Proposed mechanisms for oligonucleotide IMT504 induced diabetes reversion in a mouse model of immunodependent diabetes.

BIANCHI MS; BIANCHI S; HERNANDO-INSÚA A; MARTINEZ LM; LAGO N; LIBERTUN C; CHASSEING NA; MONTANER AD; LUX-LANTOS VA

AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM

AMER PHYSIOLOGICAL SOC

Lugar: Bethesda; Año: 2016 vol. 311 p. 380 - 395

0193-1849

Mail of the Editorial Office ( June 7, 2016)---Dear Dr. Chasseing:A decision for E-00104-2016R2, "PROPOSED MECHANISMS FOR OLIGONUCLEOTIDE IMT504 INDUCED DIABETES REVERSION IN A MOUSE MODEL OF IMMUNODEPENDENT DIABETES" for which you are listed as co-author, has been sent to the corresponding author. That letter is below. Contributing authors are: Maria Bianchi, Stefania BIanchi, Andrés Hernando-Insúa, Lenadro Martinez, Néstor LAgo, Carlos Libertun, Norma Chasseing, Alejandro MOntaner, and Victoria Lux-Lantos.-----Charles H. Lang, PhDEditor-in-Chief------------------------------------------------------------------------Subject: E-00104-2016R2 Research Article Accepted for Publication7th Jun 2016 Dear Dr. Lux-Lantos: I am pleased to inform you that your manuscript "PROPOSED MECHANISMS FOR OLIGONUCLEOTIDE IMT504 INDUCED DIABETES REVERSION IN A MOUSE MODEL OF IMMUNODEPENDENT DIABETES" (E-00104-2016R2) has been accepted and will be published online as an Article in Press within approximately two weeks, assuming all files are in order. PLEASE NOTE THAT YOUR MANUSCRIPT WILL BE PUBLISHED IN AiPS EXACTLY AS SUBMITTED, INCLUDING SPELLING OF AUTHOR NAMES AS PROVIDED IN THE METADATA OF THE MANUSCRIPT RECORD. Thank you for your continued interest in AJP - Endocrinology and Metabolism and congratulations to you and your colleagues on such an excellent study. Regards,--- Maureen Gannon, PhDAssociate Editor,AJP-Endocrinology and Metabolism.--------------------- Abstract:Type 1 diabetes (T1D) originates from autoimmune beta-cell destruction. IMT504 is an immunomodulatory oligonucleotide that increases mesenchymal stem cells cloning capacity and reverts toxic diabetes in rats. Here we evaluated long-term (20 doses) and short-term (2-6 doses) effects of IMT504 (20 mg/kg/day, sc) in an immunodependent diabetes model: multiple low dose streptozotocin-injected BALB/c mice (40 mg/kg/day, i.p. for 5 consecutive days). We determined blood glucose, glucose tolerance, serum insulin, islet morphology, islet infiltration, serum cytokines, progenitor cell markers, immunomodulatory proteins, proliferation, apoptosis, and islet gene expression. Long-term results: IMT504 reduced glycemia, induced beta-cell recovery and impaired islet infiltration. Short-term analysis: IMT504 induced early blood glucose decrease, infiltration inhibition, increased beta-cell proliferation and decreased apoptosis, increased islet indoleamine 2,3-dioxygenase (IDO) expression, increased serum tumor necrosis factor and interleukin-6 (IL-6). IMT504 affected islet gene expression: Preproinsulin-2, Proglucagon, Somatostatin, Nestin, Regenerating gene-1 and C-X-C motif ligand-1 cytokine (Cxcl1) increased in islets from diabetic mice and were decreased by IMT504. IMT504 downregulated Platelet endothelial cell adhesion molecule-1 (Pecam1) in islets from control and diabetic mice, whereas it increased Regenerating gene-2 (Reg2) in islets of diabetic mice. The IMT504-induced increase in IL-6 and islet IDO expression, and decreased islet Pecam1 and Cxcl1 mRNA expression could participate in keeping leukocyte infiltration at bay, whereas upregulation of Reg2 may mediate beta-cell regeneration. We conclude that IMT504 effectively reversed immunodependent diabetes in mice. Corroboration of these effects in a model of autoimmune diabetes more similar to human T1D could provide promising results for the treatment of this disease.