title: Proposed mechanisms for oligonucleotide IMT504 induced diabetes reversion in a mouse model of immunodependent diabetes.
abstract: Type 1 diabetes (T1D) originates from autoimmune β-cell destruction. IMT504 is an immunomodulatory oligonucleotide that increases mesenchymal stem cell 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(-1)·day(-1) sc) in an immunodependent diabetes model: multiple low-dose streptozotocin-injected BALB/c mice (40 mg·kg(-1)·day(-1) ip 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. IMT504 reduced glycemia, induced β-cell recovery, and impaired islet infiltration. IMT504 induced early blood glucose decrease and infiltration inhibition, increased β-cell proliferation and decreased apoptosis, increased islet indoleamine 2,3-dioxygenase (IDO) expression, and 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 β-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.
authors.affiliation: Instituto de Biología y Medicina Experimental (IBYME-CONICET), Buenos Aires, Argentina;
authors.forename: María S
authors.initials: MS
authors.lastname: Bianchi
authors.affiliation: Instituto de Biología y Medicina Experimental (IBYME-CONICET), Buenos Aires, Argentina;
authors.forename: Stefanía
authors.initials: S
authors.lastname: Bianchi
authors.affiliation: Fundación Pablo Cassará (ICT Milstein-CONICET), Buenos Aires, Argentina; and.
authors.forename: Andrés
authors.initials: A
authors.lastname: Hernado-Insúa
authors.affiliation: Instituto de Biología y Medicina Experimental (IBYME-CONICET), Buenos Aires, Argentina;
authors.forename: Leandro M
authors.initials: LM
authors.lastname: Martinez
authors.affiliation: Facultad de Medicina, Universidad de Buenos Aires. Buenos Aires, Argentina.
authors.forename: Néstor
authors.initials: N
authors.lastname: Lago
authors.affiliation: Instituto de Biología y Medicina Experimental (IBYME-CONICET), Buenos Aires, Argentina; Facultad de Medicina, Universidad de Buenos Aires. Buenos Aires, Argentina.
authors.forename: Carlos
authors.initials: C
authors.lastname: Libertun
authors.affiliation: Instituto de Biología y Medicina Experimental (IBYME-CONICET), Buenos Aires, Argentina;
authors.forename: Norma A
authors.initials: NA
authors.lastname: Chasseing
authors.affiliation: Fundación Pablo Cassará (ICT Milstein-CONICET), Buenos Aires, Argentina; and.
authors.forename: Alejandro D
authors.initials: AD
authors.lastname: Montaner
authors.affiliation: Instituto de Biología y Medicina Experimental (IBYME-CONICET), Buenos Aires, Argentina; vlux@ibyme.conicet.gov.ar.
authors.forename: Victoria A
authors.identifier: 0000-0003-3099-1418
authors.initials: VA
authors.lastname: Lux-Lantos
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001786:Blood Glucose / Q000187:drug effects* / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D054360:Chemokine CXCL1 / Q000187:drug effects / Q000235:genetics; D016207:Cytokines / Q000187:drug effects* / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000378:metabolism*; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D005951:Glucose Tolerance Test; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000187:drug effects / Q000378:metabolism; D007328:Insulin / Q000235:genetics / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051847:Lithostathine / Q000187:drug effects / Q000235:genetics; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D064231:Nestin / Q000187:drug effects / Q000235:genetics; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology*; D000073718:Pancreatitis-Associated Proteins; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000187:drug effects / Q000235:genetics; D052336:Proglucagon / Q000187:drug effects / Q000235:genetics; D011498:Protein Precursors / Q000187:drug effects / Q000235:genetics; D011506:Proteins / Q000187:drug effects / Q000235:genetics; D012333:RNA, Messenger / Q000187:drug effects* / Q000378:metabolism; D013004:Somatostatin / Q000187:drug effects / Q000235:genetics; D013234:Stem Cells / Q000187:drug effects / Q000378:metabolism; D059467:Transcriptome / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D054360:Chemokine CXCL1; C475895:Cxcl1 protein, mouse; D016207:Cytokines; C514285:IMT504; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007328:Insulin; D015850:Interleukin-6; D051847:Lithostathine; C577485:Nes protein, mouse; D064231:Nestin; D009838:Oligodeoxyribonucleotides; D000073718:Pancreatitis-Associated Proteins; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011498:Protein Precursors; D011506:Proteins; D012333:RNA, Messenger; C497615:Reg1 protein, mouse; C490253:Reg3b protein, mouse; D014409:Tumor Necrosis Factor-alpha; C577686:interleukin-6, mouse; D013004:Somatostatin; D052336:Proglucagon; C013737:preproinsulin
keywords: insulitis; islet gene expression; serum cytokines; β-cells