Minimal Impact of a De Novo–Expressed β-Cell Autoantigen on Spontaneous Diabetes Development in NOD Mice

• Published in: Diabetes (New York, N.Y.) Vol. 56; no. 4; pp. 1059 - 1068
• Main Authors: MARTINIC, Marianne M, JUEDES, Amy E, CHRISTEN, Urs, VON HERRATH, Matthias G, BRESSON, Damien, HOMANN, Dirk, SKAK, Kresten, HUBER, Christoph, LING, Eleanor, EJRNAES, Mette, WOLFE, Tom, TOGHER, Lisa
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.04.2007
• Subjects: Animals; Autoantigens - immunology; Biological and medical sciences; Cloning, Molecular; Diabetes; Diabetes Mellitus, Type 1 - immunology; Diabetes Mellitus, Type 1 - physiopathology; Diabetes research; Diabetes. Impaired glucose tolerance; DNA Primers; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Enzyme-Linked Immunosorbent Assay; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Gene expression; Insulin - analysis; Insulin-Secreting Cells - immunology; Lymphocytic choriomeningitis virus - genetics; Medical sciences; Mice; Mice, Inbred NOD; Mice, Transgenic; Nucleoproteins - genetics; Pancreatic beta cells; Reverse Transcriptase Polymerase Chain Reaction; Viral Proteins - genetics; United States; Endocrinopathy; Autoimmunity; Diabetes mellitus; Langerhans islet; Rodentia; Vertebrata; Mammalia; Autoantigen; Mouse; Animal; Development; β Cell; Endocrine pancreas
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/db05-0062

Minimal Impact of a De Novo–Expressed β-Cell Autoantigen on Spontaneous Diabetes Development in NOD Mice Marianne M. Martinic 1 , Amy E. Juedes 1 , Damien Bresson 1 , Dirk Homann 2 , Kresten Skak 3 , Christoph Huber 4 , Eleanor Ling 1 , Mette Ejrnaes 1 , Tom Wolfe 1 , Lisa Togher 1 , Urs Christen 5 and Matthias G. von Herrath 1 1 Division of Developmental Immunology, La Jolla Institute for Allergy and Immunology, La Jolla, California 2 Barbara Davis Center for Childhood Diabetes, University of Colorado at Denver and Health Sciences Center, Aurora, Colorado 3 Pharmacology Research, Novo Nordisk A/S, Måløv, Denmark 4 Department of Immunology, The Scripps Research Institute, La Jolla, California 5 Klinik der Johann Wolfgang Goethe Universität, Frankfurt, Germany Address correspondence and reprint requests to Marianne M. Martinic or Matthias G. von Herrath, Immune Regulation Lab DI-3, La Jolla Institute for Allergy and Immunology, 9420 Athena Circle, La Jolla, CA 92037. E-mail: marmar{at}liai.org or matthias{at}liai.org Abstract During an autoimmune process, the autoaggressive response spreads from the initiating autoantigen to other antigens expressed in the target organ. Based on evidence from experimental models for multiple sclerosis, such “antigenic spreading” can play an important role in the exacerbation of clinical disease. We evaluated whether pathogenesis of spontaneous diabetes in NOD mice could be accelerated in a similar way when a novel autoantigen was expressed in pancreatic β-cells. Unexpectedly, we found that the expression of the lymphocytic choriomeningitis virus nucleoprotein only led to marginal enhancement of diabetes, although such NOD-nucleoprotein mice were not tolerant to nucleoprotein. Although the frequency of nucleoprotein-specific CD8 T-cells in the pancreatic draining lymph node was comparable with the frequency of islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP)-specific T-cells, more IGRP-specific CD8 T-cells were found both systemically and in the islets where there was a fourfold increase. Interestingly, and in contrast to nucleoprotein-specific CD8 T-cells, IGRP-specific T-cells showed increased CXCR3 expression. Thus, autoreactivity toward de novo–expressed β-cell autoantigens will not accelerate autoimmunity unless large number s of antigen-experienced autoreactive T-cells expressing the appropriate chemokine receptors are present. CTL, cytotoxic T-lymphocyte CNS, central nervous system EAE, experimental autoimmune encephalomyelitis ELISA, enzyme-linked immunosorbent assay GAD, glutamic acid decarboxylase HBS, hepatitis B virus polyadenylation signal IFN-γ, γ-interferon IGRP, islet-specific glucose-6-phosphatase catalytic subunit-related protein IL, interleukin LCMV, lymphocytic choriomeningitis virus MHC, major histocompatibility complex PBS-T, 0.05% Tween 20 in PBS PDLN, pancreatic draining lymph node pfu, plaque forming unit RIP, rat insulin promoter Footnotes M.M.M. and A.E.J. contributed equally to this work. 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. Accepted November 22, 2006. Received January 14, 2005. DIABETES