Vol 72, No 6 (2021)
Original paper
Published online: 2021-10-06

open access

Page views 6692
Article views/downloads 637
Get Citation

Connect on Social Media

Connect on Social Media

Immunotherapy with a biologically active ICAM-1 mAb and an siRNA targeting TSHR in a BALB/c mouse model of Graves’ disease

Xuan Wang1, Wei Liu2, Zhongying Rui1, Wei Zheng1, Jian Tan1, Ning Li1, Yang Yu1
Pubmed: 34647608
Endokrynol Pol 2021;72(6):592-600.


Background: The objective was to study targeted therapies using a biologically active monoclonal antibody against intracellular adhesion molecule-1 (ICAM-1 mAb) and an siRNA targeting thyroid-stimulating hormone (TSH) receptor (TSHR) in a BALB/c mouse model of Graves’ disease (GD).

Material and methods: An improved method for establishing a stable model of GD in BALB/c mice was developed by immunization with pcDNA 3.1/TSHR 289 and electroporation (EP). The mice in which GD was successfully established were divided into a nontreated control group, which was treated with continuous immunization, and treated groups, which were treated with the siRNA and ICAM-1 mAb. Normal mice were included as a blank group. These groups were used to compare the effects of treatment with the ICAM-1 mAb and siRNA.

Results: The two novel treatments markedly improved weight loss, serum thyroxine (T4) levels, thyroid-stimulating hormone antibody (TSAb) levels, thyroid-stimulating blocking antibody (TSBAb) levels and thyroid uptake of 99mTcO4 in GD model mice. Compared with the siRNA treatment, treatment with the ICAM-1 mAb produced more obvious benefits. The differences in the posttreatment indexes between the two treatment groups were statistically significant (p < 0.05).

Conclusions: These preliminary data suggest that both the biologically active ICAM-1 mAb and the siRNA targeting TSHR were effective. The ICAM-1 mAb exerted a better therapeutic effect than the siRNA targeting TSHR. Both treatments showed potential efficacy as novel treatments for GD and may therefore represent therapeutic options in addition to the existing drugs or interventions.

