Roth D R, Roman D, Ulrich P, Mahl A, Junker U, Perentes E
Novartis Pharma AG, MUT-2881.408, CH 4002 Basel, Switzerland.
Exp Toxicol Pathol. 2006 Jul;57(5-6):367-71. doi: 10.1016/j.etp.2006.03.012. Epub 2006 May 18.
The evaluation of potential adverse effects of pharmaceuticals on the immune system is part of the standard drug development procedures and needs to be available prior to the start of phase III clinical trials. Although the histopathological assessment of lymphoid organs/tissues is considered fundamental for the identification and characterization of immunotoxic reactions, additional investigations are now recommended by the European guidelines for repeated-dose toxicity testing of medicinal products in order to achieve an accurate assessment of immune system functionality with regard to immunomodulation. In the present paper, we describe and discuss a study design which permits the investigation of the immune function in a 4-week study in rats following immunization by subcutaneous administration of the T-dependent antigen Keyhole Limpet Hemocynin (KLH). This includes assessment of hematology parameters, titration of KLH-specific antibodies in serum, lymphocyte immunophenotyping in blood, thymus, spleen and lymph nodes, macroscopic pathology and histopathological evaluation of the lymphatic organs/tissues and of the injection sites.
评估药物对免疫系统的潜在不良反应是标准药物研发程序的一部分，并且需要在III期临床试验开始之前完成。虽然淋巴器官/组织的组织病理学评估被认为是识别和表征免疫毒性反应的基础，但欧洲药品重复给药毒性试验指南现在建议进行额外的研究，以便在免疫调节方面准确评估免疫系统功能。在本文中，我们描述并讨论了一种研究设计，该设计允许在通过皮下注射T细胞依赖性抗原钥孔血蓝蛋白（KLH）免疫大鼠的4周研究中调查免疫功能。这包括评估血液学参数、血清中KLH特异性抗体的滴定、血液、胸腺、脾脏和淋巴结中的淋巴细胞免疫表型分析、淋巴器官/组织和注射部位的大体病理学和组织病理学评估。
