Superiority of thyroid peroxidase DNA over protein immunization in replicating human thyroid autoimmunity in HLA-DRB1*0301 (DR3) transgenic mice

J. C. Flynn, A. Gardas, Q. Wan, M. Gora, G. Alsharabi, W. Z. Wei, A. A. Giraldo, C. S. David, Y. M. Kong, J. Paul Banga

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Murine experimental autoimmune thyroiditis (EAT), characterized by thyroid destruction after immunization with thyroglobulin (Tg), has long been a useful model of organ-specific autoimmune disease. More recently, porcine thyroid peroxidase (pTPO) has also been shown to induce thyroiditis, but these results have not been confirmed. When (C57BL/6 × CBA)F1 mice, recently shown to be susceptible to mouse TPO-induced EAT, were immunized with plasmid DNA to human TPO (hTPO) and cytokines IL-12 or GM-CSF, significant antibody (Ab) titres were generated, but minimal thyroiditis was detected in one mouse only from the TPO + GM-CSF immunized group. However, after TPO DNA immunization of HLA-DR3 transgenic class II-deficient NOD mice, thyroiditis was present in 23% of mice injected with TPO + IL-12 or GM-CSF. We also used another marker for assessing the closeness of the model to human thyroid autoimmunity by examining the epitope profile of the anti-TPO Abs to immunodominant determinants on TPO. Remarkably, the majority of the anti-TPO Abs was directed to immunodominant regions A and B, demonstrating the close replication of the model to human autoimmunity. TPO protein immunizations of HLA-DR3 transgenic mice with recombinant hTPO did not result in thyroiditis, nor did immunization of other mice expressing HLA class II transgenes HLA-DR4 or HLA-DQ8, with differential susceptibility to Tg-induced EAT. Moreover, our efforts to duplicate exactly the experimental procedures used with pTPO also failed to induce thyroiditis. The success of hTPO plasmid DNA immunization of DR3+ mice, similar to our reports on Tg-induced thyroiditis and thyrotropin receptor DNA-induced Graves' hyperthyroidism, underscores the importance of DR3 genes for all three major thyroid antigens, and provides another humanized model to study autoimmune thyroid disease.

Original languageEnglish (US)
Pages (from-to)503-512
Number of pages10
JournalClinical and Experimental Immunology
Volume137
Issue number3
DOIs
StatePublished - Sep 2004

Fingerprint

Thyroiditis
Iodide Peroxidase
Autoimmunity
Transgenic Mice
Immunization
Thyroid Gland
Autoimmune Thyroiditis
Thyroglobulin
DNA
Granulocyte-Macrophage Colony-Stimulating Factor
Immunodominant Epitopes
Proteins
Interleukin-12
Autoimmune Diseases
Plasmids
Swine
HLA-DR4 Antigen
Thyrotropin Receptors
Inbred CBA Mouse
Inbred NOD Mouse

Keywords

  • HLA-DR3
  • Thyroid peroxidase
  • Thyroid peroxidase DNA
  • TPO DNA immunization

ASJC Scopus subject areas

  • Immunology

Cite this

Superiority of thyroid peroxidase DNA over protein immunization in replicating human thyroid autoimmunity in HLA-DRB1*0301 (DR3) transgenic mice. / Flynn, J. C.; Gardas, A.; Wan, Q.; Gora, M.; Alsharabi, G.; Wei, W. Z.; Giraldo, A. A.; David, C. S.; Kong, Y. M.; Banga, J. Paul.

In: Clinical and Experimental Immunology, Vol. 137, No. 3, 09.2004, p. 503-512.

