NOD-scid IL2R γnull mice engrafted with human peripheral blood mononuclear cells as a model to test therapeutics targeting human signaling pathways

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• 作者：Maryam Zadeh-Khorasani (1)
  Thomas Nolte (2)
  Thomas D Mueller (3)
  Markos Pechlivanis (3)
  Franziska Rueff (4)
  Andreas Wollenberg (4)
  Gert Fricker (5)
  Eckhard Wolf (2)
  Matthias Siebeck (1)
  Roswitha Gropp (1)
  
• 刊名：Journal of Translational Medicine
• 出版年：2013
• 出版时间：December 2013
• 年：2013
• 卷：11
• 期：1
• 全文大小：405KB
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• 作者单位：Maryam Zadeh-Khorasani (1)
  Thomas Nolte (2)
  Thomas D Mueller (3)
  Markos Pechlivanis (3)
  Franziska Rueff (4)
  Andreas Wollenberg (4)
  Gert Fricker (5)
  Eckhard Wolf (2)
  Matthias Siebeck (1)
  Roswitha Gropp (1)
  
  1. Department of Surgery, Klinikum der Ludwig-Maximilians Universit?t München, Munich, 80336, Germany
  2. Institute of Molecular Animal Breeding and Biotechnology, and Laboratory for Functional Genome Analysis (LAFUGA), Gene Center, LMU Munich, Munich, 81377, Germany
  3. Julius von Sachs Institute, University of Würzburg, Würzburg, 87082, Germany
  4. Department of Dermatology, Klinikum der Ludwig-Maximilians Universit?t München, Munich, 80336, Germany
  5. Institute for Pharmacy and Molecular Biotechnology, University of Heidelberg, Heidelberg, 69120, Germany
  

文摘

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 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. 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 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.