title: Therapeutic benefit of bortezomib on acute graft-versus-host disease is tissue specific and is associated with interleukin-6 levels.
abstract: Bortezomib, a proteasome inhibitor capable of direct antitumor effects, has been shown to prevent acute graft-versus-host disease (GVHD) when administered in a short course immediately after bone marrow transplantation (BMT) in mice. However, when bortezomib is given continuously, CD4(+) T cell-mediated gastrointestinal tract damage increases GVHD mortality. To investigate the protective effects of bortezomib on other organs, we used a CD8-dependent acute GVHD (aGVHD) model of C3H.SW donor T cells engrafted into irradiated C57BL/6 recipients (minor MHC mismatch), which lack significant gut GVHD. Our data in this model show that bortezomib can be given continuously to prevent and treat aGVHD mediated by CD8(+) T cells, but this effect is organ specific, such that only skin, and not liver, protection was observed. Despite the lack of hepatic protection, bortezomib still significantly improved survival, primarily because of its skin protection. Reduced skin GVHD by bortezomib was correlated with reduced serum and skin IL-6 levels. Administration of a blocking IL-6 antibody in this model also resulted in similar cutaneous GVHD protection. These results indicate that bortezomib or blockade of IL-6 may prevent CD8(+) T cell-mediated cutaneous acute GVHD.
authors: Department of Dermatology, School of Medicine, University of California, Davis, Sacramento, California.
authors: Chien-Chun Steven
authors: CC
authors: Pai
authors: Department of Dermatology, School of Medicine, University of California, Davis, Sacramento, California; Department of Internal Medicine, Kaohsiung Medical University Hospital and Faculty of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors: Hui-Hua
authors: HH
authors: Hsiao
authors: Department of Dermatology, School of Medicine, University of California, Davis, Sacramento, California; Institute of Hematology, Zhengzhou University People's Hospital, China.
authors: Kai
authors: K
authors: Sun
authors: Department of Pathology, School of Medicine, University of California, Davis, Sacramento, California.
authors: Mingyi
authors: M
authors: Chen
authors: Department of Dermatology, School of Medicine, University of California, Davis, Sacramento, California.
authors: Takeshi
authors: T
authors: Hagino
authors: Department of Dermatology, School of Medicine, University of California, Davis, Sacramento, California.
authors: Joseph
authors: J
authors: Tellez
authors: Department of Dermatology, School of Medicine, University of California, Davis, Sacramento, California.
authors: Christine
authors: C
authors: Mall
authors: Masonic Cancer Center and Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota, Minneapolis, Minnesota.
authors: Bruce R
authors: BR
authors: Blazar
authors: Department of Internal Medicine, School of Medicine, University of California, Davis, Sacramento, California.
authors: Arta
authors: A
authors: Monjazeb
authors: Department of Internal Medicine, School of Medicine, University of California, Davis, Sacramento, California.
authors: Mehrdad
authors: M
authors: Abedi
authors: Department of Dermatology, School of Medicine, University of California, Davis, Sacramento, California; Department of Internal Medicine, School of Medicine, University of California, Davis, Sacramento, California. Electronic address: wmjmurphy@ucdavis.edu.
authors: William J
authors: WJ
authors: Murphy
mesh_terms: D000208:Acute Disease; D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D006086:Graft vs Host Disease / Q000097:blood / Q000188:drug therapy / Q000473:pathology; D015850:Interleukin-6 / Q000097:blood*; D008107:Liver Diseases / Q000097:blood / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D009928:Organ Specificity; D011719:Pyrazines / Q000494:pharmacology*; D012871:Skin Diseases / Q000097:blood / Q000188:drug therapy / Q000473:pathology; D000093242:Interleukin-6 Inhibitors
chemical_list: D057134:Antibodies, Neutralizing; D000970:Antineoplastic Agents; D001897:Boronic Acids; D000069286:Bortezomib; D015850:Interleukin-6; D011719:Pyrazines; D000093242:Interleukin-6 Inhibitors
keywords: Anti–IL-6 therapy; Bortezomib; Skin acute graft-versus-host disease