IMT504, the Prototype of the Immunostimulatory Oligonucleotides of the PyNTTTTGT Class, Increases the Number of Progenitors of Mesenchymal Stem Cells Both In Vitro and In Vivo: Potential Use in Tissue Repair Therapy

Insúa, Andrés Hernando; Montaner, Alejandro D.; Rodríguez, Juan Manuel; Elı́as, Fernanda; Fló, Juan; López, Ricardo; Zorzopulos, Jorge; Hofer, Erica Leonor; Chasseing, Norma Alejandra

doi:10.1634/stemcells.2006-0479

Cited by 22 publications

(37 citation statements)

References 43 publications

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“…IMT504 (Oligos Etc., Wilsonville, OR, USA) was treated as described [5], its sequence being 5′-TCATCATTTTGT CATTTTGTCATT-3′.…”

Section: Methodsmentioning

confidence: 99%

“…Whereas CpG ODNs have been evaluated in autoimmune diseases [1], no data are available regarding IMT504. Interestingly, while IMT504 is a potent stimulator of mesenchymal stem cells (MSCs), CpG ODNs are not [5]. We have shown that IMT504 is useful for tissue repair in a bone injury model [5], presumably through expansion of the MSC pool and/or modifications in the immunochemical microenvironment at the site of damage.…”

Section: Introductionmentioning

confidence: 99%

“…Interestingly, while IMT504 is a potent stimulator of mesenchymal stem cells (MSCs), CpG ODNs are not [5]. We have shown that IMT504 is useful for tissue repair in a bone injury model [5], presumably through expansion of the MSC pool and/or modifications in the immunochemical microenvironment at the site of damage. These results prompted us to investigate the effects of IMT504 on glucose homeostasis and pancreatic progenitor cell markers (PPCMs) in a streptozotocin (STZ)-induced model of diabetes in the rat.…”

Section: Introductionmentioning

confidence: 99%

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Oligodeoxynucleotide IMT504 induces a marked recovery in a streptozotocin-induced model of diabetes in rats: correlation with an early increase in the expression of nestin and neurogenin 3 progenitor cell markers

Bianchi

Hernando-Insúa²,

Chasseing

et al. 2010

Diabetologia

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Aims/hypothesis IMT504 is an oligonucleotide that promotes tissue repair in bone injury and neuropathic pain models by stimulating progenitor cells. Here we evaluated the effect of IMT504 on the recovery of islet function in a streptozotocin (STZ)-induced model of diabetes in the rat. Methods Male Sprague-Dawley rats were injected with STZ (60 mg/kg, i.p., day1) or citrate buffer (Control). Animals with glycaemia between 11 and 20 mmol/l on day 4 were injected with IMT504 (4 mg/animal in saline, s.c., STZ-IMT504) or with saline (STZ-Saline) for 10 days. Glycaemia and water and food intake were recorded for 33 days. Intraperitoneal glucose tolerance tests (IPGTTs) were performed on day30. On day35, overnight-fasted animals were killed and blood samples and pancreases collected for hormonal and histological studies. A second group of STZ-IMT504 rats was killed, together with Control and STZ-Saline rats, after two consecutive days of blood glucose decreases after the beginning of IMT504 treatment. Pancreases were collected and proliferating cell nuclear antigen (PCNA), nestin and neurogenin 3 (NGN3) detected by immunohistochemistry. Results IMT504 greatly improved blood glucose and food and water intakes in STZ-IMT504 rats by day8, as well as IPGTTs on day30. Significant increases in islet number and beta cell content were observed in STZ-IMT504 rats (day 33). Furthermore, after two to five IMT504 injections, blood glucose decreased, and an increase in pancreatic nestin (mainly in endothelial cells), PCNA and NGN3 production (in islets) was observed in STZ-IMT504 rats. Conclusions/interpretation IMT504 induced a marked recovery of STZ-induced diabetes that correlated with early production of progenitor cell markers, such as nestin and NGN3.

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“…IMT504 (Oligos Etc., Wilsonville, OR, USA) was treated as described [5], its sequence being 5′-TCATCATTTTGT CATTTTGTCATT-3′.…”

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Oligodeoxynucleotide IMT504 induces a marked recovery in a streptozotocin-induced model of diabetes in rats: correlation with an early increase in the expression of nestin and neurogenin 3 progenitor cell markers

Bianchi

Hernando-Insúa²,

Chasseing

et al. 2010

Diabetologia

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“…However, phosphorothioate (PS) CpG ODNs induce the secretion of IFN alpha [8], while PS PyNTTTTGT ODNs do not [9], and PyNTTTTGT ODNs induce the release of GM-CSF acting on human NK and NKT cells in the presence of IL-2, while CpG ODNs do not (our unpublished data). Furthermore, PyNTTTTGT ODNs stimulate in vitro and in vivo the expansion of mesenchymal stem cell precursors while CpG ODNs do not [10]. Here, we report that IMT504, the prototype of the PyNTTTTGT class, provides a highly significant survival advantage after a lethal rabies challenge in a rat model, even with large dilutions of the rabies vaccine.…”

Section: Introductionmentioning

confidence: 85%

“…Titers of anti-rabies glycoprotein antibodies have been reported to have a reasonable correlation with the titers of serum neutralizing antibodies measured by the rapid fluorescent focus inhibition test (RFFIT), which is currently accepted as the gold standard technique [13][14][15]. Table 1 shows that after the second injection, all of the individuals in the IMT504 group reached protective levels (>0.5 IU/ml) as defined by the WHO [3][4][5][6][7][8][9][10][11][12][13][14][15][16]. Notably, four out of five reached levels 60 -90 times higher than the required protective level after the third dose.…”

