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 tu mor necrosis factor (INF) family of immune regulatory molecules, is involve d both in the development of secondary lymphoid tissues and the maintenance of organized lymphoid tissues in the adult, Defects observed in the mucosa l immune system in animals with a genetically disrupted LT alpha/beta pathw ay coupled with the expression of LT alpha/beta in activated T cells motiva ted an examination of the importance of this pathway in experimental coliti s; 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 marro w-transplanted tg epsilon 26 mice (BM --> tg epsilon 26). Results: Treatmen t with LT beta R immunoglobulin attenuated the development of both the clin ical and histological manifestations of the disease in these two murine mod els of colitis. Given the success of TNF inhibitors in the treatment of hum an Crohn's disease, the effects of LT beta R immunoglobulin have been compa red with antibody to TNF in the BM --> tg epsilon 26 model, and both treatm ents were equally efficacious, Conclusions: The LT pathway plays a role in the development of colitis as important as that of the TNF system and, ther efore, represents a potential novel intervention point for the treatment of inflammatory bowel disease.