 Silencing

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