Abstract
AbstractChronic graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (SCT) is characterized by multiorgan fibrosis and profoundly affects the quality of life of transplant survivors. Heat shock protein 47 (HSP47), a collagen-specific molecular chaperone, plays a critical role in collagen synthesis in myofibroblasts. We explored the role of HSP47 in the fibrotic process of cutaneous chronic GVHD in mice. Immunohistochemical analysis showed massive fibrosis with elevated amounts of collagen deposits and accumulation of F4/80+ macrophages, as well as myofibroblasts expressing HSP47 and retinol-binding protein 1 in the skin after allogeneic SCT. Repeated injection of anti–colony-stimulating factor (CSF-1) receptor-blocking antibodies significantly reduced HSP47+ myofibroblasts in the skin, indicating a macrophage-dependent accumulation of myofibroblasts. Vitamin A-coupled liposomes carrying HSP47 small interfering RNA (siRNA) (VA-lip HSP47) delivered HSP47 siRNA to cells expressing vitamin A receptors and knocked down their HSP47 in vitro. Intravenously injected VA-lip HSP47 were specifically distributed to skin fibrotic lesions and did not affect collagen synthesis in healthy skin. VA-lip HSP47 knocked down HSP47 expression in myofibroblasts and significantly reduced collagen deposition without inducing systemic immunosuppression. It also abrogated fibrosis in the salivary glands. These results highlight a cascade of fibrosis in chronic GVHD; macrophage production of transforming growth factor β mediates fibroblast differentiation to HSP47+ myofibroblasts that produce collagen. VA-lip HSP47 represent a novel strategy to modulate fibrosis in chronic GVHD by targeting HSP47+ myofibroblasts without inducing immunosuppression.
Highlights
Allogeneic hematopoietic stem cell transplantation (SCT) is a curative therapy for hematologic malignancies, but donor T-cell–mediated graft-versus-host disease (GVHD) hampers wider application of SCT
We initially examined if myofibroblasts could accumulate in the sclerodermatous lesion of chronic GVHD in a well-established murine model of cutaneous
A macrophage depletion study by injection of aCSF1R-blocking Abs showed that production of TGF-b and accumulation of myofibroblasts in the skin depended on macrophages (Figure 1D-F)
Summary
Allogeneic hematopoietic stem cell transplantation (SCT) is a curative therapy for hematologic malignancies, but donor T-cell–mediated graft-versus-host disease (GVHD) hampers wider application of SCT. Systemic administration of corticosteroids remains the standard therapy for chronic GVHD, but longterm use of corticosteroids is associated with poor outcomes due to increased risks of infection and other adverse effects.[5,6] Development of novel treatment strategies for chronic GVHD without induction of immunosuppression is an urgent unmet medical need
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