The Novel Immunotherapeutic Oligodeoxynucleotide IMT504 Protects Neutropenic Animals from Fatal Pseudomonas aeruginosa Bacteremia and Sepsis

Abstract

dIMT504 is a novel immunomodulatory oligonucleotide that has shown immunotherapeutic properties in early preclinical and clinical studies. IMT504 was tested in a neutropenic rat model of Pseudomonas aeruginosa bacteremia and sepsis. This animal system recapitulates many of the pathological processes found in neutropenic patients with Gram-negative, bacterial infections. The research was conducted in the setting of an academic research laboratory. The test subjects were Sprague-Dawley rats. Animals were rendered neutropenic by administration of cyclophosphamide, colonized with P. aeruginosa by oral feeding, and then randomized to receive IMT504 over a range of doses and treatment regimens representing early and late therapeutic interventions. IMT504 immunotherapy conferred a significant survival advantage over the 12-day study period compared with the results seen with placebo-treated animals when the therapy was administered at the onset of neutropenia and even in the absence of antibiotics and after the onset of fever and systemic infection. Notably, even late salvage IMT504 monotherapy was highly effective (13/14 surviving rats with IMT504 therapy versus 2/14 controls, P ‫؍‬ <0.001). Moreover, late salvage IMT504 monotherapy was as effective as antibiotic therapy (13/14 surviving rats versus 21/21 rats, P ‫؍‬ 0.88). In addition, no antagonism or loss of therapeutic efficacy was noted with combination therapy of IMT504 plus antibiotics. IMT504 immunotherapy provides a remarkable survival advantage in bacteremia and sepsis in neutropenic animals and deserves further study as a new treatment option in patients with, or at risk for, severe Gram-negative bacterial infections and sepsis. Bacteremia and sepsis remain a major cause of morbidity and mortality and a central challenge to the management of critically ill patients worldwide. Despite a considerable amount of time and effort, no new therapy for severe sepsis has proven useful other than early resuscitation with intravenous fluids, the use of vasopressors, administration of broad-spectrum antibiotics, and expert supportive care (1). Early administration of effective antibiotics has consistently proven to be critical to survival in septic shock, along with attempts to maintain tissue perfusion by intravenous fluid resuscitation (2). However, specific efforts to disrupt the underlying immunopathogenic mechanisms that cause sepsis have not proven to be of significant survival benefit. Most of these interventions have consisted of inhibitors of proinflammatory mediators and procoagulant strategies, which have failed in clinical testing (3-9).A looming crisis in the treatment of bacterial infections in general, and of infections by Gram-negative bacteria in particular, is the progressive spread of antibiotic resistance genes leading to the emergence of multiply drug-resistant (MDR) microbial pathogens (10). While MDR Pseudomonas spp. have always been a significant problem due to intrinsic antimicrobial resistance, other genera of Gram-negative bacteria are now com...

Innate and Adaptive Immune Responses against Bordetella pertussis and Pseudomonas aeruginosa in a Murine Model of Mucosal Vaccination against Respiratory Infection

“…Neutrophils in particular have been recognized within the field as important players for both the clearance of P. aeruginosa , and also for lung-pathologies associated with exacerbated responses [ 60 , 61 , 62 , 63 ]. In various animal models, P. aeruginosa infection in neutropenic animals is lethal [ 63 , 64 , 65 ]. Neutrophils can kill pathogens by phagocytosis and secretion of neutrophil extracellular traps (NETs) that trap pathogens.…”

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

“…Interestingly, IMT504 stimulated CD56ϩ NKT cells that have been postulated to convey peripheral tolerance and protection against autoimmune diabetes (30). IMT504 also promoted marked improvement in rat models of bone injury (22), neuropathic pain (7), and sepsis (5). Regarding diabetes, streptozotocin-induced toxic diabetes in rats was reversed by IMT504, improving glycemia, increasing islet number, ␤-cell content, ␤-cell proliferation, and early expression of pancreatic progenitor markers (3).…”

Pseudomonas aeruginosa: Infections, Animal Modeling, and Therapeutics

“…), or tail vein injections have been used as technical means to cause systemic infection with P. aeruginosa [172][173][174]. P. aeruginosa has also been delivered retro-orbitally to cause systemic infection and sepsis [175]. P. aeruginosa systemic infection has been shown to increase pro-inflammatory cytokines both in the blood and tissues, leading to other morbidities such as septic arthritis and gallbladder damage [172,176,177].…”