Alving C R
Department of Membrane Biochemistry, Walter Reed Army Institute of Research, Washington, DC.
Immunobiology. 1993 Apr;187(3-5):430-46. doi: 10.1016/S0171-2985(11)80355-4.
Numerous studies have demonstrated that most or all of the potent adjuvant activity of Gram-negative bacterial endotoxin resides in the lipid A moiety of lipopolysaccharide (LPS). Synthetic analogues of lipid A have provided insights into structure-activity relationships. Several cellular mechanisms of LPS and lipid A adjuvant activities have been identified. Activation of macrophages by LPS or lipid A results in cytokine secretions that enhance the immune response. LPS and lipid A cause recruitment of antigen-presenting cells, particularly macrophages. Liposomes containing lipid A serve as an in vivo adjuvant to recruit increased numbers of macrophages. Liposomal lipid A that has been phagocytized by cultured macrophages also serves as an "intracellular adjuvant" to cause increased immunologic presentation of liposomal antigen by the macrophages to specific T lymphocytes. Lipid A can abolish suppressor T cell activity, resulting in increased immune responses to polysaccharide antigens. Upon combination of lipid A or lipid A analogues with nonionic block polymers, modulation of murine antibody isotypes can be achieved with antibodies against a variety of antigens in vivo. Liposomes containing monophosphoryl lipid A (MPL) have been utilized in a phase I clinical trial of a proposed malaria vaccine in humans. The liposomal malaria vaccine resulted in very high levels of antibodies against the malarial antigen, and despite the presence of huge amounts of MPL (up to 2.2 mg), the liposomal lipid A was nonpyrogenic and safe for use in humans. Lipid A and lipid A analogues, and liposomes or other carriers containing lipid A, have shown considerable promise both as adjuvants for immunization of animals and for human vaccines.
众多研究表明，革兰氏阴性菌内毒素的大部分或全部强效佐剂活性存在于脂多糖（LPS）的脂质A部分。脂质A的合成类似物为结构 - 活性关系提供了见解。已经确定了LPS和脂质A佐剂活性的几种细胞机制。LPS或脂质A激活巨噬细胞会导致细胞因子分泌，从而增强免疫反应。LPS和脂质A会募集抗原呈递细胞，尤其是巨噬细胞。含有脂质A的脂质体可作为体内佐剂，募集更多数量的巨噬细胞。被培养的巨噬细胞吞噬的脂质体脂质A也可作为“细胞内佐剂”，使巨噬细胞将脂质体抗原更多地呈递给特异性T淋巴细胞，从而增强免疫呈递。脂质A可以消除抑制性T细胞活性，导致对多糖抗原的免疫反应增强。当脂质A或脂质A类似物与非离子嵌段聚合物结合时，在体内针对多种抗原的抗体可实现对鼠抗体亚型的调节。含有单磷酰脂质A（MPL）的脂质体已用于一种拟议的疟疾疫苗在人体的I期临床试验。脂质体疟疾疫苗产生了非常高水平的针对疟疾抗原的抗体，并且尽管存在大量的MPL（高达2.2毫克），脂质体脂质A无致热原性且对人体使用安全。脂质A和脂质A类似物，以及含有脂质A的脂质体或其他载体，在作为动物免疫佐剂和人类疫苗方面都显示出了相当大的前景。
