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

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: CD45RB hi 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