Th1-type responses mediate spontaneous ileitis in a novel murine model of Crohn's disease.
We describe here the immunologic characterization of a new mouse strain, SAMP1/Yit, which spontaneously develops a chronic intestinal inflammation localized to the terminal ileum. The resulting ileitis bears a remarkable resemblance to human Crohn's disease. This strain of mice develops discontinuous, transmural inflammatory lesions in the terminal ileum with 100% penetrance by 30 weeks of age. The intestinal inflammation is characterized by massive infiltration of activated CD4+ and CD8alpha(+)TCRalphabeta(+) T cells into the lamina propria and is accompanied by a dramatic decrease in the intraepithelial lymphocyte CD8alpha(+)TCRgammadelta(+)/CD8alpha(+)TCRalphabeta(+) ratio. The results of adoptive transfer experiments strongly suggest that CD4+ T cells that produce a Th1-like profile of cytokines, e.g., IFN-gamma and TNF, mediate the intestinal inflammation found in SAMP1/Yit mice. In addition, pretreatment of adoptive transfer recipients with a neutralizing anti-TNF antibody prevents the development of intestinal inflammation, suggesting that TNF plays an important role in the pathogenesis of intestinal inflammation in this model. To our knowledge, these data provide the first direct evidence that Th1-producing T cells mediate intestinal inflammation in a spontaneous animal model of human Crohn's disease.
Departments of Medicine and Pathology, University of Virginia Health System, Charlottesville, Virginia 22908, USA.
M M
MM
Kosiewicz
C C
CC
Nast
A
A
Krishnan
J
J
Rivera-Nieves
C A
CA
Moskaluk
S
S
Matsumoto
K
K
Kozaiwa
F
F
Cominelli
D019264:Adoptive Transfer; D000818:Animals; D003424:Crohn Disease / Q000209:etiology*; D016207:Cytokines / Q000096:biosynthesis; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007079:Ileitis / Q000209:etiology* / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008806:Mice, Inbred AKR; D008815:Mice, Inbred Strains; D016513:Mice, SCID; D009500:Neutralization Tests; D018417:Th1 Cells / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000276:immunology
D016207:Cytokines; D014409:Tumor Necrosis Factor-alpha