Keratinocyte growth factor ameliorates acute graft-versus-host disease in a novel nonmyeloablative haploidentical transplantation model

Abstract Allogeneic stem cell transplantations (SCT) are currently being used as a therapy for hematological malignancies, some solid tumors and non-malignant bone marrow deficiencies. Nevertheless, clinical applicability is limited due to toxicity of conditioning regimens, graft-versus-host disease (GVHD) and the scarcity of HLA-identical family donors. New concepts are based on nonmyeloablative conditioning to reduce toxicity, prevention or amelioration of GVHD and the use of haploidentical donors to increase donor availability. To meet these requirements, we have developed a nonmyeloablative conditioning regimen in a haploidentical F1 → F1 mouse model. These mini-transplantations, consisting of low dose total body irradiation and cyclophosphamide-based chemotherapy, resulted in stable full donor chimerism, but also in the development of GVHD. Administration of keratinocyte growth factor (KGF) before and after SCT resulted in reduced GVHD, evident as reduced weight loss and a lesser degree of dermatitis than in saline-treated controls. KGF preserved plasma citrulline and TNF-a levels, both indicative for reduced radiation-induced injury to the gastrointestinal tract. Citruline has recently been described as a new marker for gastrointestinal toxicity. Six months after transplantation, survival rates were significantly higher in KGF-treated animals (57% as compared to PBS-treated controls (5.3%). Figure Figure These data indicate that nonmyeloablative haploidentical transplantations might be feasible and that KGF might contribute substantially to reduction of lethal GVHD, also after nonmyeloablative procedures. For clinical transplantation such an effect would be significant if intensive T cell depletion might be prevented in haploidentical transplantation protocols and therefore reduced infection rates can be obtained.

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Acute Graft-Versus-Host Disease Is Less Severe and Associated with Lower Non-Relapse Mortality after Haploidentical Transplantation with Post-Cyclophosphamide Prophylaxis

Biology of Blood and Marrow Transplantation ◽

10.1016/j.bbmt.2019.12.095 ◽

2020 ◽

Vol 26 (3) ◽

pp. S26-S27

Author(s):

Rima M. Saliba ◽

Mukta Arora ◽

Stephen R. Spellman ◽

Michael T. Hemmer ◽

Tao Wang ◽

...

Keyword(s):

Graft Versus Host Disease ◽

Host Disease ◽

Graft Versus Host ◽

Haploidentical Transplantation ◽

Acute Graft

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Keratinocyte Growth Factor Separates Graft-Versus-Leukemia Effects From Graft-Versus-Host Disease

Blood ◽

10.1182/blood.v94.2.825 ◽

1999 ◽

Vol 94 (2) ◽

pp. 825-831 ◽

Cited By ~ 136

Author(s):

Oleg I. Krijanovski ◽

Geoffrey R. Hill ◽

Kenneth R. Cooke ◽

Takanori Teshima ◽

James M. Crawford ◽

...

Keyword(s):

Growth Factor ◽

Graft Versus Host Disease ◽

Cytotoxic T Lymphocyte ◽

Keratinocyte Growth Factor ◽

Allogeneic Bone Marrow Transplantation ◽

Successful Outcome ◽

Allogeneic Bone ◽

Host Disease ◽

Graft Versus Host ◽

Graft Versus Leukemia

Abstract The major obstacles to successful outcome after allogeneic bone marrow transplantation (BMT) for leukemia remain graft-versus-host disease (GVHD) and leukemic relapse. Improved survival after BMT therefore requires more effective GVHD prophylaxis that does not impair graft-versus-leukemia (GVL) effects. We studied the administration of human recombinant keratinocyte growth factor (KGF) in a well- characterized murine BMT model for its effects on GVHD. KGF administration from day -3 to +7 significantly reduced GVHD mortality and the severity of GVHD in the gastrointestinal (GI) tract, reducing serum lipopolysaccharide (LPS) and tumor necrosis factor (TNF) levels, but preserving donor T-cell responses (cytotoxic T lymphocyte [CTL] activity, proliferation, and interleukin [IL]-2 production) to host antigens. When mice received lethal doses of P815 leukemia cells at the time of BMT, KGF treatment significantly decreased acute GVHD compared with control-treated allogeneic mice and resulted in a significantly improved leukemia-free survival (42%v 4%, P < .001). KGF administration thus offers a novel approach to the separation of GVL effects from GVHD.

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Keratinocyte Growth Factor Separates Graft-Versus-Leukemia Effects From Graft-Versus-Host Disease

Blood ◽

10.1182/blood.v94.2.825.414k10_825_831 ◽

1999 ◽

Vol 94 (2) ◽

pp. 825-831 ◽

Cited By ~ 5

Author(s):

Oleg I. Krijanovski ◽

Geoffrey R. Hill ◽

Kenneth R. Cooke ◽

Takanori Teshima ◽

James M. Crawford ◽

...

