Variability Among Macaca Fascicularis In The Innate Immune Response To Toll-Like Receptor 4 (Tlr4) Agonists

Despite being highly conserved, variability exists in the innate immune response to microbial pathogens. In man, individuals with distinct phenotypes are identified as high and low responders to TLR4 agonists. Whether similar variability exists among Macaca fascicularis is not known. Whole blood collected from 45 Indonesian‐origin monkeys was treated ex vivo with lipopolysaccharide (LPS) from Yersinia Pestis (YP), Pseudomonas aeruginosa, Salmonella minnesota, and Escherichia coli. Cytokines were measured at 4 h and the data organized in rank order ‐ lowest (1) to highest (45) ‐ for each cytokine and each TLR4 agonist. We identified high responders that consistently ranked in the top 20th percentile and low responders that consistently ranked in the bottom 20th percentile across all cytokines. In the entire group, cytokine production in response to TLR agonists varied by 10–100 fold. The range for TNFα in whole blood treated with YP LPS was 328 to 9,932 pg/ml. The high responders had 10‐fold more TNFα in plasma (5,300 +/−680 pg/ml) than low responders (520 +/−61 pg/ml) (p<0.0001). Similarly, high and low responders were identified for other TLR4 agonists and cytokines. These findings suggest that significantly different innate immune response phenotypes exist among M. fascicularis. Such variability may influence outcomes in studies of the systemic inflammatory response syndrome, sepsis, or vaccine trails.