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Alteration of interleukin 4 production results in the inhibition of T helper type 2 cell-dominated inflammatory bowel disease in T cell receptor alpha chain-deficient mice.

Iijima H, Takahashi I, Kishi D, Kim JK, Kawano S, Hori M, Kiyono H - J. Exp. Med. (1999)

Bottom Line: The colitis that develops in these mice is associated with increased numbers of T helper cell (Th)2-type CD4(+)TCR-betabeta (CD4(+)betabeta) T cells producing predominantly interleukin (IL)-4.Although TCR-alpha(-/-) mice treated with either specific or mock Ab developed CD4(+)betabeta T cells, only those treated with anti-IL-4 mAb showed a decrease in Th2-type cytokine production at the level of mRNA and protein and an increase in interferon gamma-specific expression.These findings suggest that IL-4-producing Th2-type CD4(+)betabeta T cells play a major immunopathological role in the induction of IBD in TCR-alpha(-/-) mice, a role that anti-IL-4 mAb inhibits by causing Th2-type CD4(+)betabeta T cells to shift to the Th1 type.

View Article: PubMed Central - PubMed

Affiliation: Department of Mucosal Immunology, Research Institute for Microbial Diseases, Osaka University, Japan.

ABSTRACT
T cell receptor alpha chain-deficient (TCR-alpha(-/-)) mice are known to spontaneously develop inflammatory bowel disease (IBD). The colitis that develops in these mice is associated with increased numbers of T helper cell (Th)2-type CD4(+)TCR-betabeta (CD4(+)betabeta) T cells producing predominantly interleukin (IL)-4. To investigate the role of these Th2-type CD4(+)betabeta T cells, we treated TCR-alpha(-/-) mice with anti-IL-4 monoclonal antibody (mAb). Approximately 60% of TCR-alpha(-/-) mice, including those treated with mock Ab and those left untreated, spontaneously developed IBD. However, anti-IL-4 mAb-treated mice exhibited no clinical or histological signs of IBD, and their levels of mucosal and systemic Ab responses were lower than those of mock Ab-treated mice. Although TCR-alpha(-/-) mice treated with either specific or mock Ab developed CD4(+)betabeta T cells, only those treated with anti-IL-4 mAb showed a decrease in Th2-type cytokine production at the level of mRNA and protein and an increase in interferon gamma-specific expression. These findings suggest that IL-4-producing Th2-type CD4(+)betabeta T cells play a major immunopathological role in the induction of IBD in TCR-alpha(-/-) mice, a role that anti-IL-4 mAb inhibits by causing Th2-type CD4(+)betabeta T cells to shift to the Th1 type.

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Body weight of TCR-α−/− mice treated with/without anti–IL-4 mAb treatment. Body weight of TCR-α−/− mice treated with anti–IL-4 mAb (BVD4-1D11) or mock Ab (R35-38) was measured weekly for 25 wk. Data represent the mean ± SEM of eight mice per group.
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Figure 6: Body weight of TCR-α−/− mice treated with/without anti–IL-4 mAb treatment. Body weight of TCR-α−/− mice treated with anti–IL-4 mAb (BVD4-1D11) or mock Ab (R35-38) was measured weekly for 25 wk. Data represent the mean ± SEM of eight mice per group.

Mentions: We next investigated the effect of anti–IL-4 mAb on the induction of IBD in the TCR-α−/− mice. Approximately 60% of TCR-α−/− mice treated with mock Ab or left untreated were observed to develop the morphological changes that have been reported previously to be typical of IBD, including anorectal prolapse, diarrhea, and the weight loss and hunched posture characteristic of wasting syndrome 210. In contrast, the mice treated with anti–IL-4 mAb showed no significant weight loss (Fig. 6). Histological examination of the intestinal LP of TCR-α−/− mice treated with anti–IL-4 mAb showed more elongation of epithelial villi and markedly less infiltration of inflammatory cells than in that of mice treated with mock Ab (Fig. 7). Because a reduction in the number of goblet cells has also been reported in the colon of humans with IBD 20, we stained tissue sections prepared from the colon of anti–IL-4 mAb– and mock Ab–treated TCR-α−/− mice with alcian blue in order to detect goblet cells. As in the colons of humans suffering from IBD, the number of goblet cells in colons of mock Ab–treated mice was reduced. In contrast, the number of goblet cells was almost normal in the colon of TCR-α−/− mice treated with anti–IL-4 mAb (Fig. 8). These findings suggest that the inhibition of the Th2-type response by anti–IL-4 mAb treatment results in the prevention of mucosal inflammation in TCR-α−/− mice.


