title: Arsenic trioxide prevents murine sclerodermatous graft-versus-host disease.
abstract: Chronic graft-versus-host disease (GVHD) follows allogeneic hematopoietic stem cell transplantation. It results from alloreactive processes induced by minor MHC incompatibilities triggered by activated APCs, such as plasmacytoid dendritic cells (pDCs), and leading to the activation of CD4 T cells. Therefore, we tested whether CD4(+) and pDCs, activated cells that produce high levels of reactive oxygen species, could be killed by arsenic trioxide (As(2)O(3)), a chemotherapeutic drug used in the treatment of acute promyelocytic leukemia. Indeed, As(2)O(3) exerts its cytotoxic effects by inducing a powerful oxidative stress that exceeds the lethal threshold. Sclerodermatous GVHD was induced in BALB/c mice by body irradiation, followed by B10.D2 bone marrow and spleen cell transplantation. Mice were simultaneously treated with daily i.p. injections of As(2)O(3). Transplanted mice displayed severe clinical symptoms, including diarrhea, alopecia, vasculitis, and fibrosis of the skin and visceral organs. The symptoms were dramatically abrogated in mice treated with As(2)O(3). These beneficial effects were mediated through the depletion of glutathione and the overproduction of H(2)O(2) that killed activated CD4(+) T cells and pDCs. The dramatic improvement provided by As(2)O(3) in the model of sclerodermatous GVHD that associates fibrosis with immune activation provides a rationale for the evaluation of As(2)O(3) in the management of patients affected by chronic GVHD.
authors.affiliation: Laboratoire EA 1833, Faculté de Médecine, Sorbonne Paris Cité, Université Paris Descartes, 75679 Paris Cedex 14, France.
authors.forename: Niloufar
authors.initials: N
authors.lastname: Kavian
authors.forename: Wioleta
authors.initials: W
authors.lastname: Marut
authors.forename: Amélie
authors.initials: A
authors.lastname: Servettaz
authors.forename: Hélène
authors.initials: H
authors.lastname: Laude
authors.forename: Carole
authors.initials: C
authors.lastname: Nicco
authors.forename: Christiane
authors.initials: C
authors.lastname: Chéreau
authors.forename: Bernard
authors.initials: B
authors.lastname: Weill
authors.forename: Frédéric
authors.initials: F
authors.lastname: Batteux
mesh_terms: D000818:Animals; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000008:administration & dosage* / Q000627:therapeutic use; D016026:Bone Marrow Transplantation / Q000276:immunology / Q000473:pathology; D002908:Chronic Disease; D004195:Disease Models, Animal; D005260:Female; D005355:Fibrosis / Q000517:prevention & control; D006086:Graft vs Host Disease / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010087:Oxides / Q000008:administration & dosage* / Q000627:therapeutic use; D011897:Random Allocation; D012595:Scleroderma, Systemic / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D013154:Spleen / Q000276:immunology / Q000473:pathology / Q000637:transplantation
chemical_list: D001152:Arsenicals; D010087:Oxides; D000077237:Arsenic Trioxide