Alimentary TractActivation of natural killer T cells by α-galactosylceramide in the presence of CD1d provides protection against colitis in mice☆,☆☆,★
Section snippets
Mice
Wild-type (WT) and recombinase-activating gene 2 knockout (RAG−/−) C57BL/6x129/Sv mice were purchased from Jackson Laboratories (Bar Harbor, ME). CD1d−/− mice have been generated as previously described22 and were also used as a mixed background of C57BL/6x129/Sv. All animals were maintained under specific pathogen–free conditions on standard laboratory chow and water ad libitum until the desired age (8-10 weeks) and/or weight (20-30 g) were achieved. All mice were treated humanely according to
α-GalCer protects WT mice from colitis associated with DSS administration
To evaluate α-GalCer in the well-characterized DSS model of colitis,26 mice were administered DSS (2.5%) in the drinking water and the glycolipid effects were analyzed after administration of the lipid on day 1 and every other day thereafter for the duration of the study. Preliminary investigations established an optimal dose of α-GalCer at 100 μg/kg body wt (data not shown). At this dose of α-GalCer, there was a significant amelioration in the severity of colitis as observed in WT mice (Figure
Discussion
In this report, we have used a well-established model of colitis associated with administration of DSS to show that NK T cells activated by α-GalCer exhibit an important ameliorative effect on the severity of colitis associated with DSS. DSS is a sulfated polymer that causes a self-limited colitis with acute administration or colitis with chronic features on continuous exposure.26 This model allows for direct testing of cause and effect relationships between specific interventions and colitis.
Acknowledgements
The authors thank Dr. Ramnik Xavier for the donation of some RAG−/− mice; Drs. Xiaoping Zhu, Victor Morales, and Atsushi Nakajima and Dan Brown for helpful advice; and Lili Miao for technical assistance with this project.
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Supported by National Institutes of Health grants DK02532 (to L. J. S.), AI33911 (to S. P. B.), DK46906, DK53304, DK43351 (to D.K.P.), and DK44319, DK53056, DK51362 (to R.S.B.).
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Address requests for reprints to Richard S. Blumberg, M.D., Gastroenterology Division, Brigham and Women's Hospital, 75 Francis Street, Boston, Massachusetts 02115. e-mail: [email protected]; fax: (617) 264-5185.
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Lawrence J. Saubermann and Paul Beck contributed equally to the work.