Adenovirus Early Region 3 (E3) Immunomodulatory Genes Decrease the Incidence of Autoimmune Diabetes in NOD Mice
- Shimon Efrat1,
- David Serreze2,
- Anton Svetlanov3,
- Cristina M. Post2,
- Ellis A. Johnson2,
- Kevan Herold4 and
- Marshall Horwitz3
- 1Department of Human Genetics and Molecular Medicine, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
- 2The Jackson Laboratory, Bar Harbor, Maine
- 3Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx
- 4Department of Medicine and Naomi Berrie Diabetes Center, College of Physicians and Surgeons, Columbia University, New York, New York
Abstract
The early three (E3) region of the adenovirus (Ad) encodes a number of immunomodulatory proteins that interfere with class I major histocompatibility–mediated antigen presentation and confer resistance to cytokine-induced apoptosis in cells infected by the virus. Transgenic expression of Ad E3 genes under the rat insulin II promoter (RIP-E3) in β-cells in nonobese diabetic (NOD) mice decreases the incidence and delays the onset of autoimmune diabetes. The immune effector cells of RIP-E3/NOD mice maintain the ability to infiltrate the islets and transfer diabetes into NOD-scid recipients, although at a significantly reduced rate compared with wild-type littermates. The islets of RIP-E3/NOD mice can be destroyed by adoptive transfer of splenocytes from wild-type NOD mice; however, the time to onset of hyperglycemia is delayed significantly, and 40% of these recipients were not diabetic at the end of the experiment. These findings suggest that expression of E3 genes in β-cells affects both the activation of immune effector cells and the intrinsic resistance of β-cells to autoimmune destruction.
Footnotes
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Address correspondence and reprint requests to Marshall Horwitz, MD, Department of Microbiology and Immunology, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461. E-mail: horwitz{at}aecom.yu.edu.
Received for publication 3 August 2000 and accepted in revised form 19 January 2001.
S.E. holds stock in and serves on the scientific advisory board for Modex Therapeutics, Switzerland.
Ad, adenovirus; AECOM, Albert Einstein College of Medicine; CTL, cytotoxic T-lymphocytes; E3, early three; gp19, 19-kDa glycoprotein; TJL, The Jackson Laboratory; LCMV, lymphocytic choriomeningitis virus; MHC, major histocompatibility complex; PCR, polymerase chain reaction; RIP, rat insulin II promoter; TAP, transporter associated with antigen presentation; TNF-α, tumor necrosis factor-α.
