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

Background & Aims: Membrane lymphotoxin (LT) alpha/beta, a member of the tumor necrosis factor (INF) 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 LT alpha/beta pathway coupled with the expression of LT alpha/beta in activated T cells motivated an examination of the importance of this pathway in experimental colitis; Methods: Soluble LTP receptor (LT beta R) immunoglobulin fusion protein was used to inhibit the LT alpha/beta/light axis in two independent rodent models of colitis: CD45RB(hi) CD4(+)-reconstituted SCID mice and bone marrow-transplanted tg epsilon 26 mice (BM --> tg epsilon 26). Results: Treatment with LT beta R 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 LT beta R immunoglobulin have been compared with antibody to TNF in the BM --> tg epsilon 26 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.