The Journal of Experimental Medicine
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Published online 12 April 2004 doi:10.1084/jem.20031939
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 199, Number 8, 1143-1151
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Transgenic Expression of Decoy Receptor 3 Protects Islets from Spontaneous and Chemical-induced Autoimmune Destruction in Nonobese Diabetic Mice

Hsiang-Hsuan Sung1, Jyuhn-Huarng Juang7, Yu-Chun Lin2, Chien-Hung Kuo7, Jung-Tung Hung1, An Chen3, Der-Ming Chang4, Sun-Yran Chang5, Shie-Liang Hsieh8, and Huey-Kang Sytwu1,2,6

1 Graduate Institute of Life Sciences, 2 Department of Medicine, 3 Department of Pathology, 4 Department of Internal Medicine, 5 Department of Surgery, and 6 Department of Microbiology and Immunology, National Defense Medical Center, Taipei 114, Taiwan
7 Department of Internal Medicine, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan
8 Department of Microbiology and Immunology, National Yang-Ming University, Taipei 112, Taiwan

Address correspondence to Huey-Kang Sytwu, Department of Microbiology and Immunology, National Defense Medical Center, 161, Section 6, MinChuan East Road, Neihu, Taipei 114, Taiwan. Phone: 886-2-87923100 ext. 18540; Fax: 886-2-87921774; email: sytwu{at}ndmctsgh.edu.tw

Decoy receptor 3 (DCR3) halts both Fas ligand– and LIGHT-induced cell deaths, which are required for pancreatic ß cell damage in autoimmune diabetes. To directly investigate the therapeutic potential of DCR3 in preventing this disease, we generated transgenic nonobese diabetic mice, which overexpressed DCR3 in ß cells. Transgenic DCR3 protected mice from autoimmune and cyclophosphamide-induced diabetes in a dose-dependent manner and significantly reduced the severity of insulitis. Local expression of the transgene did not alter the diabetogenic properties of systemic lymphocytes or the development of T helper 1 or T regulatory cells. The transgenic islets had a higher transplantation success rate and survived for longer than wild-type islets. We have demonstrated for the first time that the immune-evasion function of DCR3 inhibits autoimmunity and that genetic manipulation of grafts may improve the success and survival of islet transplants.

Key Words: NOD • Fas ligand • LIGHT • T helper 1 cell • T regulatory cell

Abbreviations used in this paper: DCR3, decoy receptor 3; FasL, Fas ligand; IDDM, insulin-dependent diabetes mellitus; LTßR, lymphotoxin ß receptor; NOD, nonobese diabetic; PD, pancreatic DCR3; TL1A, TNF-like molecule 1A; Treg, T regulatory cell.


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