Research output: Contribution to journalArticle

Flynn, J. C. ; Gardas, A. ; Wan, Q. ; Gora, M. ; Alsharabi, G. ; Wei, W. Z. ; Giraldo, A. A. ; David, C. S. ; Kong, Y. M. ; Banga, J. Paul. / Superiority of thyroid peroxidase DNA over protein immunization in replicating human thyroid autoimmunity in HLA-DRB1*0301 (DR3) transgenic mice. In: Clinical and Experimental Immunology. 2004 ; Vol. 137, No. 3. pp. 503-512.
@article{b4cb74b83eee44d9b25902a066b5c5b6,
title = "Superiority of thyroid peroxidase DNA over protein immunization in replicating human thyroid autoimmunity in HLA-DRB1*0301 (DR3) transgenic mice",
abstract = "Murine experimental autoimmune thyroiditis (EAT), characterized by thyroid destruction after immunization with thyroglobulin (Tg), has long been a useful model of organ-specific autoimmune disease. More recently, porcine thyroid peroxidase (pTPO) has also been shown to induce thyroiditis, but these results have not been confirmed. When (C57BL/6 × CBA)F1 mice, recently shown to be susceptible to mouse TPO-induced EAT, were immunized with plasmid DNA to human TPO (hTPO) and cytokines IL-12 or GM-CSF, significant antibody (Ab) titres were generated, but minimal thyroiditis was detected in one mouse only from the TPO + GM-CSF immunized group. However, after TPO DNA immunization of HLA-DR3 transgenic class II-deficient NOD mice, thyroiditis was present in 23{\%} of mice injected with TPO + IL-12 or GM-CSF. We also used another marker for assessing the closeness of the model to human thyroid autoimmunity by examining the epitope profile of the anti-TPO Abs to immunodominant determinants on TPO. Remarkably, the majority of the anti-TPO Abs was directed to immunodominant regions A and B, demonstrating the close replication of the model to human autoimmunity. TPO protein immunizations of HLA-DR3 transgenic mice with recombinant hTPO did not result in thyroiditis, nor did immunization of other mice expressing HLA class II transgenes HLA-DR4 or HLA-DQ8, with differential susceptibility to Tg-induced EAT. Moreover, our efforts to duplicate exactly the experimental procedures used with pTPO also failed to induce thyroiditis. The success of hTPO plasmid DNA immunization of DR3+ mice, similar to our reports on Tg-induced thyroiditis and thyrotropin receptor DNA-induced Graves' hyperthyroidism, underscores the importance of DR3 genes for all three major thyroid antigens, and provides another humanized model to study autoimmune thyroid disease.",
keywords = "HLA-DR3, Thyroid peroxidase, Thyroid peroxidase DNA, TPO DNA immunization",
author = "Flynn, {J. C.} and A. Gardas and Q. Wan and M. Gora and G. Alsharabi and Wei, {W. Z.} and Giraldo, {A. A.} and David, {C. S.} and Kong, {Y. M.} and Banga, {J. Paul}",
year = "2004",
month = "9",
doi = "10.1111/j.1365-2249.2004.02553.x",
language = "English (US)",
volume = "137",
pages = "503--512",
journal = "Clinical and Experimental Immunology",
issn = "0009-9104",
publisher = "Wiley-Blackwell",
number = "3",

}

TY - JOUR

T1 - Superiority of thyroid peroxidase DNA over protein immunization in replicating human thyroid autoimmunity in HLA-DRB1*0301 (DR3) transgenic mice

AU - Flynn, J. C.

AU - Gardas, A.

AU - Wan, Q.

AU - Gora, M.

AU - Alsharabi, G.

AU - Wei, W. Z.

AU - Giraldo, A. A.

AU - David, C. S.

AU - Kong, Y. M.

