Search

Sclerodermatous graft-versus-host disease, a frequent complication of allogeneic hematopoietic stem cell graft, shares many features with systemic sclerosis, such as production of autoantibodies and fibrosis of skin and inner organs. Recent reports on the implication of signal transducer and activator of transcription 3 and of Wnt/β-catenin in fibrosis have prompted us to investigate the effects of the inhibition of both signaling pathways in a mouse model of sclerodermatous graft-versus-host disease, using niclosamide, an anthelmintic drug, with a well-defined safety profile. Sclerodermatous graft-versus-host disease was induced in BALB/c mice by B10.D2 bone marrow and spleen cell transplantation. Mice were treated every other day, 5 days a week, for 5 weeks by niclosamide. Clinical and biological features were studied 42 days after transplantation. Niclosamide reversed clinical symptoms including alopecia, vasculitis, and diarrhea and prevented fibrosis of the skin and visceral organs. Beneficial immunological effects were also observed: niclosamide decreased the production of effector memory CD4 and CD8 T cells, T-cell infiltration of the skin and visceral organs, and decreased productions of IL-4 and IL-13, and autoimmune B-cell activation. The improvement provided by niclosamide in the mouse model of sclerodermatous graft-versus-host disease provides a rationale for the evaluation of niclosamide in the management of patients affected by systemic fibrotic disease., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Chronic graft-versus-host disease (GVHD) follows allogeneic hematopoietic stem cell transplantation. It results from alloreactive processes induced by minor histocompatibility antigen incompatibilities leading to the activation of CD4 T cells and the development of fibrosis and inflammation of the skin and visceral organs and autoimmunity that resemble systemic sclerosis. EGFR is a ubiquitous cell receptor deeply involved in cell proliferation, differentiation, and motility. EGFR has recently been implicated in autoimmune and fibrotic diseases. Therefore, we tested whether Erlotinib, an EGFR tyrosine kinase inhibitor, can prevent sclerodermatous GVHD (Scl-GVHD). Scl-GVHD was induced in BALB/c mice by B10.D2 bone marrow and spleen cell transplantation. Transplanted mice displayed severe clinical symptoms including alopecia, fibrosis of the skin and visceral organs, vasculitis, and diarrhea. The symptoms were reversed in mice treated with Erlotinib. These beneficial effects were mediated by the decreased production of activated/memory CD4(+) T cells and the reduction in T-cell infiltration of the skin and visceral organs along with a decrease in IFN-γ and IL-13 production and autoimmune B-cell activation. The improvement provided by Erlotinib in the mouse model of Scl-GVHD supplies a rationale for the evaluation of Erlotinib in the management of patients affected by chronic GVHD.

Systemic sclerosis (SSc) is a connective tissue disorder characterized by skin and visceral fibrosis, microvascular damage, and autoimmunity. HOCl-induced mouse SSc is a murine model that mimics the main features of the human disease, especially the activation and hyperproliferation rate of skin fibroblasts. We demonstrate here the efficiency of a tellurium-based catalyst 2,3-bis(phenyltellanyl)naphthoquinone ((PHTE)(2)NQ) in the treatment of murine SSc, through its selective cytotoxic effects on activated SSc skin fibroblasts. SSc mice treated with (PHTE)(2)NQ displayed a significant decrease in lung and skin fibrosis and in alpha-smooth muscle actin (α-SMA) expression in the skin compared with untreated mouse SSc animals. Serum concentrations of advanced oxidation protein products, nitrate, and anti-DNA topoisomerase I autoantibodies were increased in SSc mice, but were significantly reduced in SSc mice treated with (PHTE)(2)NQ. To assess the mechanism of action of (PHTE)(2)NQ, the cytotoxic effect of (PHTE)(2)NQ was compared in normal fibroblasts and in mouse SSc skin fibroblasts. ROS production is higher in mouse SSc fibroblasts than in normal fibroblasts, and was still increased by (PHTE)(2)NQ to reach a lethal threshold and kill mouse SSc fibroblasts. Therefore, the effectiveness of (PHTE)(2)NQ in the treatment of mouse SSc seems to be linked to the selective pro-oxidative and cytotoxic effects of (PHTE)(2)NQ on hyperproliferative fibroblasts.