Open Access Dissertation
Date of Award
Immunology and Microbiology
Yi-chi M. Kong
Some clinical trials of immunotherapeutic agents against cancers have resulted in the development of autoimmune sequelae, including autoimmune thyroiditis. It has been suggested that the immunotherapy resulted in an alteration in the immunoregulatory mechanism(s). Using experimental autoimmune thyroiditis (EAT), a mouse model of Hashimoto's thyroiditis (HT), the importance of regulatory T cells (Tregs) has been well established; inhibition of Tregs leads to enhanced thyroiditis with repeated doses of mouse thyroglobulin (mTg) without adjuvant. To simulate cancer patients, we developed a combined EAT and tumor model in our EAT-susceptible mice (CBA/J). In first establishing the tumor model, we found Treg depletion and irradiated tumor cell immunization necessary for robust anti-tumor immunity. We examined the anti-tumor induction model further and found memory response where mice withstood secondary tumor challenge even 28 or 35 days after the primary challenge. Role of CD4 and CD8 T cells was elucidated and both T cell subsets were observed to mediate protection. Although it was found that the anti-tumor induction protocol induced tumor antibody, its role in the protection was unclear in our present studies.
The anti-tumor induction model was then combined with EAT induction with repeated injections of mouse thyroglobulin (mTg) without adjuvant. Although prior Treg depletion enhanced EAT and was necessary for good anti-tumor immunity induction, the concurrent induction of EAT and anti-tumor immunity had no observable influence on each other. To determine the influence of tumor immunotherapy on pre-existing autoimmune thyroiditis, we primed mice with mTg and various doses of interleukin-1β (IL-1β). We tested various doses of IL-1β (20,000, 10,000 and 5,000U) and combined it with subsequent anti-tumor and EAT induction model. We found no mutual influence of either component (either tumor immune responses or EAT) on each other with various doses tested. However, we found enhanced thyroiditis in mice tested with the lowest dose of IL-1β, i.e. 5,000U, which was enhanced with Treg depletion and repeated mTg injections. In order to examine the influence of regressing tumor on prior autoimmunity, we developed a tumor immunotherapy model and combined it with pre-existing EAT induced with mTg and 5,000U IL-1β. Our results did not show any influence of regressing tumor on prior EAT with two doses of tumors tested.
Our studies helped in dissecting out the role of various components in enhancement of pre-existing autoimmune thyroiditis. Our studies suggest that immunomodulation for tumor immunotherapy could enhance thyroiditis. Similarly, pre-existing thyroiditis primed with an mTg and lower IL-1β dose of 5,000U can be exacerbated as well.
Kari, Suresh, "Examining autoimmune sequelae during cancer immunotherapy in a combined autoimmune thyroiditis and tumor mouse model" (2012). Wayne State University Dissertations. 567.