Gastroenterology

Gastroenterology

Volume 115, Issue 6, December 1998, Pages 1464-1475
Gastroenterology

Alimentary Tract
Both the lymphotoxin and tumor necrosis factor pathways are involved in experimental murine models of colitis,☆☆

https://doi.org/10.1016/S0016-5085(98)70025-3Get rights and content

Abstract

Background & Aims: Membrane lymphotoxin (LT) α/β, a member of the tumor necrosis factor (TNF) family of immune regulatory molecules, is involved both in the development of secondary lymphoid tissues and the maintenance of organized lymphoid tissues in the adult. Defects observed in the mucosal immune system in animals with a genetically disrupted LTα/β pathway coupled with the expression of LTα/β in activated T cells motivated an examination of the importance of this pathway in experimental colitis. Methods: Soluble LTβ receptor (LTβR) immunoglobulin fusion protein was used to inhibit the LTα/β/light axis in two independent rodent models of colitis: CD45RBhi CD4+–reconstituted SCID mice and bone marrow–transplanted tgϵ26 mice (BM → tgϵ26). Results: Treatment with LTβR immunoglobulin attenuated the development of both the clinical and histological manifestations of the disease in these two murine models of colitis. Given the success of TNF inhibitors in the treatment of human Crohn's disease, the effects of LTβR immunoglobulin have been compared with antibody to TNF in the BM → tgϵ26 model, and both treatments were equally efficacious. Conclusions: The LT pathway plays a role in the development of colitis as important as that of the TNF system and, therefore, represents a potential novel intervention point for the treatment of inflammatory bowel disease.

GASTROENTEROLOGY 1998;115:1464-1475

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.

    ☆☆

    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.).

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