scholarly journals Granulocyte Colony-Stimulating Factor–Mobilized Allografts Contain Activated Immune Cell Subsets Associated with Risk of Acute and Chronic Graft-versus-Host Disease

2016 ◽  
Vol 22 (4) ◽  
pp. 658-668 ◽  
Author(s):  
Sumithira Vasu ◽  
Susan Geyer ◽  
Anissa Bingman ◽  
Jeffery J. Auletta ◽  
Samantha Jaglowski ◽  
...  
Keyword(s):  
Graft Versus Host Disease ◽  
Immune Cell ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Host Disease ◽  
Graft Versus Host ◽  
Immune Cell Subsets ◽  
Stimulating Factor

Granulocyte Colony-Stimulating Factor Induced Acute and Chronic Graft-Versus-Host Disease

2010 ◽  
Vol 90 (9) ◽  
pp. 1022-1029 ◽  
Author(s):  
Olle Ringden ◽  
Zuzana Hassan ◽  
Helen Karlsson ◽  
Richard Olsson ◽  
Brigitta Omazic ◽  
...  
Keyword(s):  
Graft Versus Host Disease ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Host Disease ◽  
Graft Versus Host ◽  
Stimulating Factor

Granulocyte Colony-Stimulating Factor–Mobilized Allogeneic Stem Cell Transplantation Maintains Graft-Versus-Leukemia Effects Through a Perforin-Dependent Pathway While Preventing Graft-Versus-Host Disease

Blood ◽  
1999 ◽  
Vol 93 (12) ◽  
pp. 4071-4078 ◽  
Author(s):  
Luying Pan ◽  
Takanori Teshima ◽  
Geoffrey R. Hill ◽  
David Bungard ◽  
Yani S. Brinson ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Graft Versus Host Disease ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Graft Versus Host ◽  
Graft Versus Leukemia ◽  
Stimulating Factor ◽  
Ctl Activity

Abstract Minimization of graft-versus-host disease (GVHD) with preservation of the graft-versus-leukemia (GVL) effect is a crucial step to improve the overall survival of allogeneic bone marrow transplantation (BMT) for patients with hematological malignancies. We and other investigators have shown that granulocyte colony-stimulating factor (G-CSF)–mobilized allogeneic peripheral stem cell transplantation (PBSCT) reduces the severity of acute GVHD in murine models. In this study, we investigated whether G-CSF–mobilized PBSC maintain their GVL effect in a murine allogeneic transplant model (B6 → B6D2F1). B6 mice (H-2b) were injected subcutaneously with human G-CSF (100 μg/kg/d) for 6 days and their splenocytes were harvested on day 7 as a source of PBSC. G-CSF mobilization dramatically improved transplant survival compared with nonmobilized controls (95% v0%, P < .001). Systemic levels of lipopolysaccharide and tumor necrosis factor- were markedly reduced in recipients of allogeneic G-CSF–mobilized donors, but cytolytic T lymphocyte (CTL) activity against host tumor target cells p815 was retained in those recipients. When leukemia was induced in recipients by coinjection of p815 tumor cells (H-2d) at the time of transplantation, all surviving recipients of G-CSF–mobilized B6 donors were leukemia-free at day 70 after transplant, whereas all mice who received T-cell–depleted (TCD) splenocytes from G-CSF–mobilized B6 donors died of leukemia. When splenocytes from G-CSF–mobilized perforin-deficient (pfp−/−) mice were used for transplantation, 90% of recipients died of leukemia, demonstrating that perforin is a crucial pathway mediating GVL effects after G-CSF–mobilized PBSCT. These data illustrate that G-CSF–mobilized allogeneic PBSCT separate GVL from GVHD by preserving perforin-dependent donor CTL activity while reducing systemic inflammation.

