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Keratinocyte growth factor facilitates alloengraftment and ameliorates graft-versus-host disease in mice by a mechanism independent of repair of conditioning-induced tissue injury.

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-alpha (TNF-alpha) and interferon gamma (IFN-gamma). 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. (Blood. 2000;96:4350-4356)
AuthorsA Panoskaltsis-Mortari, P A Taylor, J S Rubin, A Uren, L A Welniak, W J Murphy, C L Farrell, D L Lacey, B R Blazar
JournalBlood (Blood) Vol. 96 Issue 13 Pg. 4350-6 (Dec 15 2000) ISSN: 0006-4971 [Print] United States
PMID11110712 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Fgf7 protein, mouse
  • Fibroblast Growth Factor 10
  • Growth Substances
  • Interleukin-13
  • Recombinant Proteins
  • Tumor Necrosis Factor-alpha
  • Fibroblast Growth Factor 7
  • Fibroblast Growth Factors
  • Interferon-gamma
Topics
  • Animals
  • Bone Marrow Transplantation
  • Drug Evaluation, Preclinical
  • Epithelial Cells (radiation effects)
  • Fibroblast Growth Factor 10
  • Fibroblast Growth Factor 7
  • Fibroblast Growth Factors
  • Graft Survival (drug effects)
  • Graft vs Host Disease (prevention & control)
  • Growth Substances (pharmacology, therapeutic use)
  • Immunization
  • Interferon-gamma (blood)
  • Interleukin-13 (blood)
  • Lymphocyte Culture Test, Mixed
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, SCID
  • Radiation Chimera
  • Radiation Injuries, Experimental (drug therapy)
  • Recombinant Proteins (pharmacology, therapeutic use)
  • Th2 Cells (metabolism)
  • Transplantation Conditioning (adverse effects)
  • Tumor Necrosis Factor-alpha (analysis)
  • Whole-Body Irradiation (adverse effects)

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