A new immunomodulator with potential clinical applications: Monophosphoryl lipid A, a detoxified endotoxin

Abstract

I m m u n o s t i m u l a t o r y Ef fec t s of E n d o t o x i n Endotoxin is an extraordinary bacterial product because of its ability to stimulate a multitude of biologic responses in animals and in humans (3). It is isolated from the outer layer of the outer membrane of Gram-negative bacteria, (e.g., Escherichia coli), which are part of the natural intestinal flora in mammals. Endotoxin is a macromolecule composed of three regions differing in their chemical and biologic properties. The O-specific polysaccharide carries the main serologic specificity of bacteria; and is linked to a core polysaccharide common to groups of Gram-negative bacteria. This core is linked through tile 2-keto-3-deoxyoctonates to a lipid component termed lipid A, which is responsible for most of the biologic activities of endotoxin. Endotoxin is known to have numerous beneficial effects in experimental animals (3), including stimulation of lymphokine production, protection against X-radiation, enhancement of nonspecific resistance to infection, and induction of antitumor effects. In its native form, however, endotoxin cannot be used clinically because of extreme toxicity in humans, which is directly attributable to the lipid A portion of the molecule. Many investigators have explored the possibility of using various chemical methods to selectively reduce the toxicity of endotoxin, while retaining the beneficial biologic activities (8). In general, these efforts have been unsuccessful. Recently, however, a simple method of preparing nontoxic lipid A from endotoxin has been de= veloped, which has led to a better understanding of the structural relationship between lipid A and its biologic properties (4-7 , 10, 12). Detoxification of lipid A is achieved by acid hydrolysis, which removes one of the molecule's two phosphate groups. The development and optimization of this approach was closely tied to the introduction of improved physical-chemical means of separating and purifying the individual components of toxic and nontoxic lipid A from complex mixtures of naturally: occurring structural homologs. The structures of the single components could then be determined by a variety of modem spectroscopic techniques; in turn, this allowed the various structural features of the toxic and nontoxic forms of lipid A to be correlated with the observed biologic and chemical properties. This review summarizes the results of these studies. In Thi s I ssue