Vol. 282, Issue 4, G690-G701, April 2002
rHuKGF ameliorates symptoms in DSS and
CD4+CD45RBHi T cell transfer mouse models of
inflammatory bowel disease
Fergus R.
Byrne1,
Catherine L.
Farrell2,
Richard
Aranda3,
Karen
L.
Rex1,
Sheila
Scully1,
Heather L.
Brown1,
Silvia A.
Flores1,
Li H.
Gu4,
Dimitry M.
Danilenko1,
David L.
Lacey1,
Thomas R.
Ziegler4, and
Giorgio
Senaldi1
1 Departments of Pharmacology and Pathology and
2 Product Development, Amgen, Thousand Oaks, 91320, 3 Division of Digestive Diseases, UCLA School of Medicine
and Greater Los Angeles Veterans Affairs Hospital System, Los Angeles,
California 90095 and 4 Department of Medicine, Emory
University, Atlanta, Georgia 30322
There is an acute need for effective therapy
for inflammatory bowel disease (IBD), particularly at the level of
repair of the damaged epithelium. We evaluated the efficacy of
recombinant human keratinocyte growth factor (rHuKGF) in both the
dextran sodium sulfate (DSS) and the
CD4+CD45RBHi T cell transfer models of IBD.
Disease was induced either by the ad libitum administration to normal
mice of 4% DSS in the drinking water or by the injection of 4 × 105 CD4+CD45RBHi T cells into
immunodeficient scid/scid mice. rHuKGF was administered by
subcutaneous injection at doses of 1.0 or 3.0 mg/kg in both preventative and therapeutic regimens during both studies. rHuKGF significantly improved survival and body weight loss in the DSS model
in both preventative and therapeutic dosing regimens. It also improved
diarrhea, hematochezia, and hematological parameters, as well as large
intestine histopathology. In the T cell transfer model, rHuKGF improved
body weight loss, diarrhea, and levels of serum amyloid A, as well as
large intestine histopathology. In both models of IBD, the colonic
levels of intestinal trefoil factor (ITF) were elevated by the disease
state and further elevated by treatment with rHuKGF. These data suggest
that rHuKGF may prove useful in the clinical management of IBD and its
effects are likely mediated by its ability to locally increase the
levels of ITF.
colitis; growth factor; epithelial repair; intestinal trefoil
factor
