Peptide specific amelioration of T cell mediated pathogenesis in murine type 1 diabetes Valeria Judkowski, a,b Enrique Rodriguez, b Clemencia Pinilla, a Emma Masteller, c Jeffrey A. Bluestone, c Nora Sarvetnick, b and Darcy B. Wilson a, * a Torrey Pines Institute for Molecular Studies, San Diego, CA 92121, USA b Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037, USA c Diabetes Center, Department of Medicine, University of California, San Francisco, CA 94143, USA Received 26 January 2004; accepted with revision 8 March 2004 Available online 25 May 2004 Abstract NOD mice spontaneously develop insulitis and type 1 diabetes (T1D) mellitus similar to humans. Insulitis without overt disease occurs in the BDC2.5 TCR-transgenic NOD mice that express the rearranged TCR a- and h-chain genes of a diabetogenic T cell clone reactive to an unknown h cell autoantigen. A previous study identified an extensive panel of peptides that are highly active in stimulating T cells from transgenic BDC2.5 mice in culture. However, none of these peptides cause active disease in NOD and BDC2.5 animals or in NOD recipients of adoptively transferred BDC2.5 T cells following direct immunization in vivo. We show that direct immunization of transgenic BDC2.5 mice causes many BDC2.5 T cells to become activated and apoptotic. Strikingly, soluble peptides administered to recipients of activated, highly pathogenic BDC2.5 T cells results in protection from disease. These results suggest that high affinity peptide analogues of autoimmune epitopes might be useful as therapeutic modulators in active autoimmune disease. D 2004 Elsevier Inc. All rights reserved. Keywords: Autoimmunity; Diabetes; Peptide antigens; NOD mice; BDC2.5 mice Introduction The nonobese diabetic (NOD) mouse has been used as an animal model for studies directed at developing a better understanding and insight into circumstances involved in the onset of type 1 diabetes (T1D) in humans. In both this animal model and in humans, it seems clear that disease is the outcome of a pathogenic autoimmune response mediated largely by thymus derived lymphocytes (T cells) in which genetic and environmental factors play significant roles [1]. In both species, T1D involves an occult lymphocytic infil- tration in the pancreatic islets (insulitis) followed by T cell mediated destruction of insulin-producing h cells that leads ultimately to the failure to metabolize glucose and conse- quent elevated glucose levels. Numerous studies have focused on several possible can- didate autoantigens that might be causally responsible for the onset of spontaneous insulitis and h cell destruction in both humans and in the NOD mouse. These include an islet granule protein [2], insulin [3], the 64 kDa isoform of glutamic acid decarboxylase (GAD) 65 [4], heat shock protein [5], and islet glucose-related phosphatase (IGRP) [6]. Interestingly, it has been recently reported that NOD mice carrying a null proinsulin 2 allele develop increased incidence of diabetes [7] whereas insulin 1 gene knockout congenic NOD mice show reduced insulitis and diabetes incidence [8]. However, much of the evidence for the involvement of most of the candidate autoantigens is largely based either on data showing proliferative or cytokine responses to various fragments of these proteins by T cell clones and lines derived from prediabetic patients and ani- mals, or on studies showing that various treatments of NOD animals with these peptides/proteins reduce disease severity [4,5,9 – 12]. 1521-6616/$ - see front matter D 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.clim.2004.03.007 Abbreviations: IDDM, insulin-dependent diabetes mellitus; T1D, type 1 diabetes; NOD, nonobese diabetic; TCR, T cell receptor; EC 50 , the concentration of peptide that stimulates a half-maximal response; SI, stimulation index. * Corresponding author. Torrey Pines Institute for Molecular Studies, 3550 General Atomics Court, San Diego, CA 92121-1122. Fax: +1-858- 455-3804. E-mail address: dbwilson@tpims.org (D.B. Wilson). www.elsevier.com/locate/yclim Clinical Immunology 113 (2004) 29 – 37