Granulocyte Colony-Stimulating Factor–Mobilized Allogeneic Stem Cell Transplantation Maintains Graft-Versus-Leukemia Effects Through a Perforin-Dependent Pathway While Preventing Graft-Versus-Host Disease

Blood ◽  
1999 ◽  
Vol 93 (12) ◽  
pp. 4071-4078 ◽  
Author(s):  
Luying Pan ◽  
Takanori Teshima ◽  
Geoffrey R. Hill ◽  
David Bungard ◽  
Yani S. Brinson ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Graft Versus Host Disease ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Graft Versus Host ◽  
Graft Versus Leukemia ◽  
Stimulating Factor ◽  
Ctl Activity

Minimization of graft-versus-host disease (GVHD) with preservation of the graft-versus-leukemia (GVL) effect is a crucial step to improve the overall survival of allogeneic bone marrow transplantation (BMT) for patients with hematological malignancies. We and other investigators have shown that granulocyte colony-stimulating factor (G-CSF)–mobilized allogeneic peripheral stem cell transplantation (PBSCT) reduces the severity of acute GVHD in murine models. In this study, we investigated whether G-CSF–mobilized PBSC maintain their GVL effect in a murine allogeneic transplant model (B6 → B6D2F1). B6 mice (H-2b) were injected subcutaneously with human G-CSF (100 μg/kg/d) for 6 days and their splenocytes were harvested on day 7 as a source of PBSC. G-CSF mobilization dramatically improved transplant survival compared with nonmobilized controls (95% v0%, P < .001). Systemic levels of lipopolysaccharide and tumor necrosis factor- were markedly reduced in recipients of allogeneic G-CSF–mobilized donors, but cytolytic T lymphocyte (CTL) activity against host tumor target cells p815 was retained in those recipients. When leukemia was induced in recipients by coinjection of p815 tumor cells (H-2d) at the time of transplantation, all surviving recipients of G-CSF–mobilized B6 donors were leukemia-free at day 70 after transplant, whereas all mice who received T-cell–depleted (TCD) splenocytes from G-CSF–mobilized B6 donors died of leukemia. When splenocytes from G-CSF–mobilized perforin-deficient (pfp−/−) mice were used for transplantation, 90% of recipients died of leukemia, demonstrating that perforin is a crucial pathway mediating GVL effects after G-CSF–mobilized PBSCT. These data illustrate that G-CSF–mobilized allogeneic PBSCT separate GVL from GVHD by preserving perforin-dependent donor CTL activity while reducing systemic inflammation.

scholarly journals Chronic graft-versus-host disease: biological insights from preclinical and clinical studies

Blood ◽  
2017 ◽  
Vol 129 (1) ◽  
pp. 13-21 ◽  
Author(s):  
Kelli P. A. MacDonald ◽  
Geoffrey R. Hill ◽  
Bruce R. Blazar
Keyword(s):  
T Cell ◽  
Graft Versus Host Disease ◽  
Clinical Studies ◽  
Transforming Growth Factor ◽  
Interleukin 17 ◽  
Target Tissue ◽  
Colony Stimulating Factor ◽  
Host Disease ◽  
Graft Versus Host ◽  
Stimulating Factor

Abstract With the increasing use of mismatched, unrelated, and granulocyte colony-stimulating factor–mobilized peripheral blood stem cell donor grafts and successful treatment of older recipients, chronic graft-versus-host disease (cGVHD) has emerged as the major cause of nonrelapse mortality and morbidity. cGVHD is characterized by lichenoid changes and fibrosis that affects a multitude of tissues, compromising organ function. Beyond steroids, effective treatment options are limited. Thus, new strategies to both prevent and treat disease are urgently required. Over the last 5 years, our understanding of cGVHD pathogenesis and basic biology, born out of a combination of mouse models and correlative clinical studies, has radically improved. We now understand that cGVHD is initiated by naive T cells, differentiating predominantly within highly inflammatory T-helper 17/T-cytotoxic 17 and T-follicular helper paradigms with consequent thymic damage and impaired donor antigen presentation in the periphery. This leads to aberrant T- and B-cell activation and differentiation, which cooperate to generate antibody-secreting cells that cause the deposition of antibodies to polymorphic recipient antigens (ie, alloantibody) or nonpolymorphic antigens common to both recipient and donor (ie, autoantibody). It is now clear that alloantibody can, in concert with colony-stimulating factor 1 (CSF-1)-dependent donor macrophages, induce a transforming growth factor β–high environment locally within target tissue that results in scleroderma and bronchiolitis obliterans, diagnostic features of cGVHD. These findings have yielded a raft of potential new therapeutics, centered on naive T-cell depletion, interleukin-17/21 inhibition, kinase inhibition, regulatory T-cell restoration, and CSF-1 inhibition. This new understanding of cGVHD finally gives hope that effective therapies are imminent for this devastating transplant complication.

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