Superiority of thyroid peroxidase DNA over protein immunization in replicating human thyroid autoimmunity in HLA-DRB1*0301 (DR3) transgenic mice.
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 x CBA)F(1) 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.
Flynn
J C
JC
Department of Immunology and Microbiology, Wayne State University School of Medicine, Detroit, USA.
Gardas
A
A
Wan
Q
Q
Gora
M
M
Alsharabi
G
G
Wei
W Z
WZ
Giraldo
A A
AA
David
C S
CS
Kong
Y M
YM
Banga
J P
JP
D000818:Animals; D001323:Autoantibodies / Q000276:immunology; D015551:Autoimmunity; D004247:DNA / Q000008:administration & dosage*; D000939:Epitopes / Q000276:immunology; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D015803:HLA-DR3 Antigen / Q000235:genetics*; D007114:Immunization; D018664:Interleukin-12 / Q000494:pharmacology; D007453:Iodide Peroxidase / Q000235:genetics* / Q000627:therapeutic use; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D023421:Models, Animal; D013961:Thyroid Gland / Q000276:immunology*; D013967:Thyroiditis, Autoimmune / Q000276:immunology*
D001323:Autoantibodies; D000939:Epitopes; D015803:HLA-DR3 Antigen; D016179:Granulocyte Colony-Stimulating Factor; D018664:Interleukin-12; D004247:DNA; D007453:Iodide Peroxidase