Improvement of Sclerodermatous Graft-Versus-Host Disease in Mice by Niclosamide

Abstract

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.

A Fenton-like cation can improve arsenic trioxide treatment of sclerodermatous chronic Graft-versus-Host Disease in mice

“…In addition, our results are in agreement with previous studies that showed that ATO decreases the T cell response during MLR, as assessed by the production of IFN-g and increased apoptosis of T cells in a dosedependent manner (40,41). Our in vitro results allowed us to further assess the effect of the co-treatment of ATO and Cu 2+ in a mouse model of chronic GvHD (42,43). The co-treatment significantly reduced the GvHD phenotype of diseased mice.…”

“…Our in vitro results allowed us to further assess the effect of the co-treatment of ATO and Cu 2+ in a mouse model of chronic GvHD ( 42 , 43 ). The co-treatment significantly reduced the GvHD phenotype of diseased mice.…”

Universal allogeneic CAR T cells engineered with Sleeping Beauty transposons and CRISPR-CAS9 for cancer immunotherapy

“…Solid black arrows indicate GvHD pathology, including high infiltration of mononuclear cells in hepatic and lung tissues, shortening and/or structural abnormality of intestinal villi, and bronchial luminal narrowing. [55][56][57][58][59] The corresponding number at each scale bar indicates an image size (mm). was demonstrated in a previous study, 68 suggesting the feasibility of this approach.…”

“…(D) Histopathology of intestine, liver, and lung tissues obtained from all groups. Solid black arrows indicate GvHD pathology, including high infiltration of mononuclear cells in hepatic and lung tissues, shortening and/or structural abnormality of intestinal villi, and bronchial luminal narrowing [55][56][57][58][59]. The corresponding number at each scale bar indicates an image size (mm).…”

Niclosamide: Beyond an antihelminthic drug

“…This disease is a leading cause of morbidity and mortality after such transplant [91] . Morin et al reported that niclosamide treatment provided beneficial immunological effects and reversed clinical symptoms of graft-versus-host disease, including alopecia, vasculitis, and diarrhea, and also prevented fibrosis of the skin and visceral organs in the sclerodermatous graft-versus-host disease model using BALB/c mice provoked by B10.D2 bone marrow and spleen cell transplantation [92] . The beneficial effects of niclosamide were associated with inhibition of STAT3, Wnt/β-catenin, ERK 1/2, AKT, and Notch signaling pathways in earlobe skin of mice.…”