In this study, recently published in the high-ranking scientific journal Allergy the authors, including our founder Prof. Ralf Paus and acting CEO Dr. Marta Bertolini, describe the development of a novel humanized mouse model of AD that reflects the most important hallmarks of human AD (learn more here). We are proud to announce that this study is the first example, where we collaborated successfully with our sister company QIMA Life Sciences, who supported us with their expertise in lipidomic analysis.
Atopic dermatitis (AD), also referred to as eczema, is one of the most common chronic inflammatory skin diseases affecting around 5-20% of children and 1-3% of adults worldwide, while the prevalence varies substantially among different countries. Patients with AD exhibit inflamed, itchy skin lesions that result from abnormalities in innate and acquired skin immunity, where skin barrier function and associated microbiome dysbiosis, as well as neurogenic skin inflammation lead to the destructive itch-scratch cycle. Unfortunately, the key signals that trigger AD remain incompletely understood. Animal (mouse) models are commonly used to study AD in vivo; however, these models insufficiently reflect human AD.
In the current study, the authors describe a novel humanized mouse model of AD, which allows for pre-clinical research to functionally and mechanistically test hypotheses and investigate treatments for AD directly in human tissue in vivo. Healthy human skin tissue was xenotransplanted onto SCID mice that lack a functional immune system. One month after the transplantation, the human skin was fully revascularized and reinnervated. At that time point immune cells, isolated from the blood of the same individual that donated the skin, were polarized into Th2 T-cells, the key cell type involved in AD pathogenesis. These immune cells were injected into the xenotransplants and elicited an immune response in the transplanted skin, reminiscent of AD in patients. The authors confirmed that the major hallmarks of AD were adequately represented in the AD-like lesions of the skin xenografts, including a compromised skin barrier function as well as a pro-inflammatory, Th2-type cytokine millieu. Of note, markers pointing at sensory hyperinnervation, neurogenic skin inflammation and AD-associated pruritus, characteristics of human AD that have not been successfully replicated in any current mouse model, were dysregulated in the AD-like lesions of the humanized mouse model.
To further confirm that these AD-like lesions were reminiscent of human AD, and thereby prove the translational potential of the model, the authors showed that the transplanted human skin AD lesions responded to standard-of-care therapeutic drugs for AD, including application of topical glucocorticosteroids and tacrolimus. Additionally, the model was further validated by showing that once in remission, the lesions relapsed when the mice were exposed to an external stressor. This characteristic is strongly in line with patients’ reporting of the triggering or aggravation of their AD lesions by psychoemotional stress.
Next, the authors were interested whether the Th2 cytokines IL-4 and IL-13 alone were sufficient to induce an AD like phenotype in human skin. Therefore, they treated healthy human skin ex vivo with IL-4 and IL-13, which resulted into expression changes of inflammatory cytokines and skin barrier impairments. These findings highlight a key role of IL-4 and IL-13 for the development of AD, as well as the potential of the skin organ culture as model system for AD (for e.g. drug screening purposes).
Finally, the authors showed that IL-4 and IL-13 were not only required for the development of AD-like lesions ex vivo, but also in the xenotransplants in vivo. Application of Dupilumab or Tralokinumab, antibodies that neutralize IL-4 or IL-13, respectively, prevented induction of the AD-like phenotype and reduced AD characteristics when applied therapeutically. Lastly, the authors could demonstrate that also the lipid barrier was impaired in AD lesions, which was reversed under Dupilumap treatment.
Altogether, the study reports the development of a valuable, clinically relevant, and first-of-its-kind humanized mouse model of AD that will be an invaluable tool in the development of future treatments and subsequent benefit to patients.
Read the full story here: Autologous Th2-polarized lymphocytes induce atopic dermatitis lesions in non-atopic human skin xenotransplants - PubMed (nih.gov)