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Buenos Aires, Argentina

Rodriguez J.M.,Fundacion Pablo Cassara | Marchicio J.,Immunotech S.A. | Lopez M.,Immunotech S.A. | Ziblat A.,Immunotech S.A. | And 6 more authors.

CD56+ cells have been recognized as being involved in bridging the innate and acquired immune systems. Herein, we assessed the effect of two major classes of immunostimulatory oligonucleotides (ODNs), PyNTTTTGT and CpG, on CD56+ cells. Incubation of human peripheral blood mononuclear cells (hPBMC) with some of these ODNs led to secretion of significant amounts of interferon gamma (IFN-γ), tumor necrosis factor alpha (TNF-α) and granulocyte/monocyte colony-stimulating factor (GM-CSF), but only if interleukin 2 (IL2) was present. IMT504, the prototype of the PyNTTTTGT ODN class, was the most active. GM-CSF secretion was very efficient when non-CpG ODNs with high T content and PyNTTTTGT motifs lacking CpGs were used. On the other hand, CpG ODNs and IFNα inhibited this GM-CSF secretion. Selective cell type removal from hPBMC indicated that CD56+ cells were responsible for GM-CSF secretion and that plasmacytoid dendritic cells (PDCs) regulate this process. In addition, PyNTTTTGT ODNs inhibited the IFNα secretion induced by CpG ODNs in PDCs by interference with the TLR9 signaling pathway. Since IFNα is essential for CD56+ stimulation by CpG ODNs, there is a reciprocal interference of CpG and PyNTTTTGT ODNs when acting on this cell population. This suggests that these synthetic ODNs mimic different natural alarm signals for activation of the immune system. © 2015 Rodriguez et al. Source

Sanchez G.,National University of Rosario | Sanchez G.,Instituto Nacional de Tecnologia Agropecuaria | Gerhardt N.,National University of Rosario | Siciliano F.,National University of Rosario | And 3 more authors.
Molecular Plant-Microbe Interactions

To evaluate the role of salicylic acid (SA) in Nb -mediated hypersensitive resistance to Potato virus X (PVX) avirulent strain ROTH1 in Solanum tuberosum, we have constructed SA-deficient transgenic potato plant lines by overexpress-ing the bacterial enzyme salicylate hydroxylase (NahG), which degrades SA. Evaluation of these transgenic lines revealed hydrogen peroxide accumulation and spontaneous lesion formation in an age- and light-dependent manner. In concordance, NahG potato plants were more sensitive to treatment with methyl viologen, a reactive oxygen species-generating compound. In addition, when challenged with PVX ROTH1, NahG transgenic lines showed a decreased disease-resistance response to infection and were unable to induce systemic acquired resistance. However, the aviru-lent viral effector, the PVX 25-kDa protein, does induce expression of the pathogenesis-related gene PR-la in NahG potato plants. Taken together, our data indicate that SA is involved in local and systemic defense responses mediated by the Nb gene in Solanum tuberosum. This is the first report to show that basal levels of SA correlate with hyper-sensitive resistance to PVX. © 2010 The American Phytopathological Society. Source

Franco R.,Immunotech S.A. | Rodriguez J.M.,Fundacion Pablo Cassara | Elias F.,Immunotech S.A. | Hernando-Insua A.,Fundacion Pablo Cassara | And 6 more authors.
Nucleic Acid Therapeutics

IMT504 is a non-CpG 24-mer oligodeoxynucleotide (ODN) with immunomodulatory as well as tissue repair activity. IMT504 has been previously proven to be effective in animal models of vaccine potency, chronic lymphocytic leukemia, tissue regeneration, and sepsis. Here, we assessed the safety, including pharmacokinetics and toxicity studies in rats and monkeys, of IMT504 in a single- or repeated-dose administration by the subcutaneous (SC) or intravenous (IV) routes. In rats, the maximum tolerated dose was determined to be 50mg/kg when administered SC. Adverse effects at 50mg/kg were mild and reversible liver injury, revealed as lobular inflammation, focal necrosis, and small changes in the transaminase profile. Dose-dependent splenomegaly and lymphoid hyperplasia, most probably associated with immune stimulation, were commonly observed. Rats and monkeys were also IV injected with a single dose of 10 or 3.5mg/kg, and no adverse effects were observed. Rats injected IV with 10mg/kg showed a transient increase in spleen weight, together with a slight increase in the marginal zone of the white pulp and in leukocyte count 2 days post-administration. In monkeys, this dosage caused slight changes in total serum complement and leukocyte count on day 14. No adverse effects were observed at 3.5mg/kg IV in rats or monkeys. Therefore, this dose was defined as the "no observed adverse effect level" for this route. Furthermore, repeated-dose toxicity studies were performed in these species using 3.5 or 0.35mg/kg/day IV for 6 weeks. A transient increase in the spleen and liver weight was observed at 3.5mg/kg/day only in female rats. No changes in clotting time and activation of the alternative complement pathway were observed. The toxicity profile of IMT504 herein reported suggests a dose range in which IMT504 can be used safely in clinical trials. © Mary Ann Liebert, Inc. 2014. Source

Montaner A.D.,CONICET | Denichilo A.,Fundacion Pablo Cassara | Rodriguez J.M.,Fundacion Pablo Cassara | Flo J.,Immunotech S.A. | And 7 more authors.
Nucleic Acid Therapeutics

Flu vaccines are partially protective in infants and elder people. New adjuvants such as immunostimulatory oligonucleotides (ODNs) are strong candidates to solve this problem, because a combination with several antigens has demonstrated effectiveness. Here, we report that IMT504, the prototype of a major class of immunostimulatory ODNs, is a potent adjuvant of the influenza vaccine in young adult and elderly rats. Flu vaccines that use virosomes or whole viral particles as antigens were combined with IMT504 and injected in rats. Young adult and elderly animals vaccinated with IMT504-adjuvated preparations reached antibody titers 20-fold and 15-fold higher than controls, respectively. Antibody titers remained high throughout a 120 day-period. Animals injected with the IMT504-adjuvated vaccine showed expansion of the anti-hemagglutinin antibody repertoire and a significant increase in the antibody titer with hemagglutination inhibition capacity when confronted to viral strains included or not in the vaccine. This indicates that the addition of IMT504 in flu vaccines may contribute to the development of significant cross-protective immune response against shifted or drifted flu strains. © 2011 Mary Ann Liebert, Inc. Source

Bianchi M.S.,CONICET | Hernando-Insua A.,Immunotech | Chasseing N.A.,CONICET | Rodriguez J.M.,Fundacion Pablo Cassara | And 6 more authors.

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., day∈1) 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 day∈30. On day∈35, 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 day∈8, as well as IPGTTs on day∈30. 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. © 2010 Springer-Verlag. Source

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