Mast cells as mediators of fibrosis and effector cell recruitment in dermal chronic graft-versus-host disease.

Abstract

7050 Background: Allogeneic hematopoietic stem cell transplantation (allo-HCT) is a potentially curative treatment for patients with malignant neoplasms or inborn defects of hematopoiesis. Benefits of allo-HSCT are hampered by graft-versus-host-disease (GVHD), which can be debilitating and potentially lethal. In chronic GVHD (cGVHD), inflammation and aberrant wound healing lead to pathological fibrosis across multiple organs, most frequently in the skin, yet the exact pathophysiology is not well-understood. Mast cells (MCs) are primarily known for their role in atopic disease. However, recent studies have demonstrated new roles for MCs, showing that they can be involved in wound healing and in the pathogenesis of fibrotic disease. Given these new paradigms and the MC tropism to skin, alongside their reported role in other fibrotic diseases, we investigated whether MCs may play a role in the pathogenesis of dermal cGVHD. Methods: Cells: MCs were grown ex vivo from murine bone marrow. Transplant: 8 Gy radiation, followed by injection of LP/J marrow and splenocytes into C57BL/6J (WT) or B6.Cg-KitW-sh MC-deficient recipients. Results: Ex vivo, we show that MCs survive and are functional after lethal radiation, such as that used in conditioning prior to HCT. In a murine model of cGVHD WT mice had significantly more cGVHD symptoms than MC-deficient mice as measured by clinical scoring. This scoring correlated with a significant increase in skin pathology, collagen deposition, and expression of pro-fibrotic genes in WT as compared to B6.Cg-KitW-sh mice. Dermal MC numbers were increased in WT mice, but were nearly undetectable in B6.Cg-KitW-sh mice, implying that the MCs that are present were recipient-derived and had survived conditioning. Skin from WT but not B6.Cg-KitW-sh mice was enriched in cGVHD effector cells and in inflammatory cytokines and chemokines. Murine MCs, upon stimulation were sources of many of these factors, production of which was blocked when treated with ibrutinib and ruxolitinib, drugs used in cGVHD treatment. Conclusions: In summary, we show here a previously unknown role for MCs in the pathogenesis of dermal cGVHD, suggesting that MCs may be targetable to prevent and treat this devastating complication of allo HCT.