Ilar Journal最新文献

The Coronavirus Disease 2019 (COVID-19) pandemic has fueled unprecedented development of animal models to understand disease pathogenesis, test therapeutics, and support vaccine development. Models previously developed to study severe acute respiratory syndrome coronavirus (SARS-CoV) have been rapidly deployed to study SARS-CoV-2. However, it has become clear that despite the common use of ACE2 as a receptor for both viruses, the host range of the 2 viruses does not entirely overlap. Distinct ACE2-interacting residues within the receptor binding domain of SARS-CoV and SARS-CoV-2, as well as species differences in additional proteases needed for activation and internalization of the virus, are likely sources of host differences between the 2 viruses. Spontaneous models include rhesus and cynomolgus macaques, African Green monkeys, hamsters, and ferrets. Viral shedding and transmission studies are more frequently reported in spontaneous models. Mice can be infected with SARS-CoV; however, mouse and rat ACE2 does not support SARS-CoV-2 infection. Murine models for COVID-19 are induced through genetic adaptation of SARS-CoV-2, creation of chimeric SARS-CoV and SARS-CoV-2 viruses, use of human ACE2 knock-in and transgenic mice, and viral transfection of wild-type mice with human ACE2. Core aspects of COVID-19 are faithfully reproduced across species and model. These include the acute nature and predominantly respiratory source of viral shedding, acute transient and nonfatal disease with a largely pulmonary phenotype, similar short-term immune responses, and age-enhanced disease. Severity of disease and tissue involvement (particularly brain) in transgenic mice varies by promoter. To date, these models have provided a remarkably consistent template on which to test therapeutics, understand immune responses, and test vaccine approaches. The role of comorbidity in disease severity and the range of severe organ-specific pathology in humans remains to be accurately modeled.

There is no prescribed stage or standardized point at which an animal model protocol is reviewed for reproducibility and translatability. The method of review for a reproducible and translatable study is not consistently documented in peer literature, and this is a major challenge for those working with animal models of human diseases. If the study is ill designed, it is impossible to perform an accurate harm/benefit analysis. In addition, there may be an ethical challenge if the work is not reproducible and translatable. Animal welfare regulations and other documents of control clearly state the role of the Institutional Animal Care and Use Committees are to look at science justification within the context of animal welfare. This article, concentrating on models not governed by regulations, outlines issues and offers recommendations for refining animal model review with a goal to improve study reproducibility and translatability.

There is an art and science to performing mouse anesthesia, which is a significant component to animal research. Frequently, anesthesia is one vital step of many over the course of a research project spanning weeks, months, or beyond. It is critical to perform anesthesia according to the approved research protocol using appropriately handled and administered pharmaceutical-grade compounds whenever possible. Sufficient documentation of the anesthetic event and procedure should also be performed to meet the legal, ethical, and research reproducibility obligations. However, this regulatory and documentation process may lead to the use of a few possibly oversimplified anesthetic protocols used for mouse procedures and anesthesia. Although a frequently used anesthetic protocol may work perfectly for each mouse anesthetized, sometimes unexpected complications will arise, and quick adjustments to the anesthetic depth and support provided will be required. As an old saying goes, anesthesia is 99% boredom and 1% sheer terror. The purpose of this review article is to discuss the science of mouse anesthesia together with the art of applying these anesthetic techniques to provide readers with the knowledge needed for successful anesthetic procedures. The authors include experiences in mouse inhalant and injectable anesthesia, peri-anesthetic monitoring, specific procedures, and treating common complications. This article utilizes key points for easy access of important messages and authors' recommendation based on the authors' clinical experiences.

Clinical pathology testing for investigative or biomedical research and for preclinical toxicity and safety assessment in laboratory animals is a distinct specialty requiring an understanding of species specific and other influential variables on results and interpretation. This review of clinical pathology principles and testing recommendations in laboratory animal species aims to provide a useful resource for researchers, veterinary specialists, toxicologists, and clinical or anatomic pathologists.

With the possible exception of inbred mice, the identification of laboratory animals has been in a state of anarchy until very recently. In a letter to the editor of LABORATORY ANIMAL CARE (19: 121-123, 1969), Mr. Samuel Poiley outlined the general principles of a system of nomenclature being developed by the Committee on Nomenclature of the ILAR. This journal requires that authors use standard terminology for rats and mice as listed in the ILAR publication ANIMALS FOR RESEARCH. We welcome the following report which represents a system of nomenclature for outbred animals and publish it as a service to the scientific community. Authors of papers submitted to this journal will be expected to identify their animals by this system. We urge the editors of other scientific publications to consider the merits of adopting standard terminology to end the reign of confusion in animal identification.

