title: Humanized mouse model of skin inflammation is characterized by disturbed keratinocyte differentiation and influx of IL-17A producing T cells.
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.
authors.affiliation: Laboratory of Medical Immunology, Department of Laboratory Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: Vivian L
authors.initials: VL
authors.lastname: de Oliveira
authors.forename: Romy R M C
authors.initials: RR
authors.lastname: Keijsers
authors.forename: Peter C M
authors.initials: PC
authors.lastname: van de Kerkhof
authors.forename: Marieke M B
authors.initials: MM
authors.lastname: Seyger
authors.forename: Esther
authors.initials: E
authors.lastname: Fasse
authors.forename: Lars
authors.initials: L
authors.lastname: Svensson
authors.forename: Markus
authors.initials: M
authors.lastname: Latta
authors.forename: Hanne
authors.initials: H
authors.lastname: Norsgaard
authors.forename: Tord
authors.initials: T
authors.lastname: Labuda
authors.forename: Pieter
authors.initials: P
authors.lastname: Hupkens
authors.forename: Piet E J
authors.initials: PE
authors.lastname: van Erp
authors.forename: Irma
authors.initials: I
authors.lastname: Joosten
authors.forename: Hans J P M
authors.initials: HJ
authors.lastname: Koenen
mesh_terms: D000818:Animals; D000945:Antigens, Differentiation, T-Lymphocyte / Q000235:genetics / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology / Q000637:transplantation; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology / Q000637:transplantation; D002454:Cell Differentiation; D016572:Cyclosporine / Q000494:pharmacology; D004195:Disease Models, Animal; D053492:Elafin / Q000235:genetics / Q000276:immunology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D007274:Injections, Intraperitoneal; D020381:Interleukin-17 / Q000096:biosynthesis* / Q000276:immunology; D015603:Keratinocytes / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D007633:Keratins / Q000235:genetics / Q000276:immunology; D019394:Ki-67 Antigen / Q000235:genetics / Q000276:immunology; D019041:L-Selectin / Q000235:genetics / Q000276:immunology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology; D051379:Mice; D016513:Mice, SCID; D020123:Sirolimus / Q000494:pharmacology; D012867:Skin / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D016038:Skin Transplantation; D014183:Transplantation, Heterologous; D023083:beta-Defensins / Q000235:genetics / Q000276:immunology
chemical_list: D000945:Antigens, Differentiation, T-Lymphocyte; C063419:CTAGE1 protein, human; C106641:DEFB4A protein, human; D053492:Elafin; C508717:IL17A protein, human; D020381:Interleukin-17; D019394:Ki-67 Antigen; D008562:Membrane Glycoproteins; C506806:PI3 protein, human; D023083:beta-Defensins; D019041:L-Selectin; D007633:Keratins; D016572:Cyclosporine; D020123:Sirolimus