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Intestinal Immune Responses in Wild-Type and Apc^Min/+ Mouse, a Model for Colon Cancer¹

Danisco Innovation, FIN-02460 Kantvik, Finland

C57BL/6J Apc^Min/+ (Apc^Min/+) mice spontaneously develop pretumoric adenomas into the intestinal mucosa. We studied the relationship between the intestinal immune responses and adenoma formation in Apc^Min/+ mice and compared Apc^Min/+ mice with their wild-type siblings. Three time points (5, 8, and 15 weeks of age) and three high-fat dietary treatments (a non-fiber control with beef or inulin amendment) were included. The numbers of CD8+ T lymphocytes and tissue macrophages (Mac-1+ cells) per villus in ileal mucosa were determined by immunohistology, and the concentrations of secretory IgA, residual prostaglandin E₂ (PGE₂), tumor necrosis factor , and interleukin (IL)-12 in ileal contents were analyzed by ELISA. The crypt-villus ratio of the ileal mucosa was determined histologically. An immunostimulation, characterized by an increase in several parameters (PGE₂, IgA, Mac-1, and CD8), was observed in both genotypes between weeks 5 and 8. Most of the adenomas in Apc^Min/+ mice also appeared during the same period of sexual maturation. Females had smaller adenomas than males, and the beef group had fewer and smaller adenomas than the control group at 15 weeks. Females had less IgA and fewer Mac-1+ and CD8+ cells in ileal tissue than males at 15 weeks and more luminal IL-12 than males at 8 weeks. Puberty may have affected both tumorigenesis and intestinal immune responses in the Apc^Min/+ mouse. The beef group showed less luminal IgA and tumor necrosis factor but more IL-12 than the control group. The concentration of PGE₂ correlated positively with the number and size of adenomas and was higher in the Apc^Min/+ mice than in wild-type mice at 15 weeks. IgA and Mac-1 were positively correlated with the size of adenomas at 15 weeks. The positive correlations between tumor size and IgA and between tumor number and size and PGE₂ suggest that a balance toward the Th2 type immune response may affect the pace of tumorigenesis in this model. The general similarity of the intestinal immune responses in both genotypes and the lack of intestinal inflammation in the Apc^Min/+ mice suggest that the mutation in the adenomatous polyposis coli gene does not lead to major alterations in intestinal immune function and that the intestinal immunology does not explain tumorigenesis in the Apc^Min/+ mouse model.

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