Effect of recombinant human keratinocyte growth factor (rHuKGF) on the immunopathogenesis of intestinal graft-vs.-host disease induced without a preconditioning regimen

• Published in: Journal of Clinical Immunology 2004-03, Vol.24 (2), p.197-211
• Main Authors: Ellison, Cynthia A, Natuik, Shannon A, Fischer, Jacqie M M, McIntosh, Alan R, Scully, Sheila A, Bow, Eric J, Danilenko, Dimitry M, Hayglass, Kent T, Gartner, John G
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Cell Transplantation; Cells, Cultured; Cytokines - analysis; Cytokines - biosynthesis; Cytokines - genetics; Enzyme-Linked Immunosorbent Assay; Epithelial Cells - drug effects; Epithelial Cells - immunology; Epithelial Cells - pathology; Female; Fibroblast Growth Factor 7; Fibroblast Growth Factors - biosynthesis; Fibroblast Growth Factors - immunology; Fibroblast Growth Factors - pharmacology; Graft vs Host Disease - prevention & control; Humans; Intestines - drug effects; Intestines - immunology; Intestines - pathology; Lipopolysaccharides; Mice; Mice, Inbred C57BL; Nitric Oxide - analysis; Nitric Oxide - biosynthesis; Recombinant Proteins - pharmacology; RNA, Messenger - analysis; Spleen - drug effects; Spleen - immunology; Spleen - transplantation; T-Lymphocyte Subsets - immunology; Time Factors; Tumor Necrosis Factor-alpha - biosynthesis; Tumor Necrosis Factor-alpha - genetics
• ISSN: 0271-9142; 1573-2592; 1365-2567
• DOI: 10.1023/B:JOCI.0000019785.35850.a5

We studied the effect of rHuKGF on acute, lethal graft- vs.-host disease (GVHD) in the C57BL/6-->(C57BL/6 X DBA/2)F(1)-hybrid model. rHuKGF-treated recipients did not develop intestinal GVHD despite elevated levels of intestinal NO and TNF alpha, did not develop endotoxemia, and did not die. LPS augmented serum TNF alpha release and intestinal NO production, but did not induce intestinal epithelial cell apoptosis, a phenomenon associated with acute GVHD. These data suggest that KGF prevents the development of acute lethal GVHD by protecting epithelial cell injury mediated by TNF-alpha, NO, and other potential cytotoxic factors. We noted a moderate reduction in intestinal KGFR mRNA expression in untreated GVH mice on day 8, when IFN-gamma mRNA levels were highest. This reduction in KGFR mRNA levels was not seen in recipients of IFN-gamma gene knockout grafts, suggesting that IFN-gamma may be involved in reducing KGFR mRNA expression in the intestine. A similar reduction in intestinal KGFR mRNA expression was also seen in rHuKGF-treated recipients, suggesting that rHuKGF does not mediate its protective effect by maintaining KGFR at control levels. KGF-treatment also redirected the cytokine response in acute GVH mice from Th1 to a mixed pattern of both Th1 and Th2 cytokines. This was associated with histopathologic changes resembling chronic GVHD.