Alteration of interleukin 4 production results in the inhibition of T helper type 2 cell-dominated inflammatory bowel disease in T cell receptor alpha chain-deficient mice.

Iijima H, Takahashi I, Kishi D, Kim JK, Kawano S, Hori M, Kiyono H - J. Exp. Med. (1999)

Body weight of TCR-α−/− mice treated with/without anti–IL-4 mAb treatment. Body weight of TCR-α−/− mice treated with anti–IL-4 mAb (BVD4-1D11) or mock Ab (R35-38) was measured weekly for 25 wk. Data represent the mean ± SEM of eight mice per group.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2195615&req=5

Figure 6: Body weight of TCR-α−/− mice treated with/without anti–IL-4 mAb treatment. Body weight of TCR-α−/− mice treated with anti–IL-4 mAb (BVD4-1D11) or mock Ab (R35-38) was measured weekly for 25 wk. Data represent the mean ± SEM of eight mice per group.
Mentions: We next investigated the effect of anti–IL-4 mAb on the induction of IBD in the TCR-α−/− mice. Approximately 60% of TCR-α−/− mice treated with mock Ab or left untreated were observed to develop the morphological changes that have been reported previously to be typical of IBD, including anorectal prolapse, diarrhea, and the weight loss and hunched posture characteristic of wasting syndrome 210. In contrast, the mice treated with anti–IL-4 mAb showed no significant weight loss (Fig. 6). Histological examination of the intestinal LP of TCR-α−/− mice treated with anti–IL-4 mAb showed more elongation of epithelial villi and markedly less infiltration of inflammatory cells than in that of mice treated with mock Ab (Fig. 7). Because a reduction in the number of goblet cells has also been reported in the colon of humans with IBD 20, we stained tissue sections prepared from the colon of anti–IL-4 mAb– and mock Ab–treated TCR-α−/− mice with alcian blue in order to detect goblet cells. As in the colons of humans suffering from IBD, the number of goblet cells in colons of mock Ab–treated mice was reduced. In contrast, the number of goblet cells was almost normal in the colon of TCR-α−/− mice treated with anti–IL-4 mAb (Fig. 8). These findings suggest that the inhibition of the Th2-type response by anti–IL-4 mAb treatment results in the prevention of mucosal inflammation in TCR-α−/− mice.

Bottom Line: The colitis that develops in these mice is associated with increased numbers of T helper cell (Th)2-type CD4(+)TCR-betabeta (CD4(+)betabeta) T cells producing predominantly interleukin (IL)-4.Although TCR-alpha(-/-) mice treated with either specific or mock Ab developed CD4(+)betabeta T cells, only those treated with anti-IL-4 mAb showed a decrease in Th2-type cytokine production at the level of mRNA and protein and an increase in interferon gamma-specific expression.These findings suggest that IL-4-producing Th2-type CD4(+)betabeta T cells play a major immunopathological role in the induction of IBD in TCR-alpha(-/-) mice, a role that anti-IL-4 mAb inhibits by causing Th2-type CD4(+)betabeta T cells to shift to the Th1 type.

View Article: PubMed Central - PubMed

Affiliation: Department of Mucosal Immunology, Research Institute for Microbial Diseases, Osaka University, Japan.

ABSTRACT
T cell receptor alpha chain-deficient (TCR-alpha(-/-)) mice are known to spontaneously develop inflammatory bowel disease (IBD). The colitis that develops in these mice is associated with increased numbers of T helper cell (Th)2-type CD4(+)TCR-betabeta (CD4(+)betabeta) T cells producing predominantly interleukin (IL)-4. To investigate the role of these Th2-type CD4(+)betabeta T cells, we treated TCR-alpha(-/-) mice with anti-IL-4 monoclonal antibody (mAb). Approximately 60% of TCR-alpha(-/-) mice, including those treated with mock Ab and those left untreated, spontaneously developed IBD. However, anti-IL-4 mAb-treated mice exhibited no clinical or histological signs of IBD, and their levels of mucosal and systemic Ab responses were lower than those of mock Ab-treated mice. Although TCR-alpha(-/-) mice treated with either specific or mock Ab developed CD4(+)betabeta T cells, only those treated with anti-IL-4 mAb showed a decrease in Th2-type cytokine production at the level of mRNA and protein and an increase in interferon gamma-specific expression. These findings suggest that IL-4-producing Th2-type CD4(+)betabeta T cells play a major immunopathological role in the induction of IBD in TCR-alpha(-/-) mice, a role that anti-IL-4 mAb inhibits by causing Th2-type CD4(+)betabeta T cells to shift to the Th1 type.

Show MeSH
Related in: MedlinePlus