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Transgenic Expression of Single-Chain Anti-CTLA-4 Fv on β Cells Protects Nonobese Diabetic Mice from Autoimmune Diabetes¹

Shing-Jia Shieh^*, Feng-Cheng Chou^*, Pei-Ning Yu, Wen-Chi Lin, Deh-Ming Chang^¶, Steve R. Roffler^|| and Huey-Kang Sytwu^2,*,,,

^* Graduate Institute of Life Sciences, Department of Microbiology and Immunology, Graduate Institute of Medical Sciences, Department of Medical Research, ^¶ Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, ^|| Institute of Biomedical Sciences, Academic Sinica, Taipei, Taiwan

T cell-mediated immunodestruction of pancreatic β cells is the key process responsible for both the development of autoimmune diabetes and the induction of rejection during islet transplantation. In this study, we investigate the hypothesis that transgenic expression of an agonistic, membrane-bound single-chain anti-CTLA-4 Fv (anti-CTLA-4 scFv) on pancreatic β cells can inhibit autoimmune processes by selectively targeting CTLA-4 on pathogenic T cells. Strikingly, transgenic expression of anti-CTLA-4 scFv on pancreatic β cells significantly protected NOD mice from spontaneous autoimmune diabetes. Interestingly, local expression of this CTLA-4 agonist did not alter the diabetogenic properties of systemic lymphocytes, because splenocytes from transgenic mice or their nontransgenic littermates equally transferred diabetes in NOD/SCID recipients. By analyzing the T cell development in anti-CTLA-4 scFv/Th1/Th2 triple transgenic mice, we found that β cell-specific expression of CTLA-4 agonist did not affect the development of Th1/Th2 or CD4⁺CD25⁺ regulatory T cells. Most strikingly, islets from transgenic mice inhibited T cell response to immobilized anti-CD3 in a T cell-islet coculture system, suggesting a trans-mediated inhibition provided by transgenic islets. Finally, transgenic islets implanted in diabetic recipients survived much longer than did wild-type islets, indicating a therapeutic potential of this genetically modified islet graft in autoimmune diabetes.

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 the National Science Council, Taiwan, Republic of China (NSC-94-3112-B-016-005, NSC-95-3112-B-016-001, NSC-96-3112-B-016-001, and NSC-96-2628-B-016-002-MY3 to H.-K.S.), and in part by the C.Y. Foundation for Advancement of Education, Sciences, and Medicine.

² Address correspondence and reprint requests to Dr. Huey-Kang Sytwu, Graduate Institute of Medical Sciences, National Defense Medical Center, 161, Section 6, Min-Chuan East Road, Neihu, Taipei, Taiwan. E-mail address: sytwu{at}ndmctsgh.edu.tw

³ Abbreviations used in this paper: IDDM, insulin-dependent diabetes mellitus; anti-CTLA-4 scFv, single-chain anti-CTLA-4 Fv; PLN, pancreatic lymph node; TM, transmembrane; Treg, regulatory T cell; DC, dendritic cell; pINS, human insulin promoter; CT, cytosolic tail.