Experimental Autoimmune Thyroiditis in the Mouse

Kong, Yi

doi:10.1002/0471142735.im1507s78

Cited by 34 publications

(46 citation statements)

References 28 publications

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“…mTg was prepared from frozen thyroids by fractionation on a Sephadex G-200 column as we described previously (34,35) Mice were injected i.v. with 40 Ag mTg followed in 3 h with 20 Ag Salmonella enteritidis LPS.…”

Section: Methodsmentioning

confidence: 99%

Control of Her-2 Tumor Immunity and Thyroid Autoimmunity by MHC and Regulatory T Cells

et al. 2007

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Immune reactivity to self-antigens in both cancer and autoimmune diseases can be enhanced by systemic immune modulation, posing a challenge in cancer immunotherapy. To distinguish the genetic and immune regulation of tumor immunity versus autoimmunity, immune responses to human ErbB-2 (Her-2) and mouse thyroglobulin (mTg) were tested in transgenic mice expressing Her-2 that is overexpressed in several cancers, and HLA-DRB1*0301 (DR3) that is associated with susceptibility to several human autoimmune diseases, as well as experimental autoimmune thyroiditis (EAT). To induce Her-2 response, mice were electrovaccinated with pE2TM and pGM-CSF encoding the extracellular and transmembrane domains of Her-2 and the murine granulocyte macrophage colony-stimulating factor, respectively. To induce EAT, mice received mTg i.v. with or without lipopolysaccharide. Depletion of regulatory T cells (Treg) with anti-CD25 monoclonal antibody enhanced immune reactivity to Her-2 as well as mTg, showing control of both Her-2 and mTg responses by Treg. When immunized with mTg, Her-2xDR3 and B6xDR3 mice expressing H2 b xDR3 haplotype developed more profound mTg response and thyroid pathology than Her-2 or B6 mice that expressed the EAT-resistant H2 b haplotype. In Her-2xDR3 mice, the response to mTg was further amplified when mice were also immunized with pE2TM and pGM-CSF. On the contrary, Her-2 reactivity was comparable whether mice expressed DR3 or not. Therefore, induction of Her-2 immunity was independent of DR3 but development of EAT was dictated by this allele, whereas Tregs control the responses to both self-antigens. These results warrant close monitoring of autoimmunity during cancer immunotherapy, particularly in patients with susceptible MHC class II alleles. [Cancer Res 2007;67(14):7020-7]

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Section: Methodsmentioning

confidence: 99%

Control of Her-2 Tumor Immunity and Thyroid Autoimmunity by MHC and Regulatory T Cells

et al. 2007

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“…Induction of Experimental Autoimmune ThyroiditisFemale NOD-DR3 mice, 4 -6 weeks old, were injected subcutaneously with human thyroglobulin (hTg) (Cell Sciences, Canton, MA) in Complete Freund's Adjuvant (Sigma) to induce EAT as previously described (30). Mice were immunized with hTg on day 0 and boosted on day 7; mice were sacrificed on day 21.…”

Section: Methodsmentioning

confidence: 99%

“…T-cell Proliferative Responses-To test if cepharanthine can block T-cell activation by Tg.2098 presented within HLA-DR3 we induced EAT in NOD-DR3 mice by immunizing them with Tg as previously described (30). Immunized mice splenocytes were incubated with hTg with or without cepharanthine; as negative control we incubated the splenocytes with vehicle (DMSO) alone.…”

Section: Cepharanthine Blocks T-cell Activation By Tg and Tg2098mentioning

confidence: 99%

Identifying a Small Molecule Blocking Antigen Presentation in Autoimmune Thyroiditis

Menconi

Osman

et al. 2016

Journal of Biological Chemistry

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We previously showed that an HLA-DR variant containing arginine at position 74 of the DR␤1 chain (DR␤1-Arg74) is the specific HLA class II variant conferring risk for autoimmune thyroid diseases (AITD). We also identified 5 thyroglobulin (Tg) peptides that bound to DR␤1-Arg74. We hypothesized that blocking the binding of these peptides to DR␤1-Arg74 could block the continuous T-cell activation in thyroiditis needed to maintain the autoimmune response to the thyroid. The aim of the current study was to identify small molecules that can block T-cell activation by Tg peptides presented within DR␤1-Arg74 pockets. We screened a large and diverse library of compounds and identified one compound, cepharanthine that was able to block peptide binding to DR␤1-Arg74. We then showed that Tg.2098 is the dominant peptide when inducing experimental autoimmune thyroiditis (EAT) in NOD mice expressing human DR␤1-Arg74. Furthermore, cepharanthine blocked T-cell activation by thyroglobulin peptides, in particular Tg.2098 in mice that were induced with EAT. For the first time we identified a small molecule that can block Tg peptide binding and presentation to T-cells in autoimmune thyroiditis. If confirmed cepharanthine could potentially have a role in treating human AITD. Autoimmune thyroid diseases (AITD),2 Graves disease (GD), and Hashimoto thyroiditis (HT), are among the most common autoimmune disorders, afflicting up to 5% of the United States population (1). They are characterized by infiltration of the thyroid by lymphocytes reactive to thyroid antigens and production of thyroid-specific antibodies (2). Complex interaction of genetic susceptibility factors, environmental triggers, and epigenetic alterations leads to the breakdown of tolerance, resulting in AITD (3-5). Currently, there is no satisfactory therapy except for hormone replacement therapy in HT or thyroid suppression or ablation in GD (6 -10). To develop new therapies for AITD a better understanding of their etiology is needed. We have been studying the etiology of AITD using a reverse-genetics approach, i.e. dissecting the mechanisms causing disease through unbiased genetic screening studies. These studies led to the identification of a specific HLA-DR pocket sequence that is strongly associated with AITD (11). The presence of arginine at position 74 of the DR␤ chain renders the individual highly susceptible to AITD, whereas glutamine at position 74 is protective (12). These data were confirmed by other groups (13). The presence of DR␤1-Arg74 (from here on we refer to the HLA-DR3 containing arginine at position 74 as HLA-DR␤1-Arg74) results in a more positively charged P4 pocket. With this structural change in the pocket, the selectivity and binding of pathogenic peptides is affected, conferring higher risk for disease (12).Besides the HLA genes, two thyroid-specific genes, the thyroglobulin (Tg) and thyrotropin receptor (TSHR) genes also contribute to the etiology of AITD (2). Thyroglobulin is the most abundant thyroidal protein (14), and it is the precursor to ...

