Journal
BLOOD
Volume 100, Issue 2, Pages 682-691Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood.V100.2.682
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Funding
- NCI NIH HHS [R01 CA72669] Funding Source: Medline
- NHLBI NIH HHS [R01 HL63452, R01 HL54729, R01 HL54850, R01 HL55209] Funding Source: Medline
- NIAID NIH HHS [R01 AI34459] Funding Source: Medline
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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-->F-1 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 parent-->F-1 mice that received allogeneic transplants. Moreover, the characteristic GVHD-induced impairment in cell cycle progression of pro- and pre-T cells was prevented by KGR 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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