AU - Banga, J. Paul

PY - 2004/9

Y1 - 2004/9

N2 - Murine experimental autoimmune thyroiditis (EAT), characterized by thyroid destruction after immunization with thyroglobulin (Tg), has long been a useful model of organ-specific autoimmune disease. More recently, porcine thyroid peroxidase (pTPO) has also been shown to induce thyroiditis, but these results have not been confirmed. When (C57BL/6 × CBA)F1 mice, recently shown to be susceptible to mouse TPO-induced EAT, were immunized with plasmid DNA to human TPO (hTPO) and cytokines IL-12 or GM-CSF, significant antibody (Ab) titres were generated, but minimal thyroiditis was detected in one mouse only from the TPO + GM-CSF immunized group. However, after TPO DNA immunization of HLA-DR3 transgenic class II-deficient NOD mice, thyroiditis was present in 23% of mice injected with TPO + IL-12 or GM-CSF. We also used another marker for assessing the closeness of the model to human thyroid autoimmunity by examining the epitope profile of the anti-TPO Abs to immunodominant determinants on TPO. Remarkably, the majority of the anti-TPO Abs was directed to immunodominant regions A and B, demonstrating the close replication of the model to human autoimmunity. TPO protein immunizations of HLA-DR3 transgenic mice with recombinant hTPO did not result in thyroiditis, nor did immunization of other mice expressing HLA class II transgenes HLA-DR4 or HLA-DQ8, with differential susceptibility to Tg-induced EAT. Moreover, our efforts to duplicate exactly the experimental procedures used with pTPO also failed to induce thyroiditis. The success of hTPO plasmid DNA immunization of DR3+ mice, similar to our reports on Tg-induced thyroiditis and thyrotropin receptor DNA-induced Graves' hyperthyroidism, underscores the importance of DR3 genes for all three major thyroid antigens, and provides another humanized model to study autoimmune thyroid disease.

AB - Murine experimental autoimmune thyroiditis (EAT), characterized by thyroid destruction after immunization with thyroglobulin (Tg), has long been a useful model of organ-specific autoimmune disease. More recently, porcine thyroid peroxidase (pTPO) has also been shown to induce thyroiditis, but these results have not been confirmed. When (C57BL/6 × CBA)F1 mice, recently shown to be susceptible to mouse TPO-induced EAT, were immunized with plasmid DNA to human TPO (hTPO) and cytokines IL-12 or GM-CSF, significant antibody (Ab) titres were generated, but minimal thyroiditis was detected in one mouse only from the TPO + GM-CSF immunized group. However, after TPO DNA immunization of HLA-DR3 transgenic class II-deficient NOD mice, thyroiditis was present in 23% of mice injected with TPO + IL-12 or GM-CSF. We also used another marker for assessing the closeness of the model to human thyroid autoimmunity by examining the epitope profile of the anti-TPO Abs to immunodominant determinants on TPO. Remarkably, the majority of the anti-TPO Abs was directed to immunodominant regions A and B, demonstrating the close replication of the model to human autoimmunity. TPO protein immunizations of HLA-DR3 transgenic mice with recombinant hTPO did not result in thyroiditis, nor did immunization of other mice expressing HLA class II transgenes HLA-DR4 or HLA-DQ8, with differential susceptibility to Tg-induced EAT. Moreover, our efforts to duplicate exactly the experimental procedures used with pTPO also failed to induce thyroiditis. The success of hTPO plasmid DNA immunization of DR3+ mice, similar to our reports on Tg-induced thyroiditis and thyrotropin receptor DNA-induced Graves' hyperthyroidism, underscores the importance of DR3 genes for all three major thyroid antigens, and provides another humanized model to study autoimmune thyroid disease.

KW - HLA-DR3

KW - Thyroid peroxidase

KW - Thyroid peroxidase DNA

KW - TPO DNA immunization

UR - http://www.scopus.com/inward/record.url?scp=4344664698&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=4344664698&partnerID=8YFLogxK

U2 - 10.1111/j.1365-2249.2004.02553.x

DO - 10.1111/j.1365-2249.2004.02553.x

M3 - Article

VL - 137

SP - 503

EP - 512

JO - Clinical and Experimental Immunology

JF - Clinical and Experimental Immunology

SN - 0009-9104

IS - 3

ER -