help button home button Endocrine Society Endocrinology
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Kita, M.
Right arrow Articles by Davies, T. F.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Kita, M.
Right arrow Articles by Davies, T. F.
Right arrowPubmed/NCBI databases
Medline Plus Health Information
*Immunization
Endocrinology Vol. 140, No. 3 1392-1398
Copyright © 1999 by The Endocrine Society

ARTICLES

Regulation and Transfer of a Murine Model of Thyrotropin Receptor Antibody Mediated Graves’ Disease1

M. Kita, L. Ahmad, R. C. Marians, H. Vlase, P. Unger, P. N. Graves and T. F. Davies

Division of Endocrinology and Metabolism (M.K., L.A., R.C.M., H.V., P.N.G., T.F.D.), Departments of Medicine and Pathology (P.U.), Mount Sinai School of Medicine, New York, New York 10128

Address all correspondence and requests for reprints to: Dr. T. F. Davies, Mount Sinai Medical Center, Box 1055, 1 Gustave L. Levy Place, New York, New York 10128. E-mail: tdavies{at}smtplink.mssm.edu

In order to replicate a recently described murine model of Graves’ disease, we immunized AKR/N (H-2k) mice ip, every 2 weeks, with either a clone of fibroblasts expressing both the human TSH receptor (hTSHR) and murine major histocompatibility complex (MHC) class II molecules or with fibroblasts expressing the MHC class II molecules alone. Mice were bled, and their thyroid hormone levels measured, at 6, 12, and up to 18 weeks after the first immunization. Between 11–12 weeks after immunization, a significant number of mice began to die spontaneously and were found to have developed large goiters. Thirty to 40% of mice immunized with hTSHR transfected fibroblasts showed markedly increased serum T3 and T4 hormone levels by 12 weeks compared with controls, with the highest thyroid hormone levels being T3: 420 ng/dl (normal < 70) and T4: 16.5 µg/dl (normal < 5). The murine serum demonstrated the presence of antibodies to the TSHR, as evidenced by inhibition of labeled TSH binding to the hTSHR, and these sera had in vitro thyroid stimulating activity. Many of the hyperthyroid mouse exhibited weight loss and hyperactivity and, on examination, their thyroids had the histological features of thyroid hyperactivity including thyroid enlargement, thyroid cell hypertrophy, and colloid droplet formation - all consistent with Graves’ disease. In contrast, a small number of mice (< 5%) developed hypothyroidism with low serum T4 levels and markedly increased TSH concentrations and evidence of thyroid hypoplasia. Both hyperthyroidism and hypothyroidism were successfully transferred to naive mice using ip cells of immunized mice. Surprisingly, hypothyroidism occurred in many recipient mice even after transfer from hyperthyroid donors.

These results confirmed that immunization with naturally expressed hTSHR in mammalian cells was able to induce functional TSHR autoantibodies that either stimulated or blocked the mouse thyroid gland and induced hyperthyroidism or thyroid failure. Furthermore, both blocking and stimulating antibodies coexisted in the same mice as evidenced so clearly by the transfer of hypothyroidism from hyperthyroid mice. The addition of a Th2 adjuvant (pertussis toxin) caused approximately 50% of the animals to become hyperthyroid beginning early at 9 weeks, whereas a Th1 adjuvant (CFA) delayed the disease onset such that only 10% were hyperthyroid by 12 weeks. As with human autoimmune thyroid disease, the T cell control of this murine model may be critical and requires more extensive investigation.




This article has been cited by other articles:


Home page
 Endocr. Rev.Home page
S. M. McLachlan, Y. Nagayama, and B. Rapoport
Insight into Graves' Hyperthyroidism from Animal Models
Endocr. Rev., October 1, 2005; 26(6): 800 - 832.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
C.-R. Chen, H. Aliesky, P. N. Pichurin, Y. Nagayama, S. M. McLachlan, and B. Rapoport
Susceptibility Rather than Resistance to Hyperthyroidism Is Dominant in a Thyrotropin Receptor Adenovirus-Induced Animal Model of Graves' Disease as Revealed by BALB/c-C57BL/6 Hybrid Mice
Endocrinology, November 1, 2004; 145(11): 4927 - 4933.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
K. J. Land, J. S. Moll, M. H. Kaplan, and G. S. Seetharamaiah
Signal Transducer and Activator of Transcription (Stat)-6-Dependent, But Not Stat4-Dependent, Immunity Is Required for the Development of Autoimmunity in Graves' Hyperthyroidism
Endocrinology, August 1, 2004; 145(8): 3724 - 3730.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
T. Muehlberg, J. A. Gilbert, P. V. Rao, A. M. McGregor, and J. P. Banga
Dynamics of Thyroid-Stimulating and -Blocking Antibodies to the Thyrotropin Receptor in a Murine Model of Graves' Disease
Endocrinology, April 1, 2004; 145(4): 1539 - 1545.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
C.-R. Chen, P. Pichurin, G. D. Chazenbalk, H. Aliesky, Y. Nagayama, S. M. McLachlan, and B. Rapoport
Low-Dose Immunization with Adenovirus Expressing the Thyroid-Stimulating Hormone Receptor A-Subunit Deviates the Antibody Response toward That of Autoantibodies in Human Graves' Disease
Endocrinology, January 1, 2004; 145(1): 228 - 233.
[Abstract] [Full Text] [PDF]

