Mas-Coma S, Valero MA, Bargues MD

Mas-Coma S, Valero MA, Bargues MD. macaques by intravenous (i.v.) infusion with lethal doses of live exerts on the health of animals and humans, contamination with this parasite cannot be used to treat inflammatory CENP-31 diseases in humans. Additionally, the immune regulation associated with contamination lacks specificity and results in a compromised immune system unable to Nadolol respond effectively to bystander infections (13, 14). We consider it more judicious to identify and purify defined immune-modulatory molecules produced by the parasite, which have the potential for drug development, and to characterize their precise mechanism of action. Owing to its remarkable capabilities to modulate the host immune system, constitutes an enormous pharmacopeia. As soon as the parasite invades the gut wall, it Nadolol initiates a complex interaction with various host immune cells (e.g., macrophages or dendritic cells). The parasite secretes a myriad of immunomodulatory molecules termed excretory-secretory products (ESPs) that direct the host immune response toward a nonprotective Th2/Treg environment with suppressed Th1 immunity, which allows the parasite to persist in the host for a long period of time (15,C18). Proteomic studies demonstrate that one of these molecules belong to the fatty acid binding protein family (FABP). FABPs are highly abundant either in the surface or in the internal compartments of the adult parasite (19, 20). FABPs are known antioxidant molecules (21) that have been used extensively as Nadolol vaccine candidates against fascioliasis or Nadolol schistosomiasis (22,C24). In a previous study, we demonstrated that a single therapeutic dose of recombinant FABP (Fh15; 50?g) given to mice 1 h after exposure to a lethal lipopolysaccharide (LPS) dose challenge significantly suppressed the cytokine storm by concurrently modulating the dynamics of macrophages in the peritoneal cavity and the activation status of spleen macrophages in a mouse model of septic shock (25). Since nonhuman primates (NHPs) and humans originated from a common phylogenetic ancestor, they share comparable physiological and anatomical features and display a similar cytokine response to intravenous (i.v.) endotoxin and live bacteria (26). Moreover, their large size allows for invasive monitoring, tissue collection, and serial phlebotomy (27). Thus, NHPs represent a more relevant preclinical model than the rodent model to study the inflammatory responses during the acute phase of sepsis. With these advantages in mind, in a previous study, we developed a rhesus macaque model of septic shock induced by intravenous administration of live to identify inflammation-associated markers during the early phase of sepsis in rhesus macaques (28). As a result of that study, we were able to determine that bacteremia was present in all animals from 30 minutes to 4 hours following infusion, whereas endotoxin, C-reactive protein (CRP), and Procalcitonin (PCT) were detected during the full time course suggesting an ongoing inflammatory process caused by an active bacterial infection. Similarly, tumor necrosis factor alpha (TNF-) was detected at 2 h, whereas interleukin-6 (IL\6), IL\12, and interferon gamma (IFN-) were detected after 4 h of infusion (28). The present study is usually a proof of concept to assess whether these inflammatory markers can be suppressed when a single low dose of Fh15 is usually administered i.v. as an isotonic infusion 30?min before a challenge with a live infusion. Knowing that Fh15 is usually a protein molecule and its development as a drug could be hampered due to limited half-life and immunogenicity (capacity to induce the formation of anti-Fh15 antibodies), the present study also aimed to determine the duration of Fh15 in circulation as well as to determine whether its immunogenicity could hamper the anti-inflammatory effect. The present study is the first to demonstrate that although the half-life of Fh15 in circulation is usually short, it is able to significantly suppress bacteremia, endotoxemia, CRP, and PCT during the early phase of an infection were euthanized at 8 h of experimentation. At the conclusion of the experiment, the physiological parameters were comparable or slightly higher than the baseline for most of animals (see Table S2 in the supplemental material). For experimental reasons explained in the Materials and Methods section, monkeys in the Fh15 group were allowed to recover after 8 h. Therefore, it was not possible to determine by postmortem examination whether the Fh15 dose administered induced any gross type of toxicity. However, the physiological parameters of these animals remained at normal values during the entire time course of the experiment, and after recovering and returning to their respective cages, they remained healthy for.