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* Thomas E. Starzl Transplantation Institute and Department of Surgery,
Department of Dermatology, and
Department of Immunology, University of Pittsburgh Medical Center, Pittsburgh, PA 15213;
Department of Pediatrics, Division of Immunogenetics and Rangos Research Center, University of Pittsburgh. Pittsburgh, PA 15213;
¶ Department of Pathology and Jonsson Comprehensive Cancer Center, University of California Los Angeles School of Medicine, Los Angeles, CA 90095; and
|| Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute and Department of Pathology and Department of Neurology, Harvard Medical School, Boston, MA 02115
Type 1 diabetes (T1D) is a T cell-mediated autoimmune disease that targets the β-cells of the pancreas. We investigated the ability of soluble galectin-1 (gal-1), an endogenous lectin that promotes T cell apoptosis, to down-regulate the T cell response that destroys the pancreatic β-cells. We demonstrated that in nonobese diabetic (NOD) mice, gal-1 therapy reduces significantly the amount of Th1 cells, augments the number of T cells secreting IL-4 or IL-10 specific for islet cell Ag, and causes peripheral deletion of β-cell-reactive T cells. Administration of gal-1 prevented the onset of hyperglycemia in NOD mice at early and subclinical stages of T1D. Preventive gal-1 therapy shifted the composition of the insulitis into an infiltrate that did not invade the islets and that contained a significantly reduced number of Th1 cells and a higher percentage of CD4+ T cells with content of IL-4, IL-5, or IL-10. The beneficial effects of gal-1 correlated with the ability of the lectin to trigger apoptosis of the T cell subsets that cause β-cell damage while sparing naive T cells, Th2 lymphocytes, and regulatory T cells in NOD mice. Importantly, gal-1 reversed β-cell autoimmunity and hyperglycemia in NOD mice with ongoing T1D. Because gal-1 therapy did not cause major side effects or β-cell toxicity in NOD mice, the use of gal-1 to control β-cell autoimmunity represents a novel alternative for treatment of subclinical or ongoing T1D.
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 Supported by National Institutes of Health Grants R01 HL077545 and R01 HL075512 (to A.E.M.) and R33 DK63499 (to M.T.), the Thomas E. Starzl Transplantation Institute Young Investigator Award (to M.J.P.), and a grant from the Juvenile Diabetes Research Foundation (to K.W.W.).
2 M.J.P., S.B., and W.J.S. contributed equally to this work.
3 Current address: Laboratorio de Fisiologia y Biologia Molecular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria-Pabellon II-2 Piso, Buenos Aires 1428, Argentina.
4 Address correspondence and reprint requests to Dr. Adrian E. Morelli, W1556 Biomedical Science Tower, 200 Lothrop Street, Pittsburgh, PA 15213-2582. E-mail address: morelli{at}imap.pitt.edu
5 Abbreviations used in this paper: T1D, type 1 diabetes; 7-AAD, 7-aminoactinomycin D; CH, contact hypersensitivity; DAPI, 4',6-diamidino-2-phyenlindole; DC, dendritic cell; GAD, glutamic acid decarboxylase; gal, galectin; NOD, nonobese diabetic (mice); PLN, pancreatic lymph node; Tc, T cytotoxic (cell); TNCB, 2,4,6-trinitrochlorobenzene; Treg, regulatory T (cell).
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