Abstract
BackgroundAnimal models of human inflammatory diseases have limited predictive quality for human clinical trials for various reasons including species specific activation mechanisms and the immunological background of the animals which markedly differs from the genetically heterogeneous and often aged patient population.ObjectiveDevelopment of an animal model allowing for testing therapeutics targeting pathways involved in the development of Atopic Dermatitis (AD) with better translatability to the patient.MethodsNOD-scid IL2R γnull mice engrafted with human peripheral blood mononuclear cells (hPBMC) derived from patients suffering from AD and healthy volunteers were treated with IL-4 and the antagonistic IL-4 variant R121/Y124D (Pitrakinra). Levels of human (h)IgE, amount of B-, T- and plasma- cells and ratio of CD4 : CD8 positive cells served as read out for induction and inhibition of cell proliferation and hIgE secretion. Results were compared to in vitro analysis.ResultshIgE secretion was induced by IL-4 and inhibited by the IL-4 antagonist Pitrakinra in vivo when formulated with methylcellulose. B-cells proliferated in response to IL-4 in vivo; the effect was abrogated by Pitrakinra. IL-4 shifted CD4 : CD8 ratios in vitro and in vivo when hPBMC derived from healthy volunteers were used. Pitrakinra reversed the effect. Human PBMC derived from patients with AD remained inert and engrafted mice reflected the individual responses observed in vitro.ConclusionNOD-scid IL2R γnull mice engrafted with human PBMC reflect the immunological history of the donors and provide a complementary tool to in vitro studies. Thus, studies in this model might provide data with better translatability from bench to bedside.
Highlights
A large number of drug candidates fail in clinical trials due to lack of efficacy and unforeseen toxicity
The shortcomings of present animal models applies to chronic inflammatory diseases since they mostly rely on the development of the disease in 12-week-old inbred mice maintained under specific pathogen free (SPF) conditions which markedly differ from the pathophysiological mechanisms in the genetically heterogeneous and often aged patient populations [2,3,4]
Formulation of IL-4 with methylcellulose induces the secretion of hIgE In order to examine whether the formulation of IL-4 with methylcellulose enhances the secretion of hIgE in NODscid IL2R γnull mice engrafted with Human peripheral blood mononuclear cells (hPBMC), hIgE levels were measured in animals treated with 10 μg IL-4 in phosphate buffered saline (PBS) (IL-4, n = 10) and animals treated with 10 μg IL-4 formulated with 0.5% methylcellulose, 0.05% TWEEN 80 in PBS (IL-4 + Methylcellulose, n = 12)
Summary
A large number of drug candidates fail in clinical trials due to lack of efficacy and unforeseen toxicity This is especially relevant in immunological diseases where animal models might not accurately reflect activation mechanisms exerted in humans. The shortcomings of present animal models applies to chronic inflammatory diseases since they mostly rely on the development of the disease in 12-week-old inbred mice maintained under specific pathogen free (SPF) conditions which markedly differ from the pathophysiological mechanisms in the genetically heterogeneous and often aged patient populations [2,3,4]. Animal models of human inflammatory diseases have limited predictive quality for human clinical trials for various reasons including species specific activation mechanisms and the immunological background of the animals which markedly differs from the genetically heterogeneous and often aged patient population
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
