Systemic sclerosis (SSc) is an autoimmune disease characterized by fibrosis and vascular injury of skin and internal organs. Fractalkine (CX3CL1) is a chemokine that is expressed on vascular endothelial cells and functions as an adhesion molecule for CX3CR1-positive leukocytes. Additionally, soluble fractalkine is involved in the migration of CX3CR1-expressing leukocytes into the lesional tissue. We previously reported that the expression of fractalkine and its receptor CX3CR1 was both augmented in SSc patients, and anti-mouse fractalkine monoclonal antibody (mAb) suppressed inflammation, fibrosis, and vascular injury of the skin in bleomycin- or TGF-β/CTGF-induced SSc mouse models. However, these models do not develop apparent fibrosis and inflammation in internal organs. In the current study, we investigated the utility of anti-mouse fractalkine therapy in a murine sclerodermatous chronic graft-versus-host disease (Scl-cGVHD) model. Allogeneic bone marrow transplantation into sublethally irradiated BALB/c mice reproduced organ fibrosis and autoimmune phenotypes resembling human Scl-cGVHD or SSc. An intraperitoneal administration of anti-fractalkine mAb increased survival rate in a dose dependent manner. The mAb therapy significantly suppressed the fibrosis of the skin and lungs. Moreover, the mAb dose-dependently attenuated the local infiltration of T lymphocytes in the skin and lungs and macrophages in the lungs. Furthermore, the mAb inhibited the expression of proinflammatory cytokines such as IL-6, TNF-α, and profibrotic cytokine IL-4 in the skin and the TNF-α expression in the lungs. Anti-fractalkine mAb treatment did not show any apparent adverse events. These data together with our previous findings in other mouse models indicate that the systemic administration of anti-fractalkine mAb can be an attractive therapeutic approach for human Scl-cGVHD and SSc.

ESDR003 - Anti-fractalkine monoclonal antibody therapy ameliorates murine sclerodermatous chronic graft-versus-host disease

50th Annual Meeting of the European Society for Dermatological Research. VIRTUAL MEETING