title: Oxazolone and ethanol induce colitis in non-obese diabetic-severe combined immunodeficiency interleukin-2Rγ(null) mice engrafted with human peripheral blood mononuclear cells.
abstract: Oxazolone-induced colitis in mice has become a recognized model to study the efficacy of therapeutics targeting the immunological response underlying the development of inflammatory bowel disease. However, this model cannot be used when therapeutics designed to address human targets do not interact with the respective murine counterpart. In this study, we examined the induction of oxazolone mediated colitis in non-obese diabetic-severe combined immunodeficiency interleukin-2Rγ(null) (NOD-SCID IL2Rγ(null)) mice engrafted with human peripheral blood mononuclear cells (hPBMC) derived from patients suffering from ulcerative colitis (UC), atopic dermatitis (AD) and healthy volunteers. NOD-SCID IL2Rγ (null) mice were engrafted with hPBMC followed by challenge with oxazolone or ethanol vehicle. Mice developed the same symptoms as observed previously in immunocompetent mice. The clinical activity score increased and the colon architecture was characterized by the development of oedema, fibrosis, crypt loss and dense infiltration of predominantly T cells into the lamina propria. Fluorescence activated cell sorter (FACS) analysis of lymphocytes in the colon identified natural killer (NK) T cells as a major constituent. In contrast to studies with immunocompetent mice, we observed the same phenotype in the group challenged with ethanol vehicle. The phenotype was most pronounced in mice engrafted with PBMC derived from a patient suffering from UC, suggesting that the immunological history of the donors predisposes the engrafted mice to react to ethanol. The model described here has the potential to study the efficacy of therapeutics targeting human lymphocytes in a model which is more reflective of the human disease. In addition, it might be developed to elucidate molecular mechanisms underlying the disease.
authors.affiliation: Institute of Molecular Animal Breeding and Biotechnology, Laboratory for Functional Genome Analysis, Gene Center, LMU Munich, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Nolte
authors.forename: M
authors.initials: M
authors.lastname: Zadeh-Khorasani
authors.forename: O
authors.initials: O
authors.lastname: Safarov
authors.forename: F
authors.initials: F
authors.lastname: Rueff
authors.forename: V
authors.initials: V
authors.lastname: Gülberg
authors.forename: N
authors.initials: N
authors.lastname: Herbach
authors.forename: A
authors.initials: A
authors.lastname: Wollenberg
authors.forename: T
authors.initials: T
authors.lastname: Mueller
authors.forename: M
authors.initials: M
authors.lastname: Siebeck
authors.forename: E
authors.initials: E
authors.lastname: Wolf
authors.forename: R
authors.initials: R
authors.lastname: Gropp
mesh_terms: D000818:Animals; D002460:Cell Line; D003093:Colitis, Ulcerative / Q000139:chemically induced / Q000276:immunology*; D003876:Dermatitis, Atopic / Q000276:immunology*; D004195:Disease Models, Animal; D000431:Ethanol / Q000494:pharmacology*; D006086:Graft vs Host Disease / Q000276:immunology; D006801:Humans; D007073:Immunoglobulin E / Q000097:blood; D007074:Immunoglobulin G / Q000097:blood; D053631:Interleukin Receptor Common gamma Subunit / Q000235:genetics / Q000276:immunology; D007963:Leukocytes, Mononuclear / Q000637:transplantation*; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D010081:Oxazolone / Q000494:pharmacology*; D015375:Receptors, Interleukin-2 / Q000235:genetics; D014183:Transplantation, Heterologous / Q000276:immunology
chemical_list: D007074:Immunoglobulin G; D053631:Interleukin Receptor Common gamma Subunit; D015375:Receptors, Interleukin-2; D010081:Oxazolone; D007073:Immunoglobulin E; D000431:Ethanol