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Dendritic Cells Expressing Transgenic Galectin-1 Delay Onset of Autoimmune Diabetes in Mice¹

Marcelo J. Perone^2,*, Suzanne Bertera, Zakaria S. Tawadrous, William J. Shufesky^*, Jon D. Piganelli, Linda G. Baum, Massimo Trucco and Adrian E. Morelli^3,*

^* Thomas E. Starzl Transplantation Institute and Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA; Department of Pediatrics, Division of Immunogenetics, University of Pittsburgh School of Medicine, Rangos Research Center, Children’s Hospital of Pittsburgh, Pittsburgh, PA 15213; and Department of Pathology and Jonsson Comprehensive Cancer Center, School of Medicine, University of California, Los Angeles, CA 90095

Type 1 diabetes (T1D) is a disease caused by the destruction of the cells of the pancreas by activated T cells. Dendritic cells (DC) are the APC that initiate the T cell response that triggers T1D. However, DC also participate in T cell tolerance, and genetic engineering of DC to modulate T cell immunity is an area of active research. Galectin-1 (gal-1) is an endogenous lectin with regulatory effects on activated T cells including induction of apoptosis and down-regulation of the Th1 response, characteristics that make gal-1 an ideal transgene to transduce DC to treat T1D. We engineered bone marrow-derived DC to synthesize transgenic gal-1 (gal-1-DC) and tested their potential to prevent T1D through their regulatory effects on activated T cells. NOD-derived gal-1-DC triggered rapid apoptosis of diabetogenic BDC2.5 TCR-transgenic CD4⁺ T cells by TCR-dependent and -independent mechanisms. Intravenously administered gal-1-DC trafficked to pancreatic lymph nodes and spleen and delayed onset of diabetes and insulitis in the NODrag1^–/– lymphocyte adoptive transfer model. The therapeutic effect of gal-1-DC was accompanied by increased percentage of apoptotic T cells and reduced number of IFN--secreting CD4⁺ T cells in pancreatic lymph nodes. Treatment with gal-1-DC inhibited proliferation and secretion of IFN- of T cells in response to cell Ag. Unlike other DC-based approaches to modulate T cell immunity, the use of the regulatory properties of gal-1-DC on activated T cells might help to delete cell-reactive T cells at early stages of the disease when the diabetogenic T cells are already activated.

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 National Institutes of Health Grants, R21 AI55027, R01 HL 077545, and R01 HL 075512 (to A.E.M), R33 DK63499 (to M.T.), and the Thomas E. Starzl Transplantation Institute Young Investigator Award (to M.J.P.).

² Current address: Laboratorio de Fisiologia y Biologia Molecular, FCEyN, Universidad de Buenos Aires, Ciudad Universitaria-Pabellon II-2 piso, Buenos Aires 1428, Argentina.

³ Address correspondence and reprint requests to Dr. Adrian E. Morelli, Thomas E. Starzl Transplantation Institute and Department of Surgery, University of Pittsburgh Medical Center, E1513 Biomedical Science Tower, 200 Lothrop Street, Pittsburgh, PA 15213-2582. E-mail address: morelli{at}imap.pitt.edu

⁴ Abbreviations used in this paper: T1D, type 1 diabetes; gal-1, galectin-1; Treg, regulatory T cell; tg, transgenic; DC, dendritic cell; BM, bone marrow; PLN, pancreatic lymph node; TDG, thiodigalactoside; RAd, recombinant adenovirus; CMVp, CMV promoter; eGFP, enhanced GFP; GAD65_206–220, glutamic acid decarboxylase 65 peptide 206–220; EAE, experimental autoimmune encephalomyelitis; IRES, internal ribosomal entry site; CyC, CyChrome; MOI, multiplicity of infection.

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