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NOD-scid IL2R γ(null) mice engrafted with human peripheral blood mononuclear cells as a model to test therapeutics targeting human signaling pathways
BACKGROUND: 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...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2013
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3558457/ https://www.ncbi.nlm.nih.gov/pubmed/23294516 http://dx.doi.org/10.1186/1479-5876-11-4 |
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author | Zadeh-Khorasani, Maryam Nolte, Thomas Mueller, Thomas D Pechlivanis, Markos Rueff, Franziska Wollenberg, Andreas Fricker, Gert Wolf, Eckhard Siebeck, Matthias Gropp, Roswitha |
author_facet | Zadeh-Khorasani, Maryam Nolte, Thomas Mueller, Thomas D Pechlivanis, Markos Rueff, Franziska Wollenberg, Andreas Fricker, Gert Wolf, Eckhard Siebeck, Matthias Gropp, Roswitha |
author_sort | Zadeh-Khorasani, Maryam |
collection | PubMed |
description | BACKGROUND: 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. OBJECTIVE: Development of an animal model allowing for testing therapeutics targeting pathways involved in the development of Atopic Dermatitis (AD) with better translatability to the patient. METHODS: NOD-scid IL2R γ(null) 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. RESULTS: hIgE 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. CONCLUSION: NOD-scid IL2R γ(null) 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. |
format | Online Article Text |
id | pubmed-3558457 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-35584572013-01-31 NOD-scid IL2R γ(null) mice engrafted with human peripheral blood mononuclear cells as a model to test therapeutics targeting human signaling pathways Zadeh-Khorasani, Maryam Nolte, Thomas Mueller, Thomas D Pechlivanis, Markos Rueff, Franziska Wollenberg, Andreas Fricker, Gert Wolf, Eckhard Siebeck, Matthias Gropp, Roswitha J Transl Med Methodology BACKGROUND: 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. OBJECTIVE: Development of an animal model allowing for testing therapeutics targeting pathways involved in the development of Atopic Dermatitis (AD) with better translatability to the patient. METHODS: NOD-scid IL2R γ(null) 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. RESULTS: hIgE 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. CONCLUSION: NOD-scid IL2R γ(null) 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. BioMed Central 2013-01-07 /pmc/articles/PMC3558457/ /pubmed/23294516 http://dx.doi.org/10.1186/1479-5876-11-4 Text en Copyright ©2013 Zadeh-Khorasani et al.; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Methodology Zadeh-Khorasani, Maryam Nolte, Thomas Mueller, Thomas D Pechlivanis, Markos Rueff, Franziska Wollenberg, Andreas Fricker, Gert Wolf, Eckhard Siebeck, Matthias Gropp, Roswitha NOD-scid IL2R γ(null) mice engrafted with human peripheral blood mononuclear cells as a model to test therapeutics targeting human signaling pathways |
title | NOD-scid IL2R γ(null) mice engrafted with human peripheral blood mononuclear cells as a model to test therapeutics targeting human signaling pathways |
title_full | NOD-scid IL2R γ(null) mice engrafted with human peripheral blood mononuclear cells as a model to test therapeutics targeting human signaling pathways |
title_fullStr | NOD-scid IL2R γ(null) mice engrafted with human peripheral blood mononuclear cells as a model to test therapeutics targeting human signaling pathways |
title_full_unstemmed | NOD-scid IL2R γ(null) mice engrafted with human peripheral blood mononuclear cells as a model to test therapeutics targeting human signaling pathways |
title_short | NOD-scid IL2R γ(null) mice engrafted with human peripheral blood mononuclear cells as a model to test therapeutics targeting human signaling pathways |
title_sort | nod-scid il2r γ(null) mice engrafted with human peripheral blood mononuclear cells as a model to test therapeutics targeting human signaling pathways |
topic | Methodology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3558457/ https://www.ncbi.nlm.nih.gov/pubmed/23294516 http://dx.doi.org/10.1186/1479-5876-11-4 |
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