Chronic exposure in vivo to thyrotropin receptor stimulating monoclonal antibodies sustains high thyroxine levels and thyroid hyperplasia in thyroid autoimmunity-prone HLA-DRB1*0301 transgenic mice

Jeffrey C. Flynn, Jacqueline A. Gilbert, Chady Meroueh, Daniel P. Snower, Chella S. David, Yi Chi M Kong, J. Paul Banga

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

We have examined the induction of autoimmunity and the maintenance of sustained hyperthyroidism in autoimmunity-prone human leucocyte antigen (HLA) DR3 transgenic non-obese diabetic (NOD) mice following chronic stimulation of the thyrotropin receptor (TSHR) by monoclonal thyroid-stimulating autoantibodies (TSAbs). Animals received weekly injections over the course of 9 weeks of monoclonal antibodies (mAbs) with strong thyroid-stimulating properties. Administration of the mAbs KSAb1 (IgG2b) or KSAb2 (IgG2a), which have similar stimulating properties but different TSH-binding blocking activity, resulted in significantly elevated serum thyroxine (T4) levels and thyroid hyperplasia. After the first injection, an initial surge then fall in serum T4 levels was followed by sustained elevated levels with subsequent injections for at least 63 days. Examination of KSAb1 and KSAb2 serum bioactivity showed that the accumulation of the TSAbs in serum was related to their subclass half-lives. The thyroid glands were enlarged and histological examination showed hyperplastic follicles, with minimal accompanying thyroid inflammation. Our results show that chronic in vivo administration of mAbs with strong thyroid-stimulating activity resulted in elevated T4 levels, suggesting persistent stimulation without receptor desensitization, giving a potential explanation for the sustained hyperthyroid status in patients with Graves' disease. Moreover, despite the presence of HLA disease susceptibility alleles and the autoimmune prone NOD background genes, chronic stimulation of the thyroid gland did not lead to immune cell-mediated follicular destruction, suggesting the persistence of immunoregulatory influences to suppress autoimmunity.

Original languageEnglish (US)
Pages (from-to)261-267
Number of pages7
JournalImmunology
Volume122
Issue number2
DOIs
StatePublished - Oct 2007

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Thyrotropin Receptors
HLA Antigens
Autoimmunity
Thyroxine
Transgenic Mice
Hyperplasia
Thyroid Gland
Monoclonal Antibodies
Hyperthyroidism
Serum
Autoantibodies
Injections
Inbred NOD Mouse
Graves Disease
Disease Susceptibility
Alleles
Maintenance
Inflammation

Keywords

  • Graves' disease
  • HLA transgenic mice
  • Hyperthyroidism
  • Thyroid-stimulating antibodies

ASJC Scopus subject areas

  • Immunology

Cite this

Chronic exposure in vivo to thyrotropin receptor stimulating monoclonal antibodies sustains high thyroxine levels and thyroid hyperplasia in thyroid autoimmunity-prone HLA-DRB1*0301 transgenic mice. / Flynn, Jeffrey C.; Gilbert, Jacqueline A.; Meroueh, Chady; Snower, Daniel P.; David, Chella S.; Kong, Yi Chi M; Banga, J. Paul.

In: Immunology, Vol. 122, No. 2, 10.2007, p. 261-267.

Research output: Contribution to journalArticle

Flynn, Jeffrey C. ; Gilbert, Jacqueline A. ; Meroueh, Chady ; Snower, Daniel P. ; David, Chella S. ; Kong, Yi Chi M ; Banga, J. Paul. / Chronic exposure in vivo to thyrotropin receptor stimulating monoclonal antibodies sustains high thyroxine levels and thyroid hyperplasia in thyroid autoimmunity-prone HLA-DRB1*0301 transgenic mice. In: Immunology. 2007 ; Vol. 122, No. 2. pp. 261-267.
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AB - We have examined the induction of autoimmunity and the maintenance of sustained hyperthyroidism in autoimmunity-prone human leucocyte antigen (HLA) DR3 transgenic non-obese diabetic (NOD) mice following chronic stimulation of the thyrotropin receptor (TSHR) by monoclonal thyroid-stimulating autoantibodies (TSAbs). Animals received weekly injections over the course of 9 weeks of monoclonal antibodies (mAbs) with strong thyroid-stimulating properties. Administration of the mAbs KSAb1 (IgG2b) or KSAb2 (IgG2a), which have similar stimulating properties but different TSH-binding blocking activity, resulted in significantly elevated serum thyroxine (T4) levels and thyroid hyperplasia. After the first injection, an initial surge then fall in serum T4 levels was followed by sustained elevated levels with subsequent injections for at least 63 days. Examination of KSAb1 and KSAb2 serum bioactivity showed that the accumulation of the TSAbs in serum was related to their subclass half-lives. The thyroid glands were enlarged and histological examination showed hyperplastic follicles, with minimal accompanying thyroid inflammation. Our results show that chronic in vivo administration of mAbs with strong thyroid-stimulating activity resulted in elevated T4 levels, suggesting persistent stimulation without receptor desensitization, giving a potential explanation for the sustained hyperthyroid status in patients with Graves' disease. Moreover, despite the presence of HLA disease susceptibility alleles and the autoimmune prone NOD background genes, chronic stimulation of the thyroid gland did not lead to immune cell-mediated follicular destruction, suggesting the persistence of immunoregulatory influences to suppress autoimmunity.

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