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

Abstract

Ϫ1 ·day Ϫ1 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 ␤-cell recovery, and impaired islet infiltration. IMT504 induced early blood glucose decrease and infiltration inhibition, increased ␤-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 ␤-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.

IMT504 protects beta cells against apoptosis and maintains beta cell identity, without modifying proliferation

“…In vivo studies in T1D diabetes models suggested that IMT504 induced active proliferation, mainly in β‐cells (Bianchi et al, 2010 , 2016 ). Subsequently, we determined the effect of IMT504 on MIN6B1 proliferation.…”

“…With this in mind, and since IMT504 has both immunomodulatory and regenerative properties, our group started to evaluate this ODN as a possible therapy for T1D in several animal models, finding very promising results in terms of beta cell recovery, improvement on glucose and insulin blood levels, and decrease in beta cell apoptosis, and insulitis and infiltration of CD45+ leukocytes into the pancreas (Bianchi et al, 2010(Bianchi et al, , 2012(Bianchi et al, , 2016(Bianchi et al, , 2021. Nevertheless, these in vivo experiments did not hint to a possible direct effect of IMT504 on βcells.…”

“…IMT504 promoted marked improvement in rat models of bone injury (Hernando et al, 2007), neuropathic pain (Coronel et al, 2008), and sepsis (Chahin et al, 2015). Regarding diabetes, we have previously demonstrated that IMT504 promotes significant improvement in the diabetic condition in various animal models: For example, induction of βcell recovery, inhibition of leukocyte infiltration into the islet, improvement on glucose and insulin blood levels, decrease in apoptosis, and insulitis and infiltration of CD45+ leukocytes into the pancreas (Bianchi et al, 2010(Bianchi et al, , 2012(Bianchi et al, , 2016(Bianchi et al, , 2021. TLR-9 is the receptor that recognizes DNA oligonucleotides from the CpG ODN class.…”

“…Thus, therapeutic approaches designed to regulate apoptosis could be a significant new development in the management of diabetes. Bianchi et al demonstrated that in diabetic animals the immunomodulatory ODN IMT504 induced a decrease in βcell apoptosis (Bianchi et al, 2016(Bianchi et al, , 2021.…”

“…Two classes of ODNs have been identified, CpG (Krug et al, 2001 ) and non‐CpG ODNs. Our group has identified a class of non‐CpG ODN, being IMT504 the prototype of this class (Bianchi et al, 2016 ). IMT504 promoted marked improvement in rat models of bone injury (Hernando et al, 2007 ), neuropathic pain (Coronel et al, 2008 ), and sepsis (Chahin et al, 2015 ).…”