Inhibition of acute graft-versus-host disease with retention of graft-versus-tumor effects by the proteasome inhibitor bortezomib.

Abstract

Graft-versus-host disease (GVHD) represents a major hurdle impeding the efficacy of allogeneic bone marrow transplantation (BMT). Bortezomib is a proteasome inhibitor that was recently approved for treatment of myeloma. We found that bortezomib potently inhibited in vitro mixed lymphocyte responses and promoted the apoptosis of alloreactive T cells. Bortezomib given at the time of allogeneic BMT in mice resulted in significant protection from acute GVHD. Reductions in GVHD-associated parameters and biological evidence of proteasome inhibition were observed with this regimen but with no adverse effects on long-term donor reconstitution. Assessment of graft-versus-tumor responses in advanced leukemia-bearing mice demonstrated that only the combination of allogeneic BMT and T cells with bortezomib promoted significant increases in survival. Increased cytotoxic T cell killing of the tumor was also observed. Thus, the combination of proteasome inhibition with selective immune attack can markedly increase the efficacy of BMT in cancer.

• Authors: Kai Sun, Lisbeth A Welniak, Angela Panoskaltsis-Mortari, Matthew J O'Shaughnessy, Haiyan Liu, Isabel Barao, William Riordan, Raquel Sitcheran, Christian Wysocki, Jonathan S Serody, Bruce R Blazar, Thomas J Sayers, William J Murphy
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 101 Issue 21 Pg. 8120-5 (May 25 2004) ISSN: 0027-8424 [Print] United States
• PMID: 15148407 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Boronic Acids
• NF-kappa B
• Protease Inhibitors
• Pyrazines
• Bortezomib

Topics

• Acute Disease (therapy)
• Animals
• Bone Marrow Transplantation (adverse effects, immunology)
• Boronic Acids (adverse effects, pharmacology, therapeutic use)
• Bortezomib
• Cell Line, Tumor
• Female
• Graft vs Host Disease (drug therapy, immunology, prevention & control)
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• NF-kappa B (metabolism)
• Protease Inhibitors (adverse effects, pharmacology, therapeutic use)
• Pyrazines (adverse effects, pharmacology, therapeutic use)
• Survival Analysis
• T-Lymphocytes, Cytotoxic (cytology, drug effects, immunology)
• Transplantation, Homologous