Advanced model systems and tools for basic and translational human immunology

Wagar, Lisa E.; DiFazio, Robert M.; Davis, Mark M.

doi:10.1186/s13073-018-0584-8

Cited by 80 publications

(65 citation statements)

References 179 publications

(157 reference statements)

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“…The murine models that currently are closest to mimicking the human immune system are humanized mouse models, which have the most promise in testing the antitumor effects in immunotherapy strategies [188]. Humanized mouse models are developed using genetic, tissue, or environmental engineering methods, and have many immunologic factors that resemble humans [189]. However, the utility of a given model for studying RIHD is dependent on the method and type of immune engraftment.…”

Section: Radiation Therapy and The Immune Responsementioning

confidence: 99%

Advances in Preclinical Research Models of Radiation-Induced Cardiac Toxicity

Schlaak

SenthilKumar

Boerma

et al. 2020

Cancers

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Radiation therapy (RT) is an important component of cancer therapy, with >50% of cancer patients receiving RT. As the number of cancer survivors increases, the short-and long-term side effects of cancer therapy are of growing concern. Side effects of RT for thoracic tumors, notably cardiac and pulmonary toxicities, can cause morbidity and mortality in long-term cancer survivors. An understanding of the biological pathways and mechanisms involved in normal tissue toxicity from RT will improve future cancer treatments by reducing the risk of long-term side effects. Many of these mechanistic studies are performed in animal models of radiation exposure. In this area of research, the use of small animal image-guided RT with treatment planning systems that allow more accurate dose determination has the potential to revolutionize knowledge of clinically relevant tumor and normal tissue radiobiology. However, there are still a number of challenges to overcome to optimize such radiation delivery, including dose verification and calibration, determination of doses received by adjacent normal tissues that can affect outcomes, and motion management and identifying variation in doses due to animal heterogeneity. In addition, recent studies have begun to determine how animal strain and sex affect normal tissue radiation injuries. This review article discusses the known and potential benefits and caveats of newer technologies and methods used for small animal radiation delivery, as well as how the choice of animal models, including variables such as species, strain, and age, can alter the severity of cardiac radiation toxicities and impact their clinical relevance.

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Section: Radiation Therapy and The Immune Responsementioning

confidence: 99%

Advances in Preclinical Research Models of Radiation-Induced Cardiac Toxicity

Schlaak

SenthilKumar

Boerma

et al. 2020

Cancers

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“…For example, given that the anti-FVIII immune response is most likely to develop during initial infusions of infants and toddlers, there is limited availability of the required blood volumes for mechanistic studies of inhibitor development in humans. Yet, these studies are vital to understand the basis of different clinical outcomes, especially given the many differences between the diverse human population vs. other species, notably inbred mice (188). The number of cells available from genetically well-characterized mice, and even large animal models, can also be a limiting factor for studies, e.g., when attempting to characterize splenic marginal zone cells, or vascular and sinusoidal endothelial cells.…”

Section: Discussionmentioning

confidence: 99%

Tolerating Factor VIII: Recent Progress

et al. 2020

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Development of neutralizing antibodies against biotherapeutic agents administered to prevent or treat various clinical conditions is a longstanding and growing problem faced by patients, medical providers and pharmaceutical companies. The hemophilia A community has deep experience with attempting to manage such deleterious immune responses, as the lifesaving protein drug factor VIII (FVIII) has been in use for decades. Hemophilia A is a bleeding disorder caused by genetic mutations that result in absent or dysfunctional FVIII. Prophylactic treatment consists of regular intravenous FVIII infusions. Unfortunately, 1/4 to 1/3 of patients develop neutralizing anti-FVIII antibodies, referred to clinically as "inhibitors," which result in a serious bleeding diathesis. Until recently, the only therapeutic option for these patients was "Immune Tolerance Induction," consisting of intensive FVIII administration, which is extraordinarily expensive and fails in ∼30% of cases. There has been tremendous recent progress in developing novel potential clinical alternatives for the treatment of hemophilia A, ranging from encouraging results of gene therapy trials, to use of other hemostatic agents (either promoting coagulation or slowing down anti-coagulant or fibrinolytic pathways) to "bypass" the need for FVIII or supplement FVIII replacement therapy. Although these approaches are promising, there is widespread agreement that preventing or reversing inhibitors remains a high priority. Risk profiles of novel therapies are still unknown or incomplete, and FVIII will likely continue to be considered the optimal hemostatic agent to support surgery and manage trauma, or to combine with other therapies. We describe here recent exciting studies, most still pre-clinical, that address FVIII immunogenicity and suggest novel interventions to prevent or reverse inhibitor development. Studies of FVIII uptake, processing and presentation on antigen-presenting cells, epitope mapping, and the roles of complement, heme, von Willebrand factor, glycans, and the microbiome in FVIII immunogenicity are elucidating mechanisms of primary and secondary immune responses and suggesting additional novel targets. Promising tolerogenic therapies include development of FVIII-Fc fusion proteins, nanoparticle-based therapies, oral tolerance, and engineering of regulatory or cytotoxic T cells to render them FVIII-specific. Importantly, these studies are highly applicable to other scenarios where establishing immune tolerance to a defined antigen is a clinical priority.

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“…A proxy approach, allowing dynamical investigation of tissue-specific immune responses, is the use of human organoid cultures, where some aspects of the tissue-specific immune system can be ascertained (Clevers 2016). Some of these model systems can now be used to investigate local immune responses to microbial pathogens, for example, in intestinal and lung organoid cultures (Heo et al 2018), and tonsil organoids can be used to investigate antigen-specific T-and B-cell responses in vitro (Wagar et al 2018). Such tools promise to offer more insights into vaccine responses and immune responses to tumors in humans and will allow dynamical investigation into regulatory properties with tissue-specific niches.…”

Section: Layers Of Investigation In Human Immunologymentioning

confidence: 99%

New approaches to the study of immune responses in humans

Brodin

2020

Hum Genet

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The human immune system consists of multiple, layered mechanisms of sensing and responding to cellular stress, infection and tissue damage to ensure defense from pathogens, maintenance of tissue homeostasis, and the integrity of the holobiont. Every single cell in the body has a role to play, but a few dozen, specialized white blood cells are particularly important in this respect. Understanding the overall state of this multifaceted system in a single individual is challenging, and we are only beginning to do this across populations of individuals, to understand the vast range of inter-individual variation, and the influences of genes and environmental factors that collectively shape the immune system in a given individual. We are also only beginning to understand the changes occurring within this system over time, and how this relates to health and disease susceptibility. Several technological breakthroughs in recent years have enabled these developments and the emergence of a new, complementary approach to studying human immune systems, namely systems immunology. In this paradigm, the focus is shifted from the understanding of individual immune system components and their mechanisms of action, towards analyses of cell-cell interactions, and mechanisms of coordination and regulation within the human immune system.Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Advanced model systems and tools for basic and translational human immunology

Cited by 80 publications

References 179 publications

Advances in Preclinical Research Models of Radiation-Induced Cardiac Toxicity

Advances in Preclinical Research Models of Radiation-Induced Cardiac Toxicity

Tolerating Factor VIII: Recent Progress

New approaches to the study of immune responses in humans

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