Wild-type (WT) and IL-4-/- NOD.H-2h4 mice given 0.05% NaI water develop lymphocytic spontaneous autoimmune thyroiditis (L-SAT) with B and T cell infiltration of the thyroid, and production of anti-thyroglobulin antibody. IFN-/- and IFN receptor (R)-/- NOD.H-2h4 mice do not develop L-SAT, but all develop another autoimmune lesion characterized by thyroid epithelial cell hyperplasia and proliferation (TEC H/P). TEC H/P is very severe in 70% of IFN-/- mice given NaI water for 7mo. The thyroid is almost completely replaced by proliferating TEC, and there is extensive collagen deposition (fibrosis). Mice with severe TEC H/P produce anti-thyroglobulin antibodies, have low serum T4 and have some thyroid infiltrating T cells. Lymphocytes are required for development of TEC H/P. TEC H/P results from excessive proliferation of thyrocytes that occurs when IFN is absent. IL-4-/- mice are resistant to TEC H/P. The objective of this proposal is to define the mechanisms involved in development of severe TEC H/P and fibrosis, and determine how it can be inhibited. Thyrocytes of IFN-/- mice with severe TEC H/P strongly express TGF, and all transgenic mice expressing TGF on TEC develop TEC H/P. These studies will test the following hypotheses: 1) TEC H/P is initiated by T cells able to migrate to the thyroid, 2) T cells produce cytokines in the thyroid (IL-4 or a cytokine that is low in IL-4-/- mice) that promote severe TEC H/P and fibrosis, and 3) overexpression of TGF in proliferating thyrocytes is important for development and maintenance of severe TEC H/P. These studies will use gene knockout, i.e. IFN-/-, IFN-/- SCID, STAT-6-/-, and transgenic NOD.H-2h4 mice expressing TGF or dominant negative TGFRII on thyrocytes or T cells. Cell transfer experiments will be used to characterize the effector cells for TEC H/P, and to determine how cytokines such as IL-4, IL-13 and TGF interact with other T cells and TEC to promote development of severe TEC H/P and fibrosis. These studies will be applicable to understanding mechanisms involved in initiation and inhibition of abnormal cellular proliferation and fibrosis that can occur in the thyroid and also in other organs in some human autoimmune diseases such as systemic sclerosis and mixed connective tissue disease. This animal model provides a unique opportunity to clarify underlying mechanisms and may suggest novel therapeutic interventions for human diseases associated with abnormal cellular proliferation and fibrosis.

Public Health Relevance

Abnormal cellular proliferation and fibrosis are severe and often fatal complications in human autoimmune diseases such as scleroderma and mixed connective tissue disease (MCTD). Mechanisms underlying development of these complications are poorly understood, and treatment for them is currently inadequate. The animal model used in this proposal provides a unique opportunity to elucidate the mechanisms underlying development and inhibition of abnormal cellular proliferation and fibrosis, and could hasten development of novel and more effective treatments for these complications in human autoimmune diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI074857-04
Application #
8287181
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Esch, Thomas R
Project Start
2009-07-01
Project End
2013-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
4
Fiscal Year
2012
Total Cost
$358,647
Indirect Cost
$111,147
Name
University of Missouri-Columbia
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
153890272
City
Columbia
State
MO
Country
United States
Zip Code
65211
Kayes, Timothy D; Braley-Mullen, Helen (2013) Culture promotes transfer of thyroid epithelial cell hyperplasia and proliferation by reducing regulatory T cell numbers. Cell Immunol 285:84-91
Kayes, Timothy; Fang, Yujiang; Yu, Shiguang et al. (2013) Agonistic anti-CD40 induces thyrocyte proliferation and promotes thyroid autoimmunity by increasing CD40 expression on thyroid epithelial cells. J Immunol 190:3928-38
Fang, Yujiang; Yu, Shiguang; Braley-Mullen, Helen (2012) TGF-? promotes proliferation of thyroid epithelial cells in IFN-?(-/-) mice by down-regulation of p21 and p27 via AKT pathway. Am J Pathol 180:650-60
Yu, Shiguang; Fang, Yujiang; Sharav, Tumenjargal et al. (2011) CD8+ T cells induce thyroid epithelial cell hyperplasia and fibrosis. J Immunol 186:2655-62