| Co-Investigator(Kenkyū-buntansha) |
MASUKO Takashi Kinki University, School of Pharmaceutical Sciences, Professor, Ph.D., 薬学部, 教授 (30157200)
NAKAMURA Masanori Showa University, School of Dentistry, Professor, Ph.D., 歯学部, 教授 (50180394)
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| Budget Amount *help |
¥3,100,000 (Direct Cost: ¥3,100,000)
Fiscal Year 2004: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 2003: ¥2,300,000 (Direct Cost: ¥2,300,000)
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| Research Abstract |
We reported that the administration of anti-CD3 monoclonal antibody (mAb) and subsequently activation of intestinal intra-epithelial lymphocytes (i-IELs) could induce apoptosis to enterocytes. To elucidate the mechanism of the induction of apoptosis in enterocytes by activated i-IELs, we designed experiments to stimulate the IEL by anti-CD3 mAb and to examine the subsequent changes to the enterocytes. In rats, the enterocytes showed massive DNA fragmentation 30 mm and subsequent detachment 2 hours after injection of anti-CD3 mAb (1F4) made in our laboratory. Then, we newly found the growth and hypertrophy of the goblet cells in rats.
We designed experiments to inactivate the IEL by immunosuppressant, FK506 and to analyze the subsequent changes of the enterocytes. The inactivation of i-IELs by daily administration of FK506 disappeared apoptosis of enterocytes in villus. Then, in the enterocytes, the long term daily administration of FK506 caused decrease in the expression of amino acid t
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ransporter, CD98 and the activity of alkaline phosphatase (ALP). Furthermore, these treatments induced the disappearance and heterogenous expression of F-actin in microvilli of enterocytes. It showed that the inactivation of i-IELs by daily administration of FK506 could inhibit apoptosis in enterocytes, and these results suggested that the dysfunctional enterocytes, which should have been led to apoptosis, remained on the villus.
With the immunodeficiency mice that decreased i-IEL, we analyzed morphological and functional changes in epithelial cells. The enterocytes in nude and scid mice decreased in the expression of amino acid transporter, CD98, the activity of ALP, and the adhesion activity with basement membrane due to the decline in the expression of integrin α_6 on the enterocytes. The administration of CD3 mAb failed to exfoliate the epithelium and cause severe diarrhea in these immunodeficiency mice. Therefore, i-IELs may have an important role in maintenance of epithelial cells on the villus. Less
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