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.
SUMMARY(C57BL/6 Â DBA/2)F 1 -hybrid mice injected with lymphoid cells from wild-type, C57BL/6 donors develop acute, lethal graft-versus-host disease (GVHD) in which the intestine is a major target. In its destructive phase intestinal GVHD is characterized by apoptosis of intestinal crypt epithelial cells and the development of endotoxaemia. Injection of as little as 10 mg endotoxin is lethal in mice with acute GVHD, and associated with the release of large amounts of tumour necrosis factor-a (TNF-a) into the serum. To explore the role of interferon-g (IFN-g) in the pathogenesis of intestinal GVHD we used IFN-g gene knockout (gko) mice as donors. Recipients of grafts from these donors did not develop intestinal GVHD and, unlike recipients of wild-type grafts, did not die when injected with lipopolysaccharide (LPS). We also found that injection 10 mg LPS into recipients of wild-type grafts induced apoptosis of intestinal epithelial crypt cells and was associated with a burst of nitric oxide production in the intestine. Administration of N o nitro L-arginine methyl ester blocked this response. In contrast, LPS did not induce either intestinal epithelial cell apoptosis or increased nitric oxide production in recipients of IFN-g gko grafts. These ®ndings indicate that donor-derived IFN-g is instrumental for the development of intestinal GVHD. In a previous study we showed that recipients of IFN-g gko grafts develop high levels of LPS-induced TNF-a release. When our current data are viewed in the context of this observation, they suggest that intestinal epithelial cell apoptosis in the parent3F 1 -hybrid model of acute GVHD is mediated primarily by nitric oxide rather than TNF-a, and that this depends on donor-derived IFN-g.
Curcumin (diferuloylmethane), a pigment from the rhizomes of Curcuma Longa, has anti-oxidant, anti-tumor and anti-inflammatory properties. It has been shown that curcumin can inhibit the development of experimental allergic encephalomyelitis, a Th1-mediated, autoimmune, demyelinating disease that affects the central nervous system in mice. Because acute GVHD involves the development of a Th1-mediated immune response, and is characterized by the development of a potent, systemic, inflammatory response, we wished to determine whether curcumin might also protect mice from developing acute GVHD in the C57BL/6→(C57BL/6 x DBA/2)F1-hybrid model. We found that ip injections of curcumin (100 micrograms dissolved in 25 microliters of DMSO), given once a day, every 2 days, protected recipients from developing acute, lethal GVHD. Two thirds of the treated group survived well past day 100 post-transplantation. Control GVH mice treated with DMSO alone became moribund within three weeks of transplantation, the time at which mice with acute GVHD typically succumb. To ensure that the protective effects of curcumin were not due to abortion of the graft, we analyzed T cell engraftment in some of the long-term survivors. In the surviving mice tested on days 135 and 275 post-transplantation, we were unable to detect any cells of recipient origin in the spleen. Furthermore, the percentage of donor-derived CD4+ cells ranged from 32–47% and the percentage of CD8+ T cells ranged from 25–42% in the non-adherent spleen cell fraction. Data from these experiments suggest that curcumin can protect mice from developing acute, lethal GVHD.
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