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Blood, 1 November 2005, Vol. 106, No. 9, pp. 3293-3299. Prepublished online as a Blood First Edition Paper on June 16, 2005; DOI 10.1182/blood-2004-11-4526. This Article Full Text Full Text (PDF) All Versions of this Article: 2004-11-4526v1 106/9/3293    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Sun, K. Articles by Murphy, W. J. Search for Related Content PubMed PubMed Citation Articles by Sun, K. Articles by Murphy, W. J. Related Collections Immunobiology Transplantation Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  TRANSPLANTATION Differential effects of proteasome inhibition by bortezomib on murine acute graft-versus-host disease (GVHD): delayed administration of bortezomib results in increased GVHD-dependent gastrointestinal toxicity Kai Sun, Danice E. C. Wilkins, Miriam R. Anver, Thomas J. Sayers, Angela Panoskaltsis-Mortari, Bruce R. Blazar, Lisbeth A. Welniak, and William J. Murphy From the Department of Microbiology and Immunology, University of Nevada, Reno; Pathology/Histotechnology Laboratory, Science Applications International Corporation (SAIC)–Frederick, MD; Basic Sciences Program, SAIC-Frederick, Laboratory of Experimental Immunology, and National Cancer Institute Center for Cancer Research, Frederick, MD; and Cancer Center and Department of Pediatrics, Division of Bone Marrow Transplantation, University of Minnesota, Minneapolis, MN. We have recently demonstrated that the proteasome inhibitor, bortezomib, administered immediately following murine allogeneic bone marrow transplantation (BMT) resulted in marked inhibition of acute graft-versus-host disease (GVHD) with retention of graft-versus-tumor effects. We now assessed the effects of delayed bortezomib administration (5 or more days after BMT) on GVHD. Recipient C57BL/6 (H2b) mice were lethally irradiated and given transplants of bone marrow cells and splenocytes from major histocompatibility complex (MHC)–disparate BALB/c (H2d) donors. In marked contrast to the effects of bortezomib on GVHD prevention when administered immediately after BMT, delayed bortezomib administration resulted in significant acceleration of GVHD-dependent morbidity. No toxicity was observed following delayed bortezomib administration in models where donor T cells were not coadministered, indicating that these deleterious effects were critically dependent on GVHD induction. The increase in GVHD susceptibility even occurred when late administration of bortezomib was preceded by early administration. Pathologic assessment revealed that significant increases in gastrointestinal lesions occurred following delayed bortezomib administration during GVHD. This pathology correlated with significant increases of type 1 tumor necrosis factor (TNF-) receptor transcription in gastrointestinal cells and with significant increases of TNF-, interleukin 1 (IL-1), and IL-6 levels in the serum. These results indicate that the differential effects of proteasome inhibition with bortezomib on GVHD are critically dependent on the timing of bortezomib administration. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: J. Koreth, K. E. Stevenson, H. T. Kim, M. Garcia, V. T. Ho, P. Armand, C. Cutler, J. Ritz, J. H. Antin, R. J. Soiffer, et al. Bortezomib, tacrolimus, and methotrexate for prophylaxis of graft-versus-host disease after reduced-intensity conditioning allogeneic stem cell transplantation from HLA-mismatched unrelated donors Blood, October 29, 2009; 114(18): 3956 - 3959. [Abstract] [Full Text] [PDF] K. Sun, M. Li, T. J. Sayers, L. A. Welniak, and W. J. Murphy Differential effects of donor T-cell cytokines on outcome with continuous bortezomib administration after allogeneic bone marrow transplantation Blood, August 15, 2008; 112(4): 1522 - 1529. [Abstract] [Full Text] [PDF] K. P. A. MacDonald, R. D. Kuns, V. Rowe, E. S. Morris, T. Banovic, H. Bofinger, B. O'Sullivan, K. A. Markey, A. L. Don, R. Thomas, et al. Effector and regulatory T-cell function is differentially regulated by RelB within antigen-presenting cells during GVHD Blood, June 1, 2007; 109(11): 5049 - 5057. [Abstract] [Full Text] [PDF] Q. Zhou, R. A. Gault, T. R. Kozel, and W. J. Murphy Protection from Direct Cerebral Cryptococcus Infection by Interferon-{gamma}-Dependent Activation of Microglial Cells J. Immunol., May 1, 2007; 178(9): 5753 - 5761. [Abstract] [Full Text] [PDF] A. Nencioni, K. Schwarzenberg, K. M. Brauer, S. M. Schmidt, A. Ballestrero, F. Grunebach, and P. Brossart Proteasome inhibitor bortezomib modulates TLR4-induced dendritic cell activation Blood, July 15, 2006; 108(2): 551 - 558. [Abstract] [Full Text] [PDF]

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