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“…To assess thyroid pathology, the thyroids with intact trachea were sectioned vertically through both thyroid lobes (50-60 sections from 10-15 step levels) and stained with hematoxylin and eosin. Mononuclear cell infiltration was scored (blinded scorer) on an index of 0-4.0: 0, normal thyroid; 0.5, small interstitial foci of infiltration involving > 0-10% of the thyroid; 1.0, follicular destruction with > 10-20% involvement; 2.0, > 20-40% involvement; 3.0, > 40-80% involvement; and 4.0, > 80% involvement (23). Serum mTg Abs were measured by enzyme-linked immunosorbent assay, using platebound mTg (1 lg/well in Immulon II microtiter plates) and alkaline phosphatase-labeled goat anti-mouse IgG (Sigma, St. Louis, MO) (23).…”

Section: Cd4mentioning

confidence: 99%

“…Mononuclear cell infiltration was scored (blinded scorer) on an index of 0-4.0: 0, normal thyroid; 0.5, small interstitial foci of infiltration involving > 0-10% of the thyroid; 1.0, follicular destruction with > 10-20% involvement; 2.0, > 20-40% involvement; 3.0, > 40-80% involvement; and 4.0, > 80% involvement (23). Serum mTg Abs were measured by enzyme-linked immunosorbent assay, using platebound mTg (1 lg/well in Immulon II microtiter plates) and alkaline phosphatase-labeled goat anti-mouse IgG (Sigma, St. Louis, MO) (23). The optical density (OD) 405nm values were corrected for nonspecific binding by subtracting the OD of normal mouse serum.…”

Section: Cd4mentioning

confidence: 99%

Enhanced Autoimmunity Associated with Induction of Tumor Immunity in Thyroiditis-Susceptible Mice

Kari

Flynn

Zulfiqar

et al. 2013

Thyroid

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Background: Immunotherapeutic modalities to bolster tumor immunity by targeting specific sites of the immune network often result in immune dysregulation with adverse autoimmune sequelae. To understand the relative risk for opportunistic autoimmune disorders, we studied established breast cancer models in mice resistant to experimental autoimmune thyroiditis (EAT). EAT is a murine model of Hashimoto's thyroiditis, an autoimmune syndrome with established MHC class II control of susceptibility. The highly prevalent Hashimoto's thyroiditis is a prominent autoimmune sequela in immunotherapy, and its relative ease of diagnosis and treatment could serve as an early indicator of immune dysfunction. Here, we examined EAT-susceptible mice as a combined model for induction of tumor immunity and EAT under the umbrella of disrupted regulatory T cell (Treg) function. Methods: Tumor immunity was evaluated in female CBA/J mice after depleting Tregs by intravenous administration of CD25 monoclonal antibody and/or immunizing with irradiated mammary adenocarcinoma cell line A22E-j before challenge; the role of T cell subsets was determined by injecting CD4 and/or CD8 antibodies after tumor immunity induction. Tumor growth was monitored 3 · /week by palpation. Subsequent EAT was induced by mouse thyroglobulin (mTg) injections (4 daily doses/week over 4 weeks). For some experiments, EAT was induced before establishing tumor immunity by injecting mTg + interleukin-1, 7 days apart. EAT was evaluated by mTg antibodies and thyroid infiltration. Results: Strong resistance to tumor challenge after Treg depletion and immunization with irradiated tumor cells required participation of both CD4 + and CD8 + T cells. This immunity was not altered by induction of mild thyroiditis with our protocol of Treg depletion and adjuvant-free, soluble mTg injections. However, the increased incidence of mild thyroiditis can be directly related to Treg depletion needed to achieve strong tumor immunity. Moreover, when a subclinical, mild thyroiditis was induced with soluble mTg and low doses of interleukin-1, to simulate pre-existing autoimmunity in patients subjected to cancer immunotherapy, mononuclear infiltration into the thyroid was enhanced. Conclusions: Our current findings indicate that genetic predisposition to autoimmune disease could enhance autoimmunity during induction of tumor immunity in thyroiditis-susceptible mice. Thus, HLA genotyping of cancer patients should be part of any risk assessment.

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Experimental Autoimmune Thyroiditis in the Mouse

Cited by 34 publications

References 28 publications

Control of Her-2 Tumor Immunity and Thyroid Autoimmunity by MHC and Regulatory T Cells

Control of Her-2 Tumor Immunity and Thyroid Autoimmunity by MHC and Regulatory T Cells

Identifying a Small Molecule Blocking Antigen Presentation in Autoimmune Thyroiditis

Enhanced Autoimmunity Associated with Induction of Tumor Immunity in Thyroiditis-Susceptible Mice

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