Treatment of T cell-dependent experimental colitis in SCID mice by local administration of an adenovirus expressing IL-18 antisense mRNA.
Recent studies have shown that IL-18, a pleiotropic cytokine that augments IFN-gamma production, is produced by intestinal epithelial cells and lamina propria cells from patients with Crohn's disease. In this study, we show that IL-18 is strongly expressed by intestinal epithelial cells in a murine model of Crohn's disease induced by transfer of CD62L+ CD4+ T cells into SCID mice. To specifically down-regulate IL-18 expression in this model, we constructed an E1/E3-deleted adenovirus expressing IL-18 antisense mRNA, denoted Ad-asIL-18, and demonstrated the capacity of such a vector to down-regulate IL-18 expression in colon-derived DLD-1 cells and RAW264.7 macrophages. Local administration of the Ad-asIL-18 vector to SCID mice with established colitis led to transduction of epithelial cells and caused a significant suppression of colitis activity, as assessed by a newly developed endoscopic analysis system for colitis. Furthermore, treatment with Ad-asIL-18 induced a significant suppression of histologic colitis activity and caused suppression of mucosal IFN-gamma production, whereas IFN-gamma production by spleen T cells was unaffected. Taken together, these data indicate an important role for IL-18 in the effector phase of a T cell-dependent murine model of colitis and suggest that strategies targeting IL-18 expression may be used for the treatment of patients with Crohn's disease.
Wirtz
Stefan
S
Laboratory of Immunology, I Medical Clinic, University of Mainz, Langenbeckstrasse 1, Mainz, Germany.
Becker
Christoph
C
Blumberg
Richard
R
Galle
Peter R
PR
Neurath
Markus F
MF
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002460:Cell Line; D002478:Cells, Cultured; D003092:Colitis / Q000276:immunology / Q000473:pathology / Q000628:therapy; D003106:Colon / Q000276:immunology / Q000473:pathology; D003113:Colonoscopy; D003424:Crohn Disease / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D015536:Down-Regulation; D015316:Genetic Therapy; D005822:Genetic Vectors; D007371:Interferon-gamma / Q000096:biosynthesis; D020382:Interleukin-18 / Q000235:genetics* / Q000378:metabolism; D007413:Intestinal Mucosa / Q000276:immunology; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D016372:RNA, Antisense / Q000235:genetics* / Q000378:metabolism
D020382:Interleukin-18; D016372:RNA, Antisense; D007371:Interferon-gamma