Section: Immunization Of Human Volunteers With Vero Cell Rabies Vaccimentioning

confidence: 99%

IMT504: A New and Potent Adjuvant for Rabies Vaccines Permitting Significant Dose Sparing

Montaner¹,

Nichilo²,

Rodríguez³

et al. 2012

WJV

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Background: Rabies virus infection causes encephalitis, which is almost always fatal. Vaccination can be extremely effective at preventing disease but is prohibitively costly. Vaccine formulations allowing dose-sparing and fewer inoculations with faster antibody response would be extremely desirable. IMT504, an immunostimulatory non-CpG oligodeoxynucleotide, is a highly potent vaccine adjuvant. Methods: Human and rat antibody measurements, and rat challenge studies were performed. Results: In rats, highly effective immune responses with IMT504 were observed even after diluting vaccine up to 1/625. In highly lethal, live intracerebral rabies challenge studies, protection occurred even with extremely dilute vaccine plus IMT504. In humans, antibody titers developed faster and were significantly higher with IMT504-adjuvanted diluted vaccine vs non-adjuvanted vaccine (full strength or diluted). All five administered IMT504-adjuvanted diluted vaccine reached protective antibodies (≥0.5 IU/ml) after the second injection. After the third injection, individuals receiving IMT504-adjuvanted diluted vaccine reached levels approximately 10 times higher than controls (M ± SEM: 31.0 ± 10.9 vs 3.40 ± 0.99 IU/ml). Conclusions: These data suggest that IMT504 may allow fewer inoculations, highly significant dose-sparing of vaccine, rapid antibody production and protection from rabies. Extensive clinical studies are necessary to confirm if the use of IMT504 will permit significantly greater access to highly effective life-saving rabies vaccines.

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DNA‐Based Biomaterials for Immunoengineering

Maeda

Kojima

Song

et al. 2018

Adv Healthcare Materials

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of extracellular DNA in tissues and in circulation. [5] Extracellular DNA is capable of engaging with the immune system as depicted in Figure 1; therefore, as synthetic DNA-based biomaterials emerge, their potential immune responses must be considered. DNA sensors are mediators of extracellular DNA immune responses observed in vivo, including cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) and toll-like receptors (TLRs). Defining novel DNA sensors and their mechanisms is an active area of investigation. [6] Likewise, the structural and chemical properties of DNA that triggers DNA sensors continue to be uncovered. [6] This review summarizes known DNA interaction modalities with the immune system, the sources of extracellular DNA, and, finally, the relevant and emerging biotechnologies that incorporate DNA molecules. A focus is geared toward innate immune responses and doublestranded DNA (dsDNA). Leveraging the immunomodulatory capacity of DNA enables tailoring materials to initiate specific immune outcomes depending on the application, for instance, priming aggressive immune responses for localized tumor-interfacing biomaterials or immunosuppressive functions to prevent chronic inflammation on implant surfaces. Achieving this requires an improved understanding of the DNA properties, such as backbone chemistry, base pair sequence, charge, and length, that can function as design levers for the immune response. The Role of Extracellular DNA in the Immune ResponseThe immune system is designed to protect the host against infections by distinguishing between self-and non-self motifs, and by identifying pathogen and damage signals. Upon recognition of a "non-self" or foreign molecule, an array of effector functions are triggered and orchestrated by immune cells to achieve pathogen clearance and restore homeostasis. [7] These immunoactivating defense mechanisms include the release of proinflammatory cytokines, immune cell recruitment, programmed cell death, and phagocytosis. Ideally, immunoactivating responses are supplanted by immunosuppressive functions once the pathogen or agonist is resolved. This immune resolution is necessary to coordinate healing and anti-inflammatory functions such as diminished chemokine and cytokine secretion, replacement Man-made DNA materials hold the potential to modulate specific immune pathways toward immunoactivating or immunosuppressive cascades. DNAbased biomaterials introduce DNA into the extracellular environment during implantation or delivery, and subsequently intracellularly upon phagocytosis or degradation of the material. Therefore, the immunogenic functionality of biological and synthetic extracellular DNA should be considered to achieve desired immune responses. In vivo, extracellular DNA from both endogenous and exogenous sources holds immunoactivating functions which can be traced back to the molecular features of DNA, such as sequence and length. Extracellular DNA is recognized as damage-associated molecular patterns (DAMPs), or pathogen-associated mole...

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IMT504, the Prototype of the Immunostimulatory Oligonucleotides of the PyNTTTTGT Class, Increases the Number of Progenitors of Mesenchymal Stem Cells Both In Vitro and In Vivo: Potential Use in Tissue Repair Therapy

Abstract: ABSTRACT

Cited by 22 publications

References 43 publications

Oligodeoxynucleotide IMT504 induces a marked recovery in a streptozotocin-induced model of diabetes in rats: correlation with an early increase in the expression of nestin and neurogenin 3 progenitor cell markers

Oligodeoxynucleotide IMT504 induces a marked recovery in a streptozotocin-induced model of diabetes in rats: correlation with an early increase in the expression of nestin and neurogenin 3 progenitor cell markers

IMT504: A New and Potent Adjuvant for Rabies Vaccines Permitting Significant Dose Sparing

DNA‐Based Biomaterials for Immunoengineering

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