Ilar Journal最新文献

Many different adjuvants are currently being developed for subunit vaccines against a number of pathogens and diseases. Rational design is increasingly used to develop novel vaccine adjuvants, which requires extensive knowledge of, for example, the desired immune responses, target antigen-presenting cell subsets, their localization, and expression of relevant pattern-recognition receptors. The adjuvant mechanism of action and efficacy are usually evaluated in animal models, where mice are by far the most used. In this review, we present methods for assessing adjuvant efficacy and function in animal models: (1) whole-body biodistribution evaluated by using fluorescently and radioactively labeled vaccine components; (2) association and activation of immune cell subsets at the injection site, in the draining lymph node, and the spleen; (4) adaptive immune responses, such as cytotoxic T-lymphocytes, various T-helper cell subsets, and antibody responses, which may be quantitatively evaluated using ELISA, ELISPOT, and immunoplex assays and qualitatively evaluated using flow cytometric and single cell sequencing assays; and (5) effector responses, for example, antigen-specific cytotoxic potential of CD8+ T cells and antibody neutralization assays. While the vaccine-induced immune responses in mice often correlate with the responses induced in humans, there are instances where immune responses detected in mice are not translated to the human situation. We discuss some examples of correlation and discrepancy between mouse and human immune responses and how to understand them.

For more than a century, transplantation of tissues and organs from animals into man, xenotransplantation, has been viewed as a potential way to treat disease. Ironically, interest in xenotransplantation was fueled especially by successful application of allotransplantation, that is, transplantation of human tissue and organs, as a treatment for a variety of diseases, especially organ failure because scarcity of human tissues limited allotransplantation to a fraction of those who could benefit. In principle, use of animals such as pigs as a source of transplants would allow transplantation to exert a vastly greater impact than allotransplantation on medicine and public health. However, biological barriers to xenotransplantation, including immunity of the recipient, incompatibility of biological systems, and transmission of novel infectious agents, are believed to exceed the barriers to allotransplantation and presently to hinder clinical applications. One way potentially to address the barriers to xenotransplantation is by genetic engineering animal sources. The last 2 decades have brought progressive advances in approaches that can be applied to genetic modification of large animals. Application of these approaches to genetic engineering of pigs has contributed to dramatic improvement in the outcome of experimental xenografts in nonhuman primates and have encouraged the development of a new type of xenograft, a reverse xenograft, in which human stem cells are introduced into pigs under conditions that support differentiation and expansion into functional tissues and potentially organs. These advances make it appropriate to consider the potential limitation of genetic engineering and of current models for advancing the clinical applications of xenotransplantation and reverse xenotransplantation.

Disaster response planning for laboratory animal facilities is a time- and personnel-intensive undertaking. This article outlines numerous considerations in formulating a plan for disaster response in a high containment animal unit. The planning process is discussed around a set of elements: planning team formation, situational understanding, goal and objective determination, plan development, preparation, and rehearsal or implementation. The importance of an appropriate planning team and personnel development is explored in relationship to exemplary disaster scenarios such as natural disaster and terrorism. Specific risks such as hazardous agent and animal species type serve to delineate goal-setting methods. These goals provide the framework for an institutional disaster plan. The review further uses elements of the planning process to explore the difficulties of euthanasia of animals treated with hazardous agents. Ultimately, the pitfalls of handling media relations following disaster are examined. Proactive measures for preparing to speak to the media and mitigate negative perceptions of research are presented.

Influenza is a viral respiratory disease having a major impact on public health. Influenza A virus (IAV) usually causes mild transitory disease in humans. However, in specific groups of individuals such as severely obese, the elderly, and individuals with underlying inflammatory conditions, IAV can cause severe illness or death. In this review, relevant small and large animal models for human IAV infection, including the pig, ferret, and mouse, are discussed. The focus is on the pig as a large animal model for human IAV infection as well as on the associated innate immune response. Pigs are natural hosts for the same IAV subtypes as humans, they develop clinical disease mirroring human symptoms, they have similar lung anatomy, and their respiratory physiology and immune responses to IAV infection are remarkably similar to what is observed in humans. The pig model shows high face and target validity for human IAV infection, making it suitable for modeling many aspects of influenza, including increased risk of severe disease and impaired vaccine response due to underlying pathologies such as low-grade inflammation. Comparative analysis of proteins involved in viral pattern recognition, interferon responses, and regulation of interferon-stimulated genes reveals a significantly higher degree of similarity between pig, ferret, and human compared with mice. It is concluded that the pig is a promising animal model displaying substantial human translational value with the ability to provide essential insights into IAV infection, pathogenesis, and immunity.

In translational research, animal models are an important tool to aid in decision-making when taking potential therapies into human clinical trials. Recently, there have been a number of papers that have suggested limited concordance of preclinical animal experiments with subsequent human clinical experience. Assessments of preclinical animal studies have led to concerns about the reproducibility of data and have highlighted the need for an emphasis on rigor and quality in the planning, conduct, analysis, and reporting of such studies. The incorporation of a wider role for the comparative pathologist using pathology best practices in the planning and conduct of animal model-based research is one way to increase the quality and reproducibility of data. The use of optimal design and planning of tissue collection, incorporation of pathology methods into written protocols, conduct of pathology procedures using accepted best practices, and the use of optimal pathology analysis and reporting methods enhance the quality of the data acquired from many types of preclinical animal models and studies. Many of these pathology practices are well established in the discipline of toxicologic pathology and have a proven and useful track record in enhancing the data from animal-based studies used in safety assessment of human therapeutics. Some of this experience can be adopted by the wider community of preclinical investigators to increase the reproducibility of animal study data.

