Comment on Hurley, J.C. Towards clinical application of anti-endotoxin antibodies; a re-appraisal of the disconnect. Toxins 2013, 5, 2589-2620.

I have read with interest James C. Hurley’s very good review [1]. I totally agree that a reappraisal of the use of anti-endotoxin antibodies in Gram negative infections is warranted. In a study [2] we showed the possible association between endotoxin (LPS) and morbidity and mortality in septic shock. This was a study in healthy primates (vervet monkeys). We found, when these anesthetized primates received an LD100 iv infusion of Echerichia coli (E. coli) over one hour, both E. coli and endotoxin concentration significantly increased during the E. coli infusion. The anti-endotoxin (anti-LPS) on the other hand decreased significantly. Interestingly, when the animals succumbed, their LPS concentration was still raised, but there were no viable E. coli. There was also only a small amount of anti-LPS present. Hence, endotoxin concentration rather than circulating E. coli bacteria may be an important pathogen responsible for the high mortality experienced during E. coli shock. This is in agreement with Spink et al. [3] and now Hurley [1] who suggested that endotoxin which forms an integral part of the outer cellular membrane of gram negative bacteria (GNB) participates in the genesis of shock.

In our review [4] and some of the other papers we published in this field [5,6,7,8,9], we refer to successful preliminary studies using anti-lipopolysaccharide IgG (anti-LPS). The anti-LPS both present prior to the insult or given after the insult, would seem to inactivate plasma endotoxins and combat Gram-negative bacteria in sepsis. Thereby, as Hurley [1] suggests, may form part of a possible new form of therapy.

The question that needs to be addressed is: how best to accomplice this? What part of the endotoxin should be attacked, the O-specific chain or the smaller Lipid-A, or even, if possible, both?