rHuKGF ameliorates symptoms in DSS and CD4(+)CD45RB(Hi) T cell transfer mouse models of inflammatory bowel disease.
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(+)CD45RB(Hi) 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 x 10(5) CD4(+)CD45RB(Hi) 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.
Byrne
Fergus R
FR
Department of Pharmacology, Amgen, Thousand Oaks, California 91320, USA. fbyrne@amgen.com
Farrell
Catherine L
CL
Aranda
Richard
R
Rex
Karen L
KL
Scully
Sheila
S
Brown
Heather L
HL
Flores
Silvia A
SA
Gu
Li H
LH
Danilenko
Dimitry M
DM
Lacey
David L
DL
Ziegler
Thomas R
TR
Senaldi
Giorgio
G
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000637:transplantation*; D016264:Dextran Sulfate; D003967:Diarrhea; D004195:Disease Models, Animal; D005260:Female; D051523:Fibroblast Growth Factor 7; D005346:Fibroblast Growth Factors / Q000627:therapeutic use*; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D007413:Intestinal Mucosa / Q000473:pathology; D017493:Leukocyte Common Antigens / Q000032:analysis*; D007958:Leukocyte Count; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009504:Neutrophils; D011994:Recombinant Proteins / Q000627:therapeutic use; D000685:Serum Amyloid A Protein / Q000032:analysis; D015431:Weight Loss
C496453:FGF7 protein, human; C496454:Fgf7 protein, mouse; D011994:Recombinant Proteins; D000685:Serum Amyloid A Protein; D051523:Fibroblast Growth Factor 7; D005346:Fibroblast Growth Factors; D016264:Dextran Sulfate; D017493:Leukocyte Common Antigens