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NOD-scid IL2R \(\gamma^{null}\) mice engrafted with human peripheral blood mononuclear cells as a model to test therapeutics targeting human signaling pathways

Please always quote using this URN: urn:nbn:de:bvb:20-opus-122960
  • 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 IL2RBackground: 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 \(\gamma^{null}\) 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 \(\gamma^{null}\) 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.show moreshow less

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Metadaten
Author: Maryam Zadeh-Khorasani, Thomas Nolte, Thomas D. Mueller, Markos Pechlivanis, Franziska Rueff, Andreas Wollenberg, Gert Fricker, Eckhard Wolf, Matthias Siebeck, Roswitha Gropp
URN:urn:nbn:de:bvb:20-opus-122960
Document Type:Journal article
Faculties:Fakultät für Biologie / Rudolf-Virchow-Zentrum
Language:English
Parent Title (English):Journal of Translational Medicine
ISSN:1479-5876
Year of Completion:2013
Volume:11
Issue:4
Source:Journal of Translational Medicine 2013, 11:4. doi:10.1186/1479-5876-11-4
DOI:https://doi.org/10.1186/1479-5876-11-4
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Tag:T-cells; TGN1412; antagonists; atopic dermatitis; cytokine release; expression; human interleukin-4; oxazolone colitis; responses; rheumatoid arthritis
Release Date:2016/02/29
Licence (German):License LogoCC BY: Creative-Commons-Lizenz: Namensnennung