Home page
 Endocr. Rev.Home page
B. S. Prabhakar, R. S. Bahn, and T. J. Smith
Current Perspective on the Pathogenesis of Graves' Disease and Ophthalmopathy
Endocr. Rev., December 1, 2003; 24(6): 802 - 835.
[Abstract] [Full Text] [PDF]

Home page
 Endocr. Rev.Home page
Y. Tomer and T. F. Davies
Searching for the Autoimmune Thyroid Disease Susceptibility Genes: From Gene Mapping to Gene Function
Endocr. Rev., October 1, 2003; 24(5): 694 - 717.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
L. Schwarz-Lauer, P. N. Pichurin, C.-R. Chen, Y. Nagayama, C. Paras, J. C. Morris, B. Rapoport, and S. M. McLachlan
The Cysteine-Rich Amino Terminus of the Thyrotropin Receptor Is the Immunodominant Linear Antibody Epitope in Mice Immunized Using Naked Deoxyribonucleic Acid or Adenovirus Vectors
Endocrinology, May 1, 2003; 144(5): 1718 - 1725.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
Y. Nagayama, H. Mizuguchi, T. Hayakawa, M. Niwa, S. M. McLachlan, and B. Rapoport
Prevention of Autoantibody-Mediated Graves'-Like Hyperthyroidism in Mice with IL-4, a Th2 Cytokine
J. Immunol., April 1, 2003; 170(7): 3522 - 3527.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
T. Ando, M. Imaizumi, P. Graves, P. Unger, and T. F. Davies
Induction of Thyroid-Stimulating Hormone Receptor Autoimmunity in Hamsters
Endocrinology, February 1, 2003; 144(2): 671 - 680.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
P. V. Rao, P. F. Watson, A. P. Weetman, G. Carayanniotis, and J. P. Banga
Contrasting Activities of Thyrotropin Receptor Antibodies in Experimental Models of Graves' Disease Induced by Injection of Transfected Fibroblasts or Deoxyribonucleic Acid Vaccination
Endocrinology, January 1, 2003; 144(1): 260 - 266.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
P. Pichurin, O. Pichurina, G. D. Chazenbalk, C. Paras, C.-R. Chen, B. Rapoport, and S. M. McLachlan
Immune Deviation Away from Th1 in Interferon-{gamma} Knockout Mice Does Not Enhance TSH Receptor Antibody Production after Naked DNA Vaccination
Endocrinology, April 1, 2002; 143(4): 1182 - 1189.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
Y. Nagayama, M. Kita-Furuyama, T. Ando, K. Nakao, H. Mizuguchi, T. Hayakawa, K. Eguchi, and M. Niwa
A Novel Murine Model of Graves' Hyperthyroidism with Intramuscular Injection of Adenovirus Expressing the Thyrotropin Receptor
J. Immunol., March 15, 2002; 168(6): 2789 - 2794.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
P. Pichurin, X.-M. Yan, L. Farilla, J. Guo, G. D. Chazenbalk, B. Rapoport, and S. M. McLachlan
Naked TSH Receptor DNA Vaccination: A TH1 T Cell Response in Which Interferon-{gamma} Production, Rather than Antibody, Dominates the Immune Response in Mice
Endocrinology, August 1, 2001; 142(8): 3530 - 3536.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
S. Kaithamana, J. Fan, Y. Osuga, S.-G. Liang, and B. S. Prabhakar
Induction of Experimental Autoimmune Graves' Disease in BALB/c Mice
J. Immunol., November 1, 1999; 163(9): 5157 - 5164.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
R. Latif, P. Graves, and T. F. Davies
Oligomerization of the Human Thyrotropin Receptor. FLUORESCENT PROTEIN-TAGGED hTSHR REVEALS POST-TRANSLATIONAL COMPLEXES
J. Biol. Chem., November 21, 2001; 276(48): 45217 - 45224.
[Abstract] [Full Text] [PDF]


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals
Copyright © 1999 by The Endocrine Society