Alimentary TractBoth the lymphotoxin and tumor necrosis factor pathways are involved in experimental murine models of colitis☆,☆☆
Section snippets
Animals
Specific pathogen–free female C.B-17 and C.B-17 SCID mice were obtained from Taconic Farms, Inc. (Germantown, NY). tgϵ26 Mice were generated as described previously by overexpression (more than 30 copies) of the full-length human CD3ϵ gene,39, 40 were interbred on the original CBA/J × C57BL/6 background at the Beth Israel Deaconess Medical Center animal facility (Boston, MA), and were maintained under specific pathogen–free conditions. Tgϵ26 were screened for homozygosity of the transgene by
Inhibition of the LT pathway prevents disease development in the CD45RBhi colitis model
To determine the role of the LT pathway in the development of colitis, soluble LTβR-Ig was used to block all LTα/β-mediated functions without affecting signaling triggered by TNF or LTα. Inhibition of the LT pathway in a normal adult mouse leads to changes in the lymphoid architecture and in the expression of many cell surface molecules.25, 33, 35 Complete loss of the expression of several of these molecules required several weeks of LTβR-Ig treatment, whereas other effects occurred within days.
Discussion
The inhibition of LT-mediated events had a protective effect on wasting and colitis in two models of IBD at both the gross and microscopic levels, indicating that the LT axis controls essential immunologic mechanisms required for the development and/or progression of disease. In the models studied, animals develop systemic disease that is manifested primarily in the bowel under these conditions; however, other organs, such as the skin, thyroid, pancreas, and lung, are involved in other
Acknowledgements
The authors thank K. Miatkowski, J. Amatucci, D. Griffiths, P. Bourdon, and W. Meier for preparation and characterization of the fusion proteins; E. Mellulini for help with histology; and P. Cashman, C. Nickerson-Nutter, and J. Knight for assistance with the animals.
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Address requests for reprints to: Fabienne Mackay, Ph.D., Biogen, 12 Cambridge Center, Cambridge, Massachusetts 02142. e-mail: [email protected]; fax: (617) 679-2304.
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Supported by grants P30DK-433-51, ROIDK47677-01 (to A.K.B.), and RO1DK52510 (to C.T.) from the National Institutes of Health and a grant from the Crohn's and Colitis Foundation of America (to S.S.).