Herzyk Danuta J, Holsapple Michael
GlaxoSmithKline Pharmaceuticals, King of Prussia, Pennsylvania 19406-0939, USA.
J Immunotoxicol. 2007 Apr;4(2):143-7. doi: 10.1080/15476910701337308.
Increased expectations from a number of regulatory agencies, e.g., Environmental Protection Agency (EPA), Food and Drug Administration (FDA), European Medicines Agency (EMEA), and the Ministry of Health, Labour and Welfare (MHLW) of Japan, call for the evaluation of potential adverse effects on the immune system. As recently summarized in the ICH S8 guideline, the T-cell-dependent antibody response (TDAR) has been identified in a regulatory context as a main functional test of immunotoxicity. While the characterization of immunotoxic potential is pertinent to both the chemical and pharmaceutical industries, the use of immunotoxicology data for hazard identification and/or risk assessment in each case is different. Therefore, multiple approaches to immunotoxicity testing have evolved. The assays that evaluate TDAR function include both well-established tests, e.g., anti-sheep red blood cell plaque-forming cell (PFC) assay, and newer models, e.g., anti-keyhole limpet hemocyanin (KLH) antibody ELISA. These tests vary in the study design, antigen application and analytical methods. However, they all evaluate the same endpoint-a competent immune (e.g., antibody) response to an antigen. Numerous issues have been identified in the application of TDAR tests, including high animal to animal variability; differences in antigen source and potency; a lack of established "normal range" of the immune response and uncertainty about the degree of inhibition of the TDAR to be considered toxicologically important. As such, the need for a forum to discuss these issues was recognized by the immunotoxicology community, and was addressed at the 2006 Society of Toxicology (SOT) Workshop. A series of papers will summarize that forum with the ultimate objectives being to build a consensus among immunotoxicologists on the implications of these factors on using TDAR results in hazard identification and/or risk assessment, and to establish a criteria to classify compounds as immunotoxicants.
多个监管机构，如美国环境保护局（EPA）、食品药品监督管理局（FDA）、欧洲药品管理局（EMEA）以及日本厚生劳动省（MHLW），对其期望的提高，要求对免疫系统的潜在不良反应进行评估。正如最近在国际人用药品注册技术协调会（ICH）S8指南中所总结的，在监管背景下，依赖T细胞的抗体反应（TDAR）已被确定为免疫毒性的主要功能测试。虽然免疫毒性潜力的表征与化学和制药行业都相关，但在每种情况下将免疫毒理学数据用于危害识别和/或风险评估的方式有所不同。因此，已经发展出多种免疫毒性测试方法。评估TDAR功能的检测方法既包括成熟的测试，如抗绵羊红细胞空斑形成细胞（PFC）试验，也包括较新的模型，如抗钥孔血蓝蛋白（KLH）抗体酶联免疫吸附测定（ELISA）。这些测试在研究设计、抗原应用和分析方法上各不相同。然而，它们都评估相同的终点——对抗原的有效免疫（如抗体）反应。在TDAR测试的应用中已经发现了许多问题，包括动物个体之间的高变异性；抗原来源和效力的差异；免疫反应缺乏既定的“正常范围”，以及对于在毒理学上被认为重要的TDAR抑制程度存在不确定性。因此，免疫毒理学界认识到需要一个论坛来讨论这些问题，并在2006年毒理学会（SOT）研讨会上进行了探讨。一系列论文将总结该论坛，最终目标是在免疫毒理学家之间就这些因素对在危害识别和/或风险评估中使用TDAR结果的影响达成共识，并建立将化合物分类为免疫毒物的标准。