The role of comparative oncology in translational research is receiving increasing attention from drug developers and the greater biomedical research community. Pet dogs with spontaneous cancer are important and underutilized translational models, owing to dogs' large size and relative outbreeding, combined with their high incidence of certain tumor histotypes with significant biological, genetic, and histological similarities to their human tumor counterparts. Dogs with spontaneous tumors naturally develop therapy resistance and spontaneous metastasis, all in the context of an intact immune system. These fundamental features of cancer biology are often lacking in induced or genetically engineered preclinical tumor models and likely contribute to their poor predictive value and the associated overall high failure rate in oncology drug development. Thus, the conduct of clinical trials in pet dogs with naturally occurring cancer represents a viable surrogate and valuable intermediary step that should be increasingly incorporated into the cancer drug discovery and development pipeline. The development of molecular-targeted therapies has resulted in an expanded role of the pathologist in human oncology trials, and similarly the expertise of veterinary pathologists will be increasingly valuable to all phases of comparative oncology trial design and conduct. In this review, we provide a framework of clinical, ethical, and pathology-focused considerations for the increasing integration of translational research investigations in dogs with spontaneous cancer as a means to accelerate clinical cancer discovery and drug development.

Development of new biomedical products necessitates nonclinical safety assessment in animals as a means of assessing potential risk to human patients. Pivotal nonclinical safety studies that support human clinical trials are performed according to Good Laboratory Practice (GLP) guidelines, which are designed to ensure that the study was conducted under carefully controlled conditions using standardized and validated procedures that will yield a reliable, reproducible, and traceable data set. The GLP guidelines established by different regulatory agencies address organizational structure, personnel responsibilities, personnel training practices, quality assurance (ensuring compliance), facilities, equipment, standard operating procedures, study documentation (record keeping), and record and sample retention. Academic institutions engaging in nonclinical safety assessment on-site have multiple options for implementing a GLP quality system. This article outlines the rationale supporting the use of a GLP-compliant or GLP-like quality system in academia and reviews key concepts needed to efficiently and effectively implement GLP in the academic setting. Emphasis is given to provision of GLP-compliant pathology support as (1) pathology data are an essential component of GLP nonclinical safety testing, (2) familiarity with pathology-related GLP procedures typically is gained first outside the academic setting, and (3) microscopic pathology diagnoses and interpretations require special accommodations to ensure that they are undertaken in a GLP-compliant fashion.

The need for international collaboration in rodent pathology has evolved since the 1970s and was initially driven by the new field of toxicologic pathology. First initiated by the World Health Organization's International Agency for Research on Cancer for rodents, it has evolved to include pathology of the major species (rats, mice, guinea pigs, nonhuman primates, pigs, dogs, fish, rabbits) used in medical research, safety assessment, and mouse pathology. The collaborative effort today is driven by the needs of the regulatory agencies in multiple countries, and by needs of research involving genetically engineered animals, for "basic" research and for more translational preclinical models of human disease. These efforts led to the establishment of an international rodent pathology nomenclature program. Since that time, multiple collaborations for standardization of laboratory animal pathology nomenclature and diagnostic criteria have been developed, and just a few are described herein. Recently, approaches to a nomenclature that is amenable to sophisticated computation have been made available and implemented for large-scale programs in functional genomics and aging. Most terminologies continue to evolve as the science of human and veterinary pathology continues to develop, but standardization and successful implementation remain critical for scientific communication now as ever in the history of veterinary nosology.

Advancements in technology and digitization have ushered in novel ways of enhancing tissue-based research via digital microscopy and image analysis. Whole slide imaging scanners enable digitization of histology slides to be stored in virtual slide repositories and to be viewed via computers instead of microscopes. Easier and faster sharing of histologic images for teaching and consultation, improved storage and preservation of quality of stained slides, and annotation of features of interest in the digital slides are just a few of the advantages of this technology. Combined with the development of software for digital image analysis, digital slides further pave the way for the development of tools that extract quantitative data from tissue-based studies. This review introduces digital microscopy and pathology, and addresses technical and scientific considerations in slide scanning, quantitative image analysis, and slide repositories. It also highlights the current state of the technology and factors that need to be taken into account to insure optimal utility, including preanalytical considerations and the importance of involving a pathologist in all major steps along the digital microscopy and pathology workflow.

Animal research pathology encompasses a wide array of procedures and may involve work with a variety of animal species and hazards. To protect laboratory personnel and ensure data integrity, pathologists must be familiar with the activities performed in their laboratories and the applicable regulatory and safety requirements. Failure to address issues proactively may result in exposure of personnel to hazardous materials and/or collection of data in a manner that does not conform to animal welfare or quality control standards. This manuscript provides a brief introduction to important animal research pathology regulatory and safety considerations. The importance of close communication between the principal investigator, pathologist, laboratory personnel, Institutional Animal Care and Use Committee, and institutional safety office/experts is emphasized and a mechanism for improving communication is discussed.