[Timing of administration of bortezomib affects outcome in GVHD]
>>Blood First Edition Paper, prepublished online June 16, 2005; DOI 10.1182/blood-2004-11-4526.
Submitted November 30, 2004
Accepted May 21, 2005
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 Wilkins, Miriam R Anver, Thomas J Sayers, Angela Panoskaltsis- Mortari, Bruce R Blazar, Lisbeth A Welniak, and William J Murphy*
Department of Microbiology and Immunology, University of Nevada, Reno, NV, USA
Pathology/Histotechnology Laboratory, SAIC-Frederick, Frederick, MD, USA
Basic Sciences Program, SAIC-Frederick, Laboratory of Experimental Immunology, and National Cancer Institute-Center for Cancer Research, Frederick, MD, USA
Cancer Center and Department of Pediatrics, Division of BMT, University of Minnesota, Minneapolis, MN, USA
* Corresponding author; email: wmurphy@unr.edu.
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 post-BMT) on GVHD. Recipient C57BL/6 (H2b) mice were lethally irradiated and transplanted with bone marrow cells and splenocytes from 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 co-administered, 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. Pathological assessment revealed that significant increases in gastrointestinal lesions following delayed bortezomib administration during GVHD. This pathology correlated with significant increases of type I TNF-receptor transcription in gastrointestinal cells and with significant increases of TNF-, 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.<<
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