Effect of Recombinant Human Keratinocyte Growth Factor (rHuKGF) on the Immunopathogenesis of Intestinal Graft-Vs.-Host Disease Induced Without a Preconditioning Regimen

Abstract

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.

Keratinocyte Growth Factor Improves Allogeneic Bone Marrow Engraftment through a CD4+Foxp3+ Regulatory T Cell-Dependent Mechanism

“…In addition to expanding CD4 ϩ Foxp3 ϩ Treg (11), the use of KGF may also elevate the serum levels of the Th2 cytokines IL-4 and IL-13 and reduce the levels of the Th1 cytokines IFN-␥ and TNF-␣, resulting in a redirection of the Th1/Th2 cytokine profile toward Th2 cytokines (6,7,10). The data reported in this study appear in agreement with these observations.…”

“…Apart from its effects on peripheral Treg, KGF has also been shown to increase serum levels of Th2 cytokines like IL-4 and IL-13 (6,7,23). The KGF-driven redirection of the cytokine profile from Th1 to a mixed Th1/Th2 pattern may also protect against graft-rejection.…”

“…KGF administration reduces the in vivo allo-response and alters plasma cytokine levels during acute GVHD. These alterations reflect the development of a mixed Th1/ Th2 cytokine ratio in which Th2 cytokines, such as IL-4 and IL-13, predominate (6,7,10). In addition, lymphocytes isolated from KGF-pretreated allo-immunized mice exhibit reduced responsiveness in a secondary in vitro MLR (6).…”

Short-term inhibition of p53 combined with keratinocyte growth factor improves thymic epithelial cell recovery and enhances T-cell reconstitution after murine bone marrow transplantation

“…29 KGF has been shown to skew toward a T helper type 2 anti-inflammatory environment, which may consequently inhibit responses against certain pathogens, including Lm, which require robust T helper type 1 responses. 28,[63][64][65][66] However, KGF reduces incidence and severity of acute GVHD through its T helper type 2-skewing and epithelial protective effects. 25,28,65,66 Epithelial protection mediated by KGF and augmented by PFT-␤ may reduce general damage and thus hold promise for speeding T-cell recovery in the setting of GVHD.…”

Keratinocyte growth factor ameliorates acute graft-versus-host disease in a novel nonmyeloablative haploidentical transplantation model

“…Reduced TNF-a levels observed after KGF treatment might also reflect reduced GVHD rather then conditioning-induced damage alone. It is also possible that other cytokines, inflammatory as well as anti-inflammatory 30,40 play a role in the protective mechanism of KGF in our transplantation model. In our opinion, however, the most relevant observation is that KGF also protects from GVHD after nonmyeloablative conditioning regimens in a haploidentical setting.…”