MODULATION OF INNATE IMMUNE RESPONSES WITH SYNTHETIC LIPID A DERIVATIVES

University Of Georgia, Athens GA

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Abstract

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Evidence is emerging that innate immune responses can be exploited for therapeutic purposes such as the development of adjuvants for vaccines and the treatment of a wide range of diseases including asthma, infection, and cancer. An important concern of such therapies is, however, that over-activation of innate immunity may lead to the clinical symptoms of septic shock. Thus, an important issue for the design of safe immune modulators is a detailed knowledge of structure-activity relationships to harness beneficial effects without causing toxicity. Lipopolysaccharides (LPS) are structural components of the outer membrane of Gram-negative bacteria that offer great promise for the development of immuno-modulators. It has been demonstrated unequivocally that lipid A is the inflammation-inducing moiety of LPS. Recent structural studies have shown that the carbohydrate backbone, degree of phosphorylation, and fatty acid acylation patterns of lipid A vary considerably among bacterial species. These structural differences probably account for the highly variable in vivo and in vitro host responses to LPS. There is also some indication that structurally different lipid As may differentially induce proinflammatory responses. Heterogeneity in the structure of lipid A within a particular bacterial strain and possible contamination with other inflammatory components of the bacterial cell-wall complicates the use of either LPS or lipid A isolated from bacteria to dissect the molecular mechanisms responsible for the biological responses to specific lipid A molecules.