Article available in PDF format

View PDF Download PDF file


  1. Weetman AP. Graves' disease. N Engl J Med. 2000; 343(17): 1236–1248.
  2. Sundaresh V, Brito JP, Wang Z, et al. Comparative effectiveness of therapies for Graves' hyperthyroidism: a systematic review and network meta-analysis. J Clin Endocrinol Metab. 2013; 98(9): 3671–3677.
  3. Abraham-Nordling M, Törring O, Hamberger B, et al. Graves' disease: a long-term quality-of-life follow up of patients randomized to treatment with antithyroid drugs, radioiodine, or surgery. Thyroid. 2005; 15(11): 1279–1286.
  4. McKenna T. Graves' disease. Lancet. 2001; 357(9270): 1793–1796.
  5. Tozzoli R, Bagnasco M, Giavarina D, et al. TSH receptor autoantibody immunoassay in patients with Graves' disease: improvement of diagnostic accuracy over different generations of methods. Systematic review and meta-analysis. Autoimmun Rev. 2012; 12(2): 107–113.
  6. Besançon A, Beltrand J, Le Gac I, et al. Management of neonates born to women with Graves' disease: a cohort study. Eur J Endocrinol. 2014; 170(6): 855–862.
  7. Jang SY, Shin DY, Lee EJ, et al. Relevance of TSH-receptor antibody levels in predicting disease course in Graves' orbitopathy: comparison of the third-generation TBII assay and Mc4-TSI bioassay. Eye (Lond). 2013; 27(8): 964–971.
  8. Bahn Chair RS, Burch HB, Cooper DS, et al. American Thyroid Association, American Association of Clinical Endocrinologists. Hyperthyroidism and other causes of thyrotoxicosis: management guidelines of the American Thyroid Association and American Association of Clinical Endocrinologists. Thyroid. 2011; 21(6): 593–646.
  9. Ross DS, Burch HB, Cooper DS, et al. 2016 American Thyroid Association Guidelines for Diagnosis and Management of Hyperthyroidism and Other Causes of Thyrotoxicosis. Thyroid. 2016; 26(10): 1343–1421.
  10. Yan SX, Wang Y. Inhibitory effects of Triptolide on interferon-gamma-induced human leucocyte antigen-DR, intercellular adhesion molecule-1, CD40 expression on retro-ocular fibroblasts derived from patients with Graves' ophthalmopathy. Clin Exp Ophthalmol. 2006; 34(3): 265–271.
  11. Sharma RB, Alegria JD, Talor MV, et al. Iodine and IFN-gamma synergistically enhance intercellular adhesion molecule 1 expression on NOD.H2h4 mouse thyrocytes. J Immunol. 2005; 174(12): 7740–7745.
  12. Liu ZH, Zhu Y. Detection and clinical significance of serum soluble intercellular adhesion molecule-1 and soluble vascular cell adhesion molecule-1 in patients with thyroid associated ophthalmopathy. Adv Ophthalmol. 2013; 33(4): 360.
  13. Zheng W, Wang R, Tan J, et al. An improved method for the establishment of a model of Graves' disease in BALB/c mice. Mol Med Rep. 2017; 15(4): 1471–1478.
  14. Chai J, Fang P, Li N, et al. Preparation and Characterization of ICAM-1 Monoclonal Antibody. Chin J Cell Mol Imm. 2011; 11: 52–54.
  15. Li N, Fang P, Zhang Y, et al. A novel human TSHR antibody ELISA using recombinant extracellular domain fragments of human TSH receptor as antigen and initial clinical evaluation. Chin J Nucl Med 29(5. 2009; 25(5): 348–351.
  16. Ludgate M. Animal models of Graves' disease. Eur J Endocrinol. 2000; 142(1): 1–8.
  17. Shimojo N, Kohno Y, Yamaguchi K, et al. Induction of Graves-like disease in mice by immunization with fibroblasts transfected with the thyrotropin receptor and a class II molecule. Proc Natl Acad Sci U S A. 1996; 93(20): 11074–11079.
  18. Costagliola S, Many MC, Denef JF, et al. Genetic immunization of outbred mice with thyrotropin receptor cDNA provides a model of Graves' disease. J Clin Invest. 2000; 105(6): 803–811.
  19. Kim-Saijo M, Akamizu T, Ikuta K, et al. Generation of a transgenic animal model of hyperthyroid Graves' disease. Eur J Immunol. 2003; 33(9): 2531–2538.
  20. Fröhlich E, Wahl R. Thyroid Autoimmunity: Role of Anti-thyroid Antibodies in Thyroid and Extra-Thyroidal Diseases. Front Immunol. 2017; 8: 521.
  21. Molnár I, Szentmiklósi JA, Gesztelyi R, et al. Effect of antithyroid drugs on the occurrence of antibodies against type 2 deiodinase (DIO2), which are involved in hyperthyroid Graves' disease influencing the therapeutic efficacy. Clin Exp Med. 2019; 19(2): 245–254.
  22. Rahnama R, Mahmoudi AR, Kazemnejad S, et al. Thyroid peroxidase in human endometrium and placenta: a potential target for anti-TPO antibodies. Clin Exp Med. 2021; 21(1): 79–88.
  23. Song E, Lee SK, Wang J, et al. RNA interference targeting Fas protects mice from fulminant hepatitis. Nat Med. 2003; 9(3): 347–351.
  24. Yoshinari K, Miyagishi M, Taira K. Effects on RNAi of the tight structure, sequence and position of the targeted region. Nucleic Acids Res. 2004; 32(2): 691–699.
  25. Liu J, Fang P, Feng P, et al. et al.. A study of soluble intercellular adhesion molecule-1 in sera of patients with thyroid diseases. Chin J Nucl Medi. 2008; 28(4): 264.
  26. Lu M, Fang P, Zhang Z, et al. A preliminary clinical application of sICAM-1 RIA in three kinds of thyroid disease. Chin Med J (Engl). 2002; 115(10): 1552–1555.
  27. Salmaso C, Olive D, Pesce G, et al. Costimulatory molecules and autoimmune thyroid diseases. Autoimmunity. 2002; 35(3): 159–167.
  28. Fernandes AM, Valera FC, Anselmo-Lima WT. Mechanism of action of glucocorticoids in nasal polyposis. Braz J Otorhinolaryngol. 2008; 74(2): 279–283.
  29. Myśliwiec J, Kretowski A, Stepień A, et al. Serum L-selectin and ICAM-1 in patients with Graves' ophthalmopathy during treatment with corticosteroids. Immunol Lett. 2001; 78(3): 123–126.