非人灵长类动物主要免疫器官及免疫细胞的研究进展

免疫毒性是生物技术药物临床前安全性评价中最常见的毒副作用。免疫系统是由多个器官、多种细胞和多种分子组成的一个复杂的系统,其结构和功能与遗传背景、年龄、性别和环境等因素有关,其正常的生理变异范围较大,这对于评估药物所致的免疫毒性是一个巨大的挑战。非人灵长类动物是药物临床前安全性评价中较常用的实验动物。了解和熟悉非人灵长类动物免疫系统的特点,有助于正确、客观地评价药物所致的免疫毒性。本文从非人灵长类动物主要的免疫器官(胸腺、脾和淋巴结)及免疫细胞(T和B淋巴细胞)的发育、形态特征和功能特征等方面进行了详细的论述。     

实验动物黏膜相关淋巴结组织改良组织病理学评价方法研究进展

近年来,世界各国药品管理机构都非常重视药物引起免疫系统损伤的毒性病理学评价.2006年,美国STP在"免疫系统常规病理学评价最佳操作指南(2005)"岗位说明的基础上,发表了"淋巴器官改良的组织病理学评价"的方法,其作为能够运用的一种工具可协助毒性病理学工作者辩识评价免疫调制作用药物.现对黏膜相关淋巴结组织的组织结构、生理功能、形态学特征、改良的组织病理学诊断要点以及评价方法进行了归纳和概括性介绍,为相关领域的科研人员提供参考.     

淋巴结病理学检查在药物安全性评价中的特点和意义

淋巴结(LN)是重要的外周免疫器官,免疫应答发生的场所。LN形态结构的改变可敏感提示药物免疫毒性的有无,表明LN毒性病理学评价是免疫毒性筛选的有力手段。本文综述了LN复杂的生理结构和毒性病理学变化特点,并阐述了LN病理检查在药物安全性评价中的作用和意义。     

药物的免疫毒性评价

药物对机体免疫系统的影响越来越受到广泛关注,免疫毒性研究已作为药物非临床安全性评价的一项重要内容,也是全面评价药物毒性的重要组成部分.参照近年国内外有关药物免疫毒性的相关研究报道,尤其是临床人用药物注册技术要求国际协调会颁布的ICH S8指导原则,对免疫毒性评价的基本原则、常用方法和检测技术、其他相关试验方法和免疫毒性评价等进行综述,阐述药物在非临床安全性评价中进行的免疫毒性研究进展,为我国药物非临床安全性评价免疫毒性研究提供研究思路和方法.     

胸腺在免疫毒性病理学评价中的作用和意义

胸腺是中枢性淋巴器官,无须抗原的刺激T淋巴细胞在皮质自主地进行分化和成熟,这是免疫系统正常功能发育的重要组成部分。当暴露于免疫毒性物质和内源性糖皮质激素时,胸腺是敏感的靶器官,胸腺的大小或重量出现明显的降低,这往往是化合物或药物导致的敏感的皮质胸腺细胞改变最初观测到的指标。因此,胸腺组织病理学和重量的改变与免疫毒性的筛选具有特定的关联,对胸腺的病理学评价在免疫毒性研究中具有重要作用和意义。文中从胸腺生理和毒性病理学的角度对其作用和研究意义进行综述。     

胸腺在免疫毒性病理学评价中的作用和意义

胸腺是中枢性淋巴器官，无须抗原的刺激T淋巴细胞在皮质自主地进行分化和成熟，这是免疫系统正常功能发育的重要组成部分。当暴露于免疫毒性物质和内源性糖皮质激素时，胸腺是敏感的靶器官，胸腺的大小或重量出现明显的降低，这往往是化合物或药物导致的敏感的皮质胸腺细胞改变最初观测到的指标。因此，胸腺组织病理学和重量的改变与免疫毒性的筛选具有特定的关联，对胸腺的病理学评价在免疫毒性研究中具有重要作用和意义。文中从胸腺生理和毒性病理学的角度对其作用和研究意义进行综述。     

胸腺在免疫毒性病理学评价中的作用和意义

胸腺是中枢性淋巴器官，无须抗原的刺激T淋巴细胞在皮质自主地进行分化和成熟，这是免疫系统正常功能发育的重要组成部分。当暴露于免疫毒性物质和内源性糖皮质激素时，胸腺是敏感的靶器官，胸腺的大小或重量出现明显的降低，这往往是化合物或药物导致的敏感的皮质胸腺细胞改变最初观测到的指标。因此，胸腺组织病理学和重量的改变与免疫毒性的筛选具有特定的关联，对胸腺的病理学评价在免疫毒性研究中具有重要作用和意义。文中从胸腺生理和毒性病理学的角度对其作用和研究意义进行综述。     

