Macrophage Activation by Liposomal Lipid A: Implications for Vaccines

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Abstract
Introduction Vaccine technology has fostered many promising immunologic strategies for disease prevention, especially vaccination with synthetic peptides and recombinant proteins. Such products, even if considered good candidates for vaccines, are often incomplete in that they may require the 'help' of an adjuvant to become immunogenic (1). However, an immunologist considering peptide epitopes for immunization, must in tandem carefully reflect on how the adjuvant directs the immune response. In our experience, while the expected response to an antigen has often been extensively characterized, less attention is given to adjuvant-immune system interactions beyond the desire to enhance the immune response. This is in part due to the lag in studies focusing on adjuvant-immune system interactions when compared to the immunizing antigens themselves, although the study of adjuvants has begun to receive increasing attention. The adjuvant effect on the immune response can be the determining factor in terms of the effector arm of the immune system recruited (e.g., cytoxoxic T lymphocytes, particular IgG subclass antibodies, etc.) (2-4). Our laboratory has had a long-standing interest in the immune response to liposomal antigens, beginning with phospholipid antibodies (5). This interest has grown and our laboratories are currently participating in several vaccine trials in humans (6-9). This is in large part due to the effectiveness of liposomes containing lipid A in inducing strong antibody and cytotoxic lymphocyte responses to antigens, coupled with minimal or no adverse reactions (6, 10). Our understanding of the mechanisms by which liposomes containing lipid A exert such adjuvant effects is incomplete but is rapidly growing. This review endeavors to highlight some of the known interactions between liposomes containing lipid A and the macrophage that might be of interest to the vaccinologisl, with a particular focus on macrophage activation and the mechanisms by which liposomes containing lipid A cause this to occur.