Humanized Mouse Model of Skin Inflammation Is Characterized by Disturbed Keratinocyte Differentiation and Influx of IL-17A Producing T Cells
Open Access
- 19 October 2012
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLOS ONE
- Vol. 7 (10), e45509
- https://doi.org/10.1371/journal.pone.0045509
Abstract
Humanized mouse models offer a challenging possibility to study human cell function in vivo. In the huPBL-SCID-huSkin allograft model human skin is transplanted onto immunodeficient mice and allowed to heal. Thereafter allogeneic human peripheral blood mononuclear cells are infused intra peritoneally to induce T cell mediated inflammation and microvessel destruction of the human skin. This model has great potential for in vivo study of human immune cells in (skin) inflammatory processes and for preclinical screening of systemically administered immunomodulating agents. Here we studied the inflammatory skin response of human keratinocytes and human T cells and the concomitant systemic human T cell response. As new findings in the inflamed human skin of the huPBL-SCID-huSkin model we here identified: 1. Parameters of dermal pathology that enable precise quantification of the local skin inflammatory response exemplified by acanthosis, increased expression of human β-defensin-2, Elafin, K16, Ki67 and reduced expression of K10 by microscopy and immunohistochemistry. 2. Induction of human cytokines and chemokines using quantitative real-time PCR. 3. Influx of inflammation associated IL-17A-producing human CD4+ and CD8+ T cells as well as immunoregulatory CD4+Foxp3+ cells using immunohistochemistry and -fluorescence, suggesting that active immune regulation is taking place locally in the inflamed skin. 4. Systemic responses that revealed activated and proliferating human CD4+ and CD8+ T cells that acquired homing marker expression of CD62L and CLA. Finally, we demonstrated the value of the newly identified parameters by showing significant changes upon systemic treatment with the T cell inhibitory agents cyclosporine-A and rapamycin. In summary, here we equipped the huPBL-SCID-huSkin humanized mouse model with relevant tools not only to quantify the inflammatory dermal response, but also to monitor the peripheral immune status. This combined approach will gain our understanding of the dermal immunopathology in humans and benefit the development of novel therapeutics for controlling inflammatory skin diseases.Keywords
This publication has 57 references indexed in Scilit:
- Techniques: Species' finest blend – humanized mouse models in inflammatory skin disease researchTrends in Pharmacological Sciences, 2004
- Monitoring hyperproliferative disorders in human skin: Flow cytometry of changing cytokeratin expressionCytometry, 2003
- The frequency of CLA+ CD8+ T cells in the blood of psoriasis patients correlates closely with the severity of their diseaseClinical and Experimental Immunology, 2001
- Regulatory T Cells: Key Controllers of Immunologic Self-ToleranceCell, 2000
- Human T-cell-mediated destruction of allogeneic dermal microvessels in a severe combined immunodeficient mouse.Proceedings of the National Academy of Sciences of the United States of America, 1994
- SKALP/elafin is an inducible proteinase inhibitor in human epidermal keratinocytesJournal of Cell Science, 1994
- Up-Regulation of Elafin/SKALP Gene Expression in Psoriatic EpidermisJournal of Investigative Dermatology, 1994
- Immunohistochemical Localization of SKALP/Elafin in Psoriatic EpidermisJournal of Investigative Dermatology, 1993
- Homozygous scid/scid;beige/beige mice have low levels of spontaneous or neonatal T cell-induced B cell generation.The Journal of Experimental Medicine, 1993
- Convulsions with an Occult Neural-Crest TumorThe New England Journal of Medicine, 1979