胸腺在免疫毒性病理学评价中的作用和意义

胸腺是中枢性淋巴器官，无须抗原的刺激T淋巴细胞在皮质自主地进行分化和成熟，这是免疫系统正常功能发育的重要组成部分。当暴露于免疫毒性物质和内源性糖皮质激素时，胸腺是敏感的靶器官，胸腺的大小或重量出现明显的降低，这往往是化合物或药物导致的敏感的皮质胸腺细胞改变最初观测到的指标。因此，胸腺组织病理学和重量的改变与免疫毒性的筛选具有特定的关联，对胸腺的病理学评价在免疫毒性研究中具有重要作用和意义。文中从胸腺生理和毒性病理学的角度对其作用和研究意义进行综述。     

非临床药物安全性评价中毒性病理学评价基本要素

毒性病理学是结合病理学和毒理学原理的科学,关注化合物潜在的毒性作用。毒理学研究中的组织病理学评价经毒性病理学家的长期实践已形成标准技术规程,在药物风险评估过程中起重要作用。本文针对非临床药物安全性评价中毒性病理学评价中病理学家的资质和职责、镜检前病理学家应获取的资料和信息、毒性病理学评价的一般流程、影响毒性病理学评价准确性和一致性因素等国际公认的基本要素进行了简要的阐述,同时说明按照标准技术规程进行非临床药物毒理学试验组织病理学评价可以减少诊断偏差,获得高质量的病理学报告,为病理学家、毒理学家以及监管机构的审查人员提供重要的数据和信息。     

影响药物毒性神经病理学评价质量的主要因素

神经毒性是许多药物或化合物常见的毒副作用。在新药研发早期要进行神经毒性筛选。对于可能通过血脑屏障影响神经系统的小分子药物或疫苗类的生物制品在临床前安全性评价中要进行非人灵长类动物的神经毒性评价。毒性病理学或神经病理学评价是临床前药物神经毒性评价的金标准。针对影响药物毒性神经病理学评价质量的几个主要因素,包括神经病理学评价的一般策略、最佳的评价时机、特殊的神经组织屏障系统、神经组织病理制片中的取材方法以及人工假象对神经病理学诊断的干扰,进行详细的解析,以期为我国神经毒性评价指导原则的制定和药物非临床神经毒性研究提供参考。     

树突细胞评价免疫毒性的研究进展

树突细胞作为皮肤接触性过敏反应评价模型的研究越来越多,研究内容也从最初的确定该模型的适宜性到更深入的基因组学机制以及替代细胞系的研究,目前该模型已处于接触性过敏反应评价的替代实验的验证阶段,这就为其能够作为其他免疫毒性评价的模型奠定了基础。树突细胞作为免疫毒性评价模型还可以弥补现有的免疫毒性评价环节的缺失以及为自身免疫反应评价提供突破点。所以树突细胞在免疫毒性评价中具有重要的意义。     

Immunotoxicity of organophosphorous pesticides

This study reviews the toxic effects of organophosphate (OP) pesticides on the immune systems and immune functions of invertebrates, fish, and higher vertebrate wildlife. The fundamental features and mechanisms of OP-induced immunotoxicity are illustrated with reference to parathion, chlorpyrifos, malathion, and diazinon. Immunotoxicity may be direct via inhibition of serine hydrolases or esterases in components of the immune system, through oxidative damage to immune organs, or by modulation of signal transduction pathways controlling immune functions. Indirect effects include modulation by the nervous system, or chronic effects of altered metabolism/nutrition on immune organs. Immunotoxicities are varied and include pathology of immune organs, and decreased humoral and/or cell mediated immunity. Altered non-specific immunity, decreased host resistance, hypersensitivity and autoimmunity are also features of immunotoxicity; although not all of these have been conclusively demonstrated in terms of pollutant exposure and immunotoxic effects in wildlife within individual experiments. Immunotoxicological biomarkers and biological monitoring tools are urgently needed to assess the extent of immunotoxicity in wildlife. Selection of universal biomarkers is hampered by the physiological diversity of immune systems in animals. However, by drawing on evidence from human epidemiology and tiered approaches in mammalian immunotoxicity evaluation, a selection of generic biomarkers of immunotoxicity in animals is suggested. Priorities for future research are also identified.     

Adequate immunotoxicity testing in drug development

Modulation of the immune system can lead to either immunostimulation or immunosuppression and can be either intended or unintended. While many effects on the immune system's components can be found as a result of a drug treatment or chemical exposure, true immunotoxicity occurs when such treatment results in adverse effects or defects in the immune response. Regulatory expectations to evaluate potential adverse effects of pharmaceuticals warrants a need for reliable and readily standardized methods. Moreover, criteria to classify a drug as an "immunotoxicant" need to be established. Examples of studies using a modified approach to measure T-cell-dependent antibody responses (the rat KLH model) and interpretation of the results in the context of immunotoxicity evaluation are discussed in this paper.     

