Coexpression of Susceptible and Resistant HLA Class II Transgenes in Murine Experimental Autoimmune Thyroiditis: DQ8 Molecules Downregulate DR3-Mediated Thyroiditis

Flynn, Jeffrey C.; Wan, Qiang; Panos, John C.; McCormick, Daniel J.; Giraldo, Alvaro A.; David, Chella S.; Kong, Yi

doi:10.1006/jaut.2002.0587

Cited by 18 publications

(26 citation statements)

References 35 publications

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“…Reports of disease-associated alleles are not consistent, but associations appear to be strongest with alleles in the HLA-DR and -DQ loci. This has also been suggested by studies in transgenic mouse [30,52,85-87]. …”

Section: Introductionsupporting

confidence: 58%

“…A role for HLA-DQ polymorphism was shown with human thyroglobulin-induced EAT in HLA-DQ*0301/DQB1*0302 (DQ8), but not HLA-DQ*0103/DQB1*0601 (DQ6), transgenic mice [52]. In summary, DR3 and DQ8 alleles are found to be susceptible, whereas DR2, DR4 and DQ6 alleles are resistant [30,87]. Studies on EAT-developing mice showed the differential effects of class II molecules on EAT induction.…”

Section: Introductionmentioning

confidence: 99%

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Chistiakov

2005

J Autoimmune Dis

121

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Section: Introductionsupporting

confidence: 58%

Section: Introductionmentioning

confidence: 99%

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Chistiakov

2005

J Autoimmune Dis

121

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“…Similarly, we have shown that the presence of an HLA-DQ8 transgene plays a moderating role in HLA-DR3-mediated response to hTg in DR3/DQ8 double transgenic mice [47]. The existence of Tregs influencing EAT induction in the context of this H2A b class II molecule [23] suggested that they may be responsible for the suppressive effect of H2A expression on H2E-mediated thyroiditis.…”

Section: Possible Reciprocal Role Of Tregs In the Suppressive Effementioning

confidence: 99%

Autoimmune thyroiditis: A model uniquely suited to probe regulatory T cell function

Kong

Morris

Brown

et al. 2009

Journal of Autoimmunity

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Murine experimental autoimmune thyroiditis (EAT) is a model for Hashimoto’s thyroiditis that has served as a prototype of T cell-mediated autoimmunity for more than three decades. Key roles for MHC restriction and autoantigen influence on susceptibility to autoimmunity have been demonstrated in EAT. Moreover, it has served a unique role in investigations of self tolerance. In the early 1980s, self tolerance and resistance to EAT induction could be enhanced by increasing circulating levels of the autoantigen, thyroglobulin (Tg), by exogenous addition as well as endogenous release. This observation, directly linking circulating self antigen to self tolerance, led to subsequent investigations of the role of regulatory T cells (Tregs) in self tolerance. These studies revealed that protection against autoimmunity, in both naive and tolerized mice, was mediated by thymically-derived CD4+CD25+Foxp3+ Tregs. Moreover, these naturally-existing Tregs required proper costimulation, in context with autoantigen presentation, to maintain and enhance self tolerance. In particular was the selected use of MHC- and heterologous Tg-restricted models from both conventional and transgenic mice. These models helped to elucidate the complex interplay between autoantigen presentation and MHC class II-mediated T cell selection in the development of Treg and autoreactive T cell repertoires determining susceptibility to autoimmunity. Here we describe these investigations in further detail, providing a context for how EAT has helped shape our understanding of self tolerance and autoimmunity.

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“…In Her-2 tolerant, EAT-resistant C57BL/6 mice also harboring the HLA-DRB1*03:01 transgene to encode EAT susceptibility (15), the (H2 b -Her-2xDR3)F 1 mice withstood tumor challenge again only after Treg depletion and Her-2 DNA vaccination (16). Although the presence of the DR3 allele in F 1 mice increased the autoimmune response, it was moderated by the EAT-resistant A b allele, consistent with EAT-resistant DQ8 (HLA-DQA1*03:01/DQB1*03:02) transgene downregulation of DR3-mediated thyroiditis (17). In all three combined models, immune stimuli from concurrent tumor regression and EAT development had a detectable, mutually enhancing effect.…”

mentioning

confidence: 63%

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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Coexpression of Susceptible and Resistant HLA Class II Transgenes in Murine Experimental Autoimmune Thyroiditis: DQ8 Molecules Downregulate DR3-Mediated Thyroiditis

Cited by 18 publications

References 35 publications

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Autoimmune thyroiditis: A model uniquely suited to probe regulatory T cell function

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

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