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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.

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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 {alpha} (TNF-{alpha}) receptor transcription in gastrointestinal cells and with significant increases of TNF-{alpha}, interleukin 1{beta} (IL-1{beta}), 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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