Keratinocyte growth factor facilitates alloengraftment and ameliorates graft-versus-host disease in mice by a mechanism independent of repair of conditioning-induced …
A Panoskaltsis-Mortari, PA Taylor… - Blood, The Journal …, 2000 - ashpublications.org
Blood, The Journal of the American Society of Hematology, 2000•ashpublications.org
We have previously shown that pretreatment of mice with keratinocyte growth factor (KGF),
an epithelial tissue repair factor, can ameliorate graft-versus-host disease (GVHD) after
intensive chemoradiotherapeutic conditioning and allogeneic bone marrow transplantation
(BMT). To determine whether this effect was dependent on a KGF-mediated mechanism
affecting repair of conditioning-induced epithelial cell injury, we studied GVHD in the
absence of conditioning using BALB/c severe combined immune-deficient (SCID) recipients …
an epithelial tissue repair factor, can ameliorate graft-versus-host disease (GVHD) after
intensive chemoradiotherapeutic conditioning and allogeneic bone marrow transplantation
(BMT). To determine whether this effect was dependent on a KGF-mediated mechanism
affecting repair of conditioning-induced epithelial cell injury, we studied GVHD in the
absence of conditioning using BALB/c severe combined immune-deficient (SCID) recipients …
Abstract
We have previously shown that pretreatment of mice with keratinocyte growth factor (KGF), an epithelial tissue repair factor, can ameliorate graft-versus-host disease (GVHD) after intensive chemoradiotherapeutic conditioning and allogeneic bone marrow transplantation (BMT). To determine whether this effect was dependent on a KGF-mediated mechanism affecting repair of conditioning-induced epithelial cell injury, we studied GVHD in the absence of conditioning using BALB/c severe combined immune-deficient (SCID) recipients given C57BL/6 T cells. KGF (5 mg/kg per day, subcutaneously) given either before or after T-cell transfer enhanced body weights and extended survival. KGF-treated recipients had elevated serum levels of the Th2 cytokine interleukin 13 (IL-13) on day 6 after T-cell transfer concomitant with reduced levels of the inflammatory cytokines tumor necrosis factor-α (TNF-α) and interferon gamma (IFN-γ). A 3-day KGF pretreatment also depressed the secondary in vitro mixed lymphocyte response (MLR) of C57BL/6 splenocytes taken 7 days after in vivo alloimmunization with irradiated BALB/c spleen cells. To determine whether KGF would inhibit host-antidonor–mediated BM rejection, pan-T-cell–depleted BALB/c BM cells were infused into sublethally irradiated C57BL/6 mice and administered KGF either before or before and after BMT. Surprisingly, all KGF schedules tested actually resulted in enhanced alloengraftment. The presence of KGF receptor on donor antihost alloreactive T cells could not be detected by binding studies with radiolabeled KGF, reverse transcriptase–polymerase chain reaction, and Western blotting. Therefore, the mechanism of action of KGF on inhibiting T-cell–mediated immune effects may not be due to a direct effect of KGF on T cells. These studies demonstrate that KGF, by mechanisms independent of repair of conditioning-induced injury, has great potential as an anti-GVHD therapeutic agent with the added benefit of inhibiting the rejection of pan-T-cell–depleted donor BM allografts.
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