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Tumor Regression following DNA Vaccination and Regulatory T Cell Depletion in neu Transgenic Mice Leads to an Increased Risk for Autoimmunity¹

Jennifer B. Jacob^*, Yi-chi M. Kong, Ilke Nalbantoglu, Daniel P. Snower and Wei-Zen Wei^2,*

^* Karmanos Cancer Institute, Wayne State University, Detroit, MI 48201; Department of Immunology and Microbiology, Wayne State University School of Medicine, Detroit, MI 48201; and St. John Hospital and Medical Center, Detroit, MI 48236

Modulation of the immune system to amplify anti-tumor immunity carries the risk of developing autoimmune diseases, including hypothyroidism, as seen with cancer patients undergoing clinical trials for immunotherapeutic regimens. Although there is a tendency to view autoimmunity as a positive indicator for cancer immunotherapy, some autoimmune manifestations can be life-threatening and necessitate prolonged medical intervention or removal from trial. We have established murine test models to assess such risks by monitoring, simultaneously, the immune reactivity to tumor-associated rat erbB-2 (neu) and another self Ag, mouse thyroglobulin (mTg). We previously reported that in wild-type, thyroiditis-resistant BALB/c mice that underwent regression of neu⁺ TUBO tumors following regulatory T cell (Treg) depletion, immune responses to rat neu and mTg with resultant autoimmune thyroiditis (EAT) were both enhanced. In this study, we tested the balance between tumor immunity and autoimmunity in neu-transgenic BALB NeuT female mice. First, growth and progression of neu⁺ tumor were compared in neu tolerant mice treated with either CD25 mAb to deplete Tregs and/or DNA vaccination. Only Treg depletion followed by neu DNA vaccination abrogated tolerance to neu, resulting in complete regression of neu⁺ tumors, as well as long-term protection from spontaneous tumorigenesis in 58% of mice. The risk of developing EAT was then assessed by incorporated mTg immunization with or without LPS as adjuvant. In mice with induced tumor regression, mTg response was enhanced with modest increases in EAT development. Therefore, tumor regression induced by Treg depletion and DNA vaccination can exacerbate autoimmunity, which warrants close monitoring during immunotherapy.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by NIH CA125680 and CA76340 (to W.Z.W.), DK45960 (to Y.M.K.), and St. John Hospital and Medical Center (to Y.M.K.).

² Address correspondence and reprint requests to Dr. Wei-Zen Wei, Karmanos Cancer Institute, Wayne State University, 4100 John R. PR04IM, Detroit, MI 48201. E-mail address: weiw{at}karmanos.org

³ Abbreviations used in this paper: mTg, mouse thyroglobulin; Treg, regulatory T cell; EAT, experimental autoimmune thyroiditis; NeuT, neu transgenic mice; pneuTM, plasmid encoding the extracellular and transmembrane domains of neu.

⁴ The online version of this article contains supplemental material.