Therapeutic benefit of bortezomib on acute graft-versus-host disease is tissue specific and is associated with interleukin-6 levels

Biol Blood Marrow Transplant. 2014 Dec;20(12):1899-904. doi: 10.1016/j.bbmt.2014.07.022. Epub 2014 Jul 23.


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.

Keywords: Anti–IL-6 therapy; Bortezomib; Skin acute graft-versus-host disease.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Acute Disease
  • Animals
  • Antibodies, Neutralizing / pharmacology
  • Antineoplastic Agents / pharmacology*
  • Boronic Acids / pharmacology*
  • Bortezomib
  • CD8-Positive T-Lymphocytes / metabolism
  • CD8-Positive T-Lymphocytes / pathology
  • Disease Models, Animal
  • Female
  • Graft vs Host Disease* / blood
  • Graft vs Host Disease* / drug therapy
  • Graft vs Host Disease* / pathology
  • Interleukin-6 / antagonists & inhibitors
  • Interleukin-6 / blood*
  • Liver Diseases / blood
  • Liver Diseases / drug therapy
  • Liver Diseases / pathology
  • Mice
  • Organ Specificity
  • Pyrazines / pharmacology*
  • Skin Diseases* / blood
  • Skin Diseases* / drug therapy
  • Skin Diseases* / pathology


  • Antibodies, Neutralizing
  • Antineoplastic Agents
  • Boronic Acids
  • Interleukin-6
  • Pyrazines
  • Bortezomib