WATSON D W, KIM Y B
J Exp Med. 1963 Sep 1;118(3):425-46. doi: 10.1084/jem.118.3.425.
Evidence is presented suggesting that the apparent non-specificity of pyrogenic tolerance observed with Gram-negative bacterial endotoxins is due to related antigenic determinants associated with the macromolecular toxins. This is based on results obtained in rabbits from pyrogenic cross-tolerance tests with selected endotoxins. In these tests, purified endotoxins from Escherichia coli (COO8) and Chromobacterium violaceum (CV) gave results one might expect with non-reciprocal cross-reacting antigens in classical immune systems. Additional evidence for an immune mechanism in tolerance is suggested by the highly significant anamnestic response observed. Lipid A, a toxic derivative of the purified COO8 endotoxin, failed to induce pyrogenic tolerance against the parent toxin. These results are explained by assuming that endotoxins have two interdependent activities associated with different portions of the macromolecule; one is assumed to be responsible for the primary toxicity, and the other is involved in secondary toxicity. The latter is dependent on the hypersensitive state of the host. Additional evidence for the role of hypersensitivity in secondary toxicity is based on the observation that adult rabbits are highly sensitive to the pyrogenic, lethal, and skin-reacting activities of endotoxin in contrast to young animals which are more resistant to all of these attributes of toxicity. In adults, the host responses to pyrogenicity, lethality, and skin reactivity could be partially inhibited by the early exposure of the animals to massive doses of endotoxin equivalent to a LD(50). The pyrogenic tolerance shown in these animals was specific indicating that the inhibition of the hypersusceptibility to endotoxin involved an immunological mechanism. A mechanism of endotoxin tolerance is proposed and discussed based on the induction of specific antibodies capable of assisting the RES in the clearance and destruction of endotoxin. It is suggested that the present inconsistencies relative to the chemical nature and biological activities of endotoxins might be explained on the basis of these two activities and the failure to recognize the importance of the immunological state of the host in which the toxins are tested.
有证据表明，革兰氏阴性菌内毒素所呈现的热原耐受性的明显非特异性，是由于与大分子毒素相关的抗原决定簇所致。这是基于对家兔进行的、用选定内毒素进行的热原交叉耐受性试验所获得的结果。在这些试验中，来自大肠杆菌（COO8）和紫色杆菌（CV）的纯化内毒素所产生的结果，与经典免疫系统中不可逆交叉反应抗原的预期结果一致。所观察到的高度显著的回忆反应，也为耐受性中的免疫机制提供了额外证据。脂质A是纯化后的COO8内毒素的一种有毒衍生物，未能诱导出对亲本毒素的热原耐受性。这些结果可以这样解释：假定内毒素具有与大分子不同部分相关的两种相互依存的活性；一种被认为负责主要毒性，另一种参与次要毒性。后者取决于宿主的超敏状态。超敏反应在次要毒性中作用的额外证据，基于以下观察结果：成年家兔对内毒素的热原性、致死性和皮肤反应活性高度敏感，而幼龄动物对所有这些毒性特征则更具抵抗力。在成年动物中，动物早期接触相当于半数致死量的大量内毒素，可部分抑制宿主对热原性、致死性和皮肤反应性的反应。这些动物所表现出的热原耐受性具有特异性，表明对内毒素超敏感性的抑制涉及一种免疫机制。基于能够协助网状内皮系统清除和破坏内毒素的特异性抗体的诱导，提出并讨论了一种内毒素耐受性机制。有人认为，目前关于内毒素化学性质和生物学活性的不一致之处，或许可以基于这两种活性以及未能认识到宿主免疫状态在测试毒素时的重要性来解释。
