Department of Basic Medical Science, School of Medicine, Shock/Trauma Research Center, University of Missouri, 2411 Holmes Street, Kansas City, MO 64108, USA.
Adv Exp Med Biol. 2010;667:81-99. doi: 10.1007/978-1-4419-1603-7_8.
The term "tolerance" from an immunological perspective, broadly encompasses a number of phenomena, but generally refers to a diminished responsiveness to LPS and/or other microbial products. With the discovery that many of the immunological, physiological and/or pathophysiological effects of LPS can be attributed to the lipid A moiety of the LPS molecule, a number of different lipid A analogs were synthesized with the goal of developing a drug that could be used clinically to treat cancer. In many instances, the development of tolerance to the lipid A congeners confounded the utility of these analogs as cancer therapeutics. In certain circumstances, however, the development of tolerance in patients has been utilized therapeutically to protect immunosuppressed patients from sepsis. Although numerous studies have been designed to investigate the development of tolerance, the underlying molecular mechanism remains unclear. This may be due, in part, to differences in the experimental models used, the sources and types of microbes and microbial products studied, kinetics of responses, and/or other experimental conditions. Nonetheless, a number of different signaling pathways have been identified as potentially modulating and/or triggering the development of tolerance. Though complex and incompletely understood, the capacity of tolerance to impact lipid A-based therapeutics, either positively or negatively, is inarguable, thus underscoring the necessity for further investigation toward elucidating the mechanisms contributing to the development of tolerance to lipid A and its analogs.
从免疫学角度来看，“耐受性”广泛涵盖了许多现象，但通常是指对 LPS 和/或其他微生物产物的反应性降低。随着人们发现 LPS 的许多免疫学、生理学和/或病理生理学效应都可以归因于 LPS 分子的脂质 A 部分，因此合成了许多不同的脂质 A 类似物，以期开发出一种可用于临床治疗癌症的药物。在许多情况下，对脂质 A 同系物的耐受性的发展使这些类似物作为癌症治疗剂的应用变得复杂。然而，在某些情况下，患者对脂质 A 类似物的耐受性发展已被用于治疗，以保护免疫抑制患者免受败血症的侵害。尽管已经设计了许多研究来调查耐受性的发展，但潜在的分子机制仍不清楚。这可能部分归因于所用实验模型的差异、研究的微生物和微生物产物的来源和类型、反应动力学和/或其他实验条件的差异。尽管如此，已经确定了许多不同的信号通路可能作为潜在的调节剂和/或触发因素来调节和/或触发耐受性的发展。尽管复杂且尚未完全理解，但耐受性对基于脂质 A 的治疗药物的影响（无论是积极的还是消极的）是不可否认的，因此，进一步研究阐明导致对脂质 A 及其类似物的耐受性发展的机制是必要的。
