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Blood, 15 July 2002, Vol. 100, No. 2, pp. 682-691
TRANSPLANTATION
Keratinocyte growth factor preserves normal thymopoiesis and
thymic microenvironment during experimental graft-versus-host
disease
Simona Rossi,
Bruce R. Blazar,
Catherine L. Farrell,
Dimitry M. Danilenko,
David L. Lacey,
Kenneth I. Weinberg,
Werner Krenger, and
Georg A. Holländer
From the Department of Research, University Hospital,
Basel, Switzerland; the Department of Pediatrics, Heme/Onc/BMT
Division, University of Minnesota Cancer Center, Minneapolis; Amgen
Inc, Thousand Oaks, CA; and the Division of Research Immunology/BMT,
Children's Hospital, Los Angeles, CA.
Thymus-dependent reconstitution of the peripheral T-cell
compartment is critical for the successful outcome of bone marrow transplantation. However, graft-versus-host disease (GVHD) affects thymic stromal function and thus prevents normal T-cell maturation and
selection. To determine whether cytoprotection of thymic epithelial cells (TECs) by keratinocyte growth factor (KGF) averts
GVHD-related injury to the thymus, a nonirradiated murine
parent F1 transplantation model was investigated.
Administration of KGF between days  3 and +3 of GVHD induction
preserved normal thymic size, cellularity, and thymocyte phenotype when
measured 2 weeks after transplantation and compared with saline-treated
parentF1 mice that received allogeneic transplants.
Moreover, the characteristic GVHD-induced impairment in cell cycle
progression of pro- and pre-T cells was prevented by KGF. However, the
normal phenotypic and functional status of the thymus did not correlate
with the higher number of GVHD-inducing mature donor T cells in thymi
of KGF-treated mice. Importantly, extensive analysis of the different
TEC populations within the thymic cortex and medulla revealed an almost
normal stromal architecture and composition in GVHD mice treated with KGF. These observations are likely to reflect an indirect effect of KGF
on thymopoiesis as KGF-receptor expression was demonstrated to be
restricted to TECs. Thus, pharmacologic doses of KGF appear to exert a
potent effect on TEC function, which in turn allows for normal T
lymphopoiesis to occur during acute GVHD.
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