Mast Cells Are Mediators of Fibrosis and Effector Cell Recruitment in Dermal Chronic Graft-vs.-Host Disease

Abstract

Allogeneic hematopoietic stem cell transplant (allo-HSCT) is often used to treat acute leukemia or defects of hematopoiesis. Its widespread use is hampered by graft-vs.-host disease (GVHD), which has high morbidity and mortality in both acute and chronic subtypes. Chronic GVHD (cGVHD) occurs most frequently in skin and often is characterized by pathogenic fibrosis. Mast cells (MCs) are known to be involved in the pathogenesis of other fibrotic diseases. In a murine model of cGVHD after allo-HSCT, C57BL/6J recipients of allogeneic LP/J donor cells develop sclerodermatous dermal cGVHD which is significantly decreased in mast cell-deficient B6.Cg-KitW−sh/HNihrJaeBsmGlliJ recipients. The presence of MCs is associated with fibrosis, chemokine production, and recruitment of GVHD effector cells to the skin. Chemokine production by MCs is blocked by drugs used to treat cGVHD. The importance of MCs in skin cGVHD is mirrored by increased MCs in the skin of patients with dermal cGVHD. We show for the first time a role for MCs in skin cGVHD that may be targetable for preventive and therapeutic intervention in this disease.

A Review of the Evidence for and against a Role for Mast Cells in Cutaneous Scarring and Fibrosis

“…Skin fibrosis is a recognized complication of graft-versus-host disease (GVHD), and the fibrotic process associated with GVHD shares several key features with progressive SSc [ 117 ]. An increase in mast cells has been reported in the skin of human GVHD samples compared to normal skin [ 118 ], and mast cells are commonly found in areas with irregular collagen fibers and active fibroblasts along with other immune cells [ 119 ]. Murine models of GVHD also develop cutaneous fibrosis, which is accompanied by prominent mast cell degranulation [ 118 , 120 , 121 , 122 , 123 , 124 , 125 , 126 ].…”

“…An increase in mast cells has been reported in the skin of human GVHD samples compared to normal skin [ 118 ], and mast cells are commonly found in areas with irregular collagen fibers and active fibroblasts along with other immune cells [ 119 ]. Murine models of GVHD also develop cutaneous fibrosis, which is accompanied by prominent mast cell degranulation [ 118 , 120 , 121 , 122 , 123 , 124 , 125 , 126 ]. Studies have shown that GVHD mice treated with nedocromil sodium, a mast cell stabilizer, had less of a fibrotic response [ 126 ].…”

“…In contrast, mice treated with 48/80, which stimulates mast cell degranulation, developed more severe fibrosis [ 126 ]. In addition, less fibrosis and collagen deposition were noted in mast cell-deficient Kit W-sh/W-sh mice with GVHD compared to control mice with GVHD [ 118 ].…”

Mast Cell Involvement in Fibrosis in Chronic Graft-Versus-Host Disease

“…We examined this further in our studies [ 38 ], finding that supernatants from activated mast cells did indeed induce fibroblast proliferation when compared to supernatants from quiescent mast cells. This lends credence to the idea of a mast cell/fibroblast feedback loop in cGVHD.…”

Senescence of fibroblastic reticular cells in draining lymph nodes: immunoregulation following transplantation

“…Mast cells are present in connective tissues throughout the body and serve multiple functions including effecting or regulating allergic responses, innate and adaptive immunity, autoimmunity, and inflammation. Mast cells serve as mediators of fibrosis and effector cell recruitment through chemokine production in dermal chronic graft-versus-host disease following bone marrow transplantation (16). Li, Zhao, and colleagues (11) demonstrated that ischemia and oxidative stress in mice…”