Both the lymphotoxin and tumor necrosis factor pathways are involved in experimental murine models of colitis.
OBJECTIVE
Membrane lymphotoxin (LT) alpha/beta, 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 LTalpha/beta pathway coupled with the expression of LTalpha/beta in activated T cells motivated an examination of the importance of this pathway in experimental colitis.


METHODS
Soluble LTbeta receptor (LTbetaR) immunoglobulin fusion protein was used to inhibit the LTalpha/beta/light axis in two independent rodent models of colitis: CD45RBhi CD4(+)-reconstituted SCID mice and bone marrow-transplanted tg26 mice (BM --> tg26).


RESULTS
Treatment with LTbetaR 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 LTbetaR immunoglobulin have been compared with antibody to TNF in the BM --> tg26 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.
Mackay
F
F
Department of Immunology, Inflammation and Cell Biology, Biogen, Cambridge, MA 02142, USA. fabienne_mackay@biogen.com
Browning
J L
JL
Lawton
P
P
Shah
S A
SA
Comiskey
M
M
Bhan
A K
AK
Mizoguchi
E
E
Terhorst
C
C
Simpson
S J
SJ
D000818:Animals; D003092:Colitis / Q000209:etiology*; D008233:Lymphotoxin-alpha / Q000502:physiology*; D051379:Mice; D016513:Mice, SCID; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
D008233:Lymphotoxin-alpha; D014409:Tumor Necrosis Factor-alpha