The organization and function of the institutional animal care and use committee (IACUC) is the key component of government regulation and oversight of necessary scientific research using live animals and of AAALAC - International accreditation of animal care and use programs in the United States. The regulations, roles, and responsibilities of IACUCs have evolved since their inception 35 years ago from a limited focus on animal welfare and specific animal procedures to embracing scientific quality, data reproducibility and translation, and animal welfare as inextricably interdependent and critical components of generation of new scientific knowledge and medical treatments. A current challenge for IACUCs is in evaluating whether benefits to be derived (eg, new knowledge or treatments) justify any unavoidable pain, stress, or injury associated with proposed research protocols, because the former are long-term and at best speculative outcomes, whereas the latter are immediate and tangible for the study animals. Scientific consensus is that research most likely to generate significant new knowledge and medical treatments is that conducted to high scientific, technical, and quality standards and reported with full transparency to facilitate reproducibility. As an alternative to current benefits evaluations included in risk benefit and harm benefit constructs, the authors propose that IACUCs assess the proposed research for scientific quality and alignment of study elements with the study purpose (e.g., Fit for Purpose [FfP]), including justifications for study design components, selection of primary endpoints and technologies, rationale for data and statistical analyses, and research communication plans. Fit for Purpose endpoints are objective, immediate, and impactful as are the potential risks for study animals, and at the same time they are the best predictors for achievement of longer-term benefits. We propose that IACUCs and any revision of The ILAR Guide consider FfP concepts in place of traditional benefits assessment to accelerate the generation of new knowledge and treatments benefiting medical and veterinary patients and the environment through better science and animal welfare rather than to continue to rely on speculative future outcomes.

Developing strong animal models is essential for furthering our understanding of how the immune system functions in response to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection. The alarming speed at which SARS-CoV-2 has spread, and the high mortality rate of severe Coronavirus Disease 2019 (COVID-19), has required both basic science and clinical research to move at an unprecedented pace. Models previously developed to study the immune response against SARS-CoV have been rapidly deployed to now study SARS-CoV-2. To date, both small and large animal models are remarkably consistent when infected with SARS-CoV-2; however, certain models have proven more useful when answering specific immunological questions than others. Small animal models, such as Syrian hamsters, ferrets, and mice carrying the hACE2 transgene, appear to reliably recapitulate the initial cytokine surge seen in COVID-19 as well as show significant innate and adaptive cell infiltration in to the lung early in infection. Additionally, these models develop strong antibody responses to the virus, are protected from reinfection, and genetically modified versions exist that can be used to ask specific immunological questions. Large animal models such as rhesus and cynomologus macaques and African green monkeys are critical to understanding how the immune system responds to SARS-CoV-2 infection because they are considered to be the most similar to humans. These models are considered the gold standard for assessing vaccine efficacy and protection, and recapitulate the initial cytokine surge, immune cell infiltration into the lung, certain aspects of thrombosis, and the antibody and T-cell response to the virus. In this review, we discuss both small and large animal model studies previously used in SARS-CoV-2 research that may be useful in elucidating the immunological contributions to hallmark syndromes observed with COVID-19.

Animals are valuable resources in biomedical research in investigations of biological processes, disease pathogenesis, therapeutic interventions, safety, toxicity, and carcinogenicity. Interpretation of data from animals requires knowledge not only of the processes or diseases (pathophysiology) under study but also recognition of spontaneous conditions and background lesions (pathology) that can influence or confound the study results. Species, strain/stock, sex, age, anatomy, physiology, spontaneous diseases (noninfectious and infectious), and neoplasia impact experimental results and interpretation as well as animal welfare. This review and the references selected aim to provide a pathology resource for researchers, pathologists, and veterinary personnel who strive to achieve research rigor and validity and must understand the spectrum of "normal" and expected conditions to accurately identify research-relevant experimental phenotypes as well as unusual illness, pathology, or other conditions that can compromise studies involving laboratory mice, rats, gerbils, guinea pigs, hamsters, naked mole rats, and rabbits.