41: Pre-Transplant Administration of Keratinocyte Growth Factor Affects Peripheral T-cell Homeostasis Through Increased Recent Thymic Emigrant Export and Affects the Course of Murine Chronic Graft-Vs.-Host Disease

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

Blood ◽

10.1182/blood.v96.13.4350.h8004350_4350_4356 ◽

2000 ◽

Vol 96 (13) ◽

pp. 4350-4356 ◽

Cited By ~ 5

Author(s):

Angela Panoskaltsis-Mortari ◽

Patricia A. Taylor ◽

Jeffrey S. Rubin ◽

Aykut Uren ◽

Lisbeth A. Welniak ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Growth Factor ◽

Graft Versus Host Disease ◽

Keratinocyte Growth Factor ◽

Allogeneic Bone ◽

Cell Transfer ◽

Host Disease ◽

Graft Versus Host ◽

T Cell Transfer

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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Low-Dose Interleukin-2 Therapy Restores Regulatory T Cell Homeostasis in Patients with Chronic Graft-Versus-Host Disease

Science Translational Medicine ◽

10.1126/scitranslmed.3005265 ◽

2013 ◽

Vol 5 (179) ◽

pp. 179ra43-179ra43 ◽

Cited By ~ 255

Author(s):

K.-i. Matsuoka ◽

J. Koreth ◽

H. T. Kim ◽

G. Bascug ◽

S. McDonough ◽

...

Keyword(s):

T Cell ◽

Graft Versus Host Disease ◽

Regulatory T Cell ◽

Low Dose ◽

Interleukin 2 ◽

T Cell Homeostasis ◽

Cell Homeostasis ◽

Host Disease ◽

Graft Versus Host

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Keratinocyte growth factor preserves normal thymopoiesis and thymic microenvironment during experimental graft-versus-host disease

Blood ◽

10.1182/blood.v100.2.682 ◽

2002 ◽

Vol 100 (2) ◽

pp. 682-691 ◽

Cited By ~ 142

Author(s):

Simona Rossi ◽

Bruce R. Blazar ◽

Catherine L. Farrell ◽

Dimitry M. Danilenko ◽

David L. Lacey ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Growth Factor ◽

Graft Versus Host Disease ◽

Keratinocyte Growth Factor ◽

Receptor Expression ◽

Successful Outcome ◽

Thymic Epithelial Cells ◽

Host Disease ◽

Graft Versus Host

Abstract 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 parent→F1 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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