Keyword(s):

Growth Factor ◽

Graft Versus Host Disease ◽

Cytotoxic T Lymphocyte ◽

Keratinocyte Growth Factor ◽

Allogeneic Bone Marrow Transplantation ◽

Successful Outcome ◽

Allogeneic Bone ◽

Host Disease ◽

Graft Versus Host ◽

Graft Versus Leukemia

The major obstacles to successful outcome after allogeneic bone marrow transplantation (BMT) for leukemia remain graft-versus-host disease (GVHD) and leukemic relapse. Improved survival after BMT therefore requires more effective GVHD prophylaxis that does not impair graft-versus-leukemia (GVL) effects. We studied the administration of human recombinant keratinocyte growth factor (KGF) in a well- characterized murine BMT model for its effects on GVHD. KGF administration from day -3 to +7 significantly reduced GVHD mortality and the severity of GVHD in the gastrointestinal (GI) tract, reducing serum lipopolysaccharide (LPS) and tumor necrosis factor (TNF) levels, but preserving donor T-cell responses (cytotoxic T lymphocyte [CTL] activity, proliferation, and interleukin [IL]-2 production) to host antigens. When mice received lethal doses of P815 leukemia cells at the time of BMT, KGF treatment significantly decreased acute GVHD compared with control-treated allogeneic mice and resulted in a significantly improved leukemia-free survival (42%v 4%, P < .001). KGF administration thus offers a novel approach to the separation of GVL effects from GVHD.

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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 ◽

2000 ◽

Vol 96 (13) ◽

pp. 4350-4356 ◽

Cited By ~ 73

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

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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Vascular Endothelial Growth Factor Gene Polymorphisms May Predict the Risk of Acute Graft-versus-Host Disease following Allogeneic Transplantation: Preventive Effect of Vascular Endothelial Growth Factor Gene on Acute Graft-versus-Host Disease

Biology of Blood and Marrow Transplantation ◽

10.1016/j.bbmt.2008.09.022 ◽

2008 ◽

Vol 14 (12) ◽

pp. 1408-1416 ◽

Cited By ~ 22

Author(s):

Dong Hwan Kim ◽

Nan Young Lee ◽

Myung-Hoon Lee ◽

Sang Kyun Sohn

Keyword(s):

Vascular Endothelial Growth Factor ◽

Growth Factor ◽

Graft Versus Host Disease ◽

Vascular Endothelial ◽

Host Disease ◽

Factor Gene ◽

Graft Versus Host ◽

Growth Factor Gene ◽

Endothelial Growth Factor ◽

Acute Graft

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A Case of Severe COVID-19 in a Patient with Acute Graft-versus-Host Disease after Haploidentical Transplantation

Case Reports in Hematology ◽

10.1155/2021/8878803 ◽

2021 ◽

Vol 2021 ◽

pp. 1-5

Author(s):

Dan Han ◽

Yuqian Sun ◽

Rong Xie ◽

Xiaojian Zhu ◽

Zhaodong Zhong

Keyword(s):

Septic Shock ◽

Multiple Organ Failure ◽

Graft Versus Host Disease ◽

Poor Prognosis ◽

Multiple Organ ◽

Host Disease ◽

Graft Versus Host ◽

Haploidentical Transplantation ◽

Disease Condition ◽

Acute Graft

We report a case of coronavirus disease 2019 (COVID-19) after haploidentical transplantation with acute graft-versus-host disease (aGVHD). COVID-19 and aGVHD were improved under treatment with arbidol, remdesivir, methylprednisolone, and ruxolitinib. However, eventually, the patient died of septic shock and multiple organ failure. It was concluded that the disease condition of this COVID-19 patient after transplantation was serious, complex, and variable, with poor prognosis.

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Hepatocyte growth factor ameliorates acute graft-versus-host disease and promotes hematopoietic function

Journal of Clinical Investigation ◽

10.1172/jci11808 ◽

2001 ◽

Vol 107 (11) ◽

pp. 1365-1373 ◽

Cited By ~ 91

Author(s):

Takanori Kuroiwa ◽

Eizo Kakishita ◽

Teruaki Hamano ◽

Yasuro Kataoka ◽

Yoshifumi Seto ◽

...

Keyword(s):

Growth Factor ◽

Hepatocyte Growth Factor ◽

Graft Versus Host Disease ◽

Host Disease ◽

Graft Versus Host ◽

Hepatocyte Growth ◽

Acute Graft

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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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