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)
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Authors | A 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 |
Journal | Blood
(Blood)
Vol. 96
Issue 13
Pg. 4350-6
(Dec 15 2000)
ISSN: 0006-4971 [Print] United States |
PMID | 11110712
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
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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
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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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