Endotoxic lipopolysaccharides are one of the most potent adjuvants known to immunologists. Their use in human vaccine has been precluded by their profound toxicity. However, recently a monophosphoryl lipid A (MPL) was fractionated from bacterial cell walls which was shown by multiple parameters to be non- toxic in animals. In addition phase I trails for toxicity in human beings have been passed successfully. Of importance, the MPL retained the capacity of native endotoxin to enhance antibody formation. During the tenure of this proposed grant it is hoped to determine the cellular and molecular mediator of the adjuvant action of MPL. Two model systems will be studied: one, a model of immunodeficiency, the aging mouse, in which the MPL effectively restores the response; and a second, the C3H/HeJ mouse, which does not respond to the adjuvant action of the native endotoxin, but can be stimulated readily by the MPL. To accomplish this, macrophage, T cell and B cell populations will be isolated from the aging and C3H/HeJ mice, exposed to MPL and added in vitro to spleen cells from the normally poorly responding aging mouse, or the C3H/HeJ strain, from which the MPL stimulated population has been deleted. When as MPL treated cell has been show to increase the response of the cell culture system, this cell's ability to secrete an MPL induced supernatant fluid to mediate the enhanced response will be tested. Characterization of any active fluid with respect to known cytokines is proposed. The long range goal of this study is to understand the mode of action of MPL to ensure intelligent use of this important, practical candidate for enhancement of the immune response in human beings to future weakly antigenic vaccines.
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