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NOD-scid IL2R γnull mice engrafted with human peripheral blood mononuclear cells as a model to test therapeutics
Maryam Zadeh-Khorasani1, Thomas Nolte, Thomas D Mueller
1Department of Surgery, Klinikum der Ludwig-Maximilians Universität München, Munich, Germany.
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.
Insights
This study developed a novel animal model for Atopic Dermatitis (AD) using human cells in mice. The model successfully demonstrated therapeutic targeting of IL-4 pathways, showing promise for better drug development in AD.
Area of Science:
- Immunology
- Dermatology
- Translational Medicine
Background:
- Current animal models for human inflammatory diseases lack predictive accuracy for clinical trials due to species-specific differences and dissimilar immunological backgrounds.
- The genetic heterogeneity and advanced age of patient populations further complicate direct translation from animal studies.
Purpose of the Study:
- To develop a more translatable animal model for testing therapeutics targeting pathways involved in Atopic Dermatitis (AD).
- To improve the predictive quality of preclinical studies for human clinical trials in AD.
Main Methods:
- NOD-scid IL2R γnull mice were engrafted with human peripheral blood mononuclear cells (hPBMC) from AD patients and healthy donors.
- Mice were treated with IL-4 and an IL-4 antagonist (Pitrakinra) to assess therapeutic effects on human IgE, B-cells, T-cells, and CD4:CD8 ratios.
- In vivo results were compared with in vitro analyses.
Main Results:
- IL-4 induced human IgE secretion and B-cell proliferation in vivo, which were inhibited by Pitrakinra.
- IL-4 altered CD4:CD8 ratios, an effect reversed by Pitrakinra, particularly in hPBMC from healthy donors.
- Engrafted mice reflected individual patient responses, showing inertness in AD patient-derived hPBMC.
Conclusions:
- Engrafted NOD-scid IL2R γnull mice carrying human PBMC mirror donor immunological histories.
- This model serves as a valuable complement to in vitro studies, offering improved translatability from preclinical research to clinical application.
- The findings suggest this model can yield more predictive data for Atopic Dermatitis therapeutics.
