RESULTS: Administration of DSS for 7 days resulted in severe acute
colitis that was associated with a marked increase in stool and colon tissue TNF levels. Initiation of
therapy with intraperitoneal (i.p.)
LMP-420 on day 4 of DSS exposure decreased colonic TNF to near normal levels on day 7. However, neither i.p. nor oral treatment with
LMP-420 affected the development or severity of acute DSS
colitis. Initiation of
LMP-420 therapy after 3 cycles of DSS administration to establish chronic
colitis also had no effect on the severity of chronic
colitis. Analysis of colonic TNF combined with longitudinal analysis of TNF and
TNF receptor (
TNF-RII) levels in stool during the development of chronic DSS
colitis demonstrated that the initially elevated colonic TNF levels returned to normal despite intense on-going
inflammation in mice with chronic
colitis. RAG-2-/- mice deficient in T and B cells also developed severe ongoing
colitis in response to 3 cycles of DSS, but showed marked differences vs. wild type mice in stool TNF and
TNF-RII in response to DSS exposure. Systemic and oral
LMP-420 treatment for 16 days decreased colonic TNF levels in IL-10-deficient mice with chronic
colitis, with a trend to decreased histologic
inflammation for oral
LMP-420.
CONCLUSION: These studies demonstrate that short-term treatment with a transcriptional inhibitor of TNF production can decrease systemic and local colonic levels of TNF but may not decrease the histologic severity of
colitis. Longer term studies using
colitis models that are more dependent on TNF elevation should be performed to more accurately assess the potential of
LMP-420 for
therapy of
inflammatory bowel disease.