纳米药物免疫毒性研究进展

纳米药物由于粒径小等特性,极易进入体内,并透过多种生理屏障与免疫细胞或细胞表面蛋白相互作用,发生特异性反应,诱发免疫应答,增强或降低机体的免疫功能。此外,免疫系统自身的复杂性和纳米药物类型多样性增加了研究纳米药物免疫毒性的难度。纳米药物对机体可能具有免疫抑制或免疫刺激包括抗原性、佐剂特性和炎症反应等免疫学特性,不同的纳米药物也已发现可以诱导机体产生不同程度的免疫反应。本文就纳米药物的免疫学特性、免疫系统与纳米药物的相互作用以及不同纳米药物免疫毒性研究方法进行综述。     

Approaches to the identification and recording of findings in the lymphoreticular organs indicative for immunotoxicity in regulatory type toxicity studies

Recent validation studies showed that histopathological examination of the hematopoietic and lymphoreticular system is one of the most sensitive tools in the evaluation of non-specific immune stimulatory or immune suppressive effects and hazard identification of potential immunotoxicity in routine safety tests. Most immunotoxic effects have a classical dose-response relationship and an immediate effect (i.e. do not need an induction phase). The findings associated with a specific immunomodulatory response are generally not detected morphologically in routine sections of the immune system in safety studies, but may be detected, because of their effects on other organs such as skin (contact dermatitis) or joints and kidneys (immune complex deposits). Careful detailed examination of the immune system may give valuable clues for the possible mechanism of action of the test material, as was also demonstrated in these validation studies.     

中药注射剂免疫毒性评价研究进展

为考察中药注射剂免疫毒性评价研究的发展近况,就近年来文献报道的中药注射剂免疫毒性相关实验研究从免疫毒性评价技术、类过敏反应研究、长期毒性评价中免疫指标的观察3个方面进行了概括,发现虽然在敏感动物选择、过敏原检查、新技术应用、细胞实验研究、吐温-80与类过敏反应关系及长期毒性试验中免疫系统指标观察等方面取得了一定进步,但仍需完善评价方法及指导原则,进一步加强提高操作规范性等方面。     

Adverse effects of immunotherapeutics involving the immune system

Immunotherapeutics are pharmaceutical products intended to modify immune functions either directly or indirectly by influencing physiological systems that affect immunological functions. They include conventional immunosuppressants, monoclonal antibodies, recombinant cytokines, gene therapy products or therapeutic vaccines. A variety of adverse effects involving the immune system have been described in laboratory animals as well as in the clinic. Some of these adverse effects can be predicted, at least to some extent, from the immunopharmacological profile of these drugs, but a number of unpredicted adverse effects have been described. Immunosuppression, allergy, autoimmunity, immunoactivation are the major adverse consequences to be expected as illustrated by this overview of the leading immunotherapeutics already used in the clinic. These untoward and potentially severe consequences support the need for a careful preclinical and clinical evaluation of the immunotoxicity of these products.     

Importance of immunotoxicity in safety assessment: a medical toxicologist's perspective

The clinical data accumulated so far unequivocally demonstrate that immunotoxicity is associated with significant morbidity. Immunotoxic effects are divided into four categories: immunosuppression, immunostimulation, hypersensitivity and autoimmunity. Each category is associated with distinct adverse effects. Even though concern primarily focused on immunosuppression, hypersensitivity and immunostimulation are also key issues, especially with pharmaceuticals. Histology of the lymphoid organs is not sufficient to reliably predict immunosuppression and at least one immune function assay is recommended. It is not known whether function assays used to predict immunosuppression are applicable to the prediction of immunostimulation. Specific assays can be helpful. Most available animal models and assays are not valid to assess the potential for hypersensitivity, and autoimmunity is not predictable at all. Conflicting guidelines and the lack of human data contribute further to this situation. Several critical factors deserve consideration. Dose-response relationships are often atypical and this should impact on the study design. Due to the redundancy of the immune system, a single change is not necessarily sufficient evidence for immunotoxicity so that a global assessment of all preclinical findings is advisable. Genetic factors play a major role in immune responses. As wide inter-individual variability is unavoidable, sufficient numbers of animals, a cautious comparison with both study and historical controls, and the possible use of inbred or genetically modified animals are to be considered. Marked interspecies differences in the immune system should lead to use more than one animal species and to confirm animal data during clinical trials. The inclusion of certain immune endpoints applicable to animals and man is therefore essential. The optimal timing of immunotoxicity studies is debated, but early studies are recommended. Despite significant progress, quite a few issues are still pending. Nevertheless, due to the many adverse effects reported in man, the immunotoxicity potential of every new molecular entity should be systematically and specifically evaluated.