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Immunologic responses to various forms of allergen immunotherapy
Published in Richard F. Lockey, Dennis K. Ledford, Allergens and Allergen Immunotherapy, 2020
Umit Murat Sahiner, Mohamed H. Shamji, Sakura Sato, Ozge Soyer, Stephen J. Till, Motohiro Ebisawa, Mübeccel Akdis, Stephen R. Durham
Identifying the mechanism by which SCIT induces IL-10 producing T cells could be important in the design of new vaccines. Murine models provide some insights. Nevertheless, important differences exist between SCIT administered to patients to modulate mature Th2 responses and animal models where the emphasis is on tolerizing regimes given before sensitization. Tolerizing animals by oral or intranasal exposure to ovalbumin prior to intraperitoneal sensitization induces IL-10 producing regulatory T cells [80,81]. In the intranasal tolerance model, induction of these Tr1-like cells is dependent on pulmonary lymph node dendritic cells expressing IL-10 and the costimulatory molecule ICOS ligand. Indeed, adoptive transfer of these dendritic cells or Tr1 cells alone is sufficient to confer tolerance on the recipients [80,82]. Human peripheral blood pDCs stimulated with a TLR 9 agonist express ICOS ligand and induce differentiation of Tr1 cells from naïve T cells in vitro [83]. Furthermore, cross-linking of the high-affinity IgE receptor (FcεRI) on pDCs by allergen also induces IL-10 expression [84]. Although these mechanisms have not yet been directly implicated during SCIT, they do indicate that dendritic cells could induce T-cell responses following allergen vaccination.
Hematopoietic Stem Cell Transplantation for Systemic Lupus Erythematosus
Published in Richard K. Burt, Alberto M. Marmont, Stem Cell Therapy for Autoimmune Disease, 2019
Ann E. Traynor, Richard K. Burt, Alberto Marmont
The availability of multiple highly inbred murine models has been pivotal to our understanding of genetic and environmental factors.13-15 Thus far, at least 45 named loci are linked to one or more lupus traits in murine lupus,16 while the presence of susceptibility genes in several chromosomal regions has been confirmed in humans.17 Recent studies of genetic reconstitution in polycongenic murine strains have characterized three susceptibility genes.18 Sle 1 mediates the loss of tolerance to chromatin; sle 2 lowers the activation threshold of B cells, and sle 3 mediates a dysregulation of CD 4+ T cells, which in humans have been shown to mediate a secondary antigen-driven immune response19 and to stimulate the B-cell dependent production of antinuclear antibodies.20 The whole process has been imaginatively equated by Alarcón-Segovia to the effect of three troikas, Russian carriages in which teams of three horses pull independently but concertedly.21
Hits and Lead Discovery in the Identification of New Drugs against the Trypanosomatidic Infections
Published in Venkatesan Jayaprakash, Daniele Castagnolo, Yusuf Özkay, Medicinal Chemistry of Neglected and Tropical Diseases, 2019
Theodora Calogeropoulou, George E. Magoulas, Ina Pöhner, Joanna Panecka-Hofman, Pasquale Linciano, Stefania Ferrari, Nuno Santarem, Ma Dolores Jiménez-Antón, Ana Isabel Olías-Molero, José María Alunda, Anabela Cordeiro da Silva, Rebecca C. Wade, Maria Paola Costi
Murine models, due to their small size, availability of tools for genetic manipulation and immunological studies, are at the forefront of animal use in science (Vandamme 2015). Notwithstanding, the use of animals in scientific research has always been a socially polarizing subject even with the implementation of the three Rs (Replacement, Reduction and Refinement) proposed more than 60 years ago (Russell and Burch 1959). For an animal model to be considered, there must be similarities related to disease etiology, pathophysiology, symptomatology and also response to therapeutic or prophylactic agents. In this sense, animal models have contributed decisively to the understanding of pathophysiological processes associated with infection and disease and have also been instrumental in pre-clinical vaccine and drug development.
Addressing the challenges to increase the efficiency of translating nanomedicine formulations to patients
Published in Expert Opinion on Drug Discovery, 2021
Sourav Bhattacharjee, David J. Brayden
Harmonization of experimental protocols, addressing scale-up for manufacturing, the use of quality-by-design, and reduction in batch variation are areas for improvement. Moreover, a better correlation between the in vitro and in vivo assays is required to convert the translational potential of available nanoformulations into viable products [228]. Only a few of the issues that are essential for translation are being addressed in academic labs, who tend to focus on the efficacy of their latest NP design, perhaps in just a single study conducted in rodent models. Academic labs are usually not equipped for large scale production of nanomaterials, and, at the same time, upscaling initiatives require an extensive risk assessment, given the toxic potential of nanoscale materials. Thus, collaboration with industry is important from a manufacturing perspective. A rationale should also dictate the choice of animal models for academic labs. In vivo murine models should be used only if they offer a clear advantage over in vitro platforms. It can be argued that the ‘publish or perish’ culture in academia has encouraged nanoformulations toward premature and inappropriate in vivo studies [229].
Exposure to air pollutants and the gut microbiota: a potential link between exposure, obesity, and type 2 diabetes
Published in Gut Microbes, 2020
Maximillian J. Bailey, Noopur N. Naik, Laura E. Wild, William B. Patterson, Tanya L. Alderete
The use of murine models has allowed for experimental studies that are not feasible in humans. While these investigations are a useful tool for predicting the possible effects of environmental exposures on the human gut microbiota, there are limitations to using animal studies to infer the impact of air pollutants on the human gut. For example, only 15% of the genera of microbes in the distal gut of mice have been identified in the human gut.89 Moreover, there are differences in the anatomy of the human and murine GI tract as humans lack a forestomach and mice lack an appendix and have different distributions of goblet and Paneth cells.90 These differences in the composition of the gut microbiota and anatomy of the GI tract have the potential to impact microbe, host, and environment interactions. Given this, it is important to examine the associations between increased exposure to air pollutants and the gut microbiome in humans.
An overview of drug discovery efforts for eczema: why is this itch so difficult to scratch?
Published in Expert Opinion on Drug Discovery, 2020
Kam Lun Hon, Steven Loo, Alexander K. C. Leung, Joyce T. S. Li, Vivian W. Y. Lee
Murine models in AD certainly have facilitated novel drug development. In the last decade, the molecular concept for the pathophysiology of AD had increasingly been delineated, particularly in regard to immune abnormalities, barrier dysfunction and the role of the microbiome. Although controversies persist if the pathogenesis of AD is primarily ‘inside out’ versus ‘outside in’, it is now clear that the role of the epidermal barrier, immune dysfunction, and microbiota are all linked with each other [47,48]. Our understanding of these contributing factors has enabled the development of new therapeutics which target the epidermal barrier, suppress aberrant immune pathways, normalize the skewed microbiota of affected skin, and ultimately reduce pruritus. Consequently, in the process of new drug development and evaluation at a preclinical level, murine models are essential.