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

Blood. 2005 Nov 1;106(9):3293-9. doi: 10.1182/blood-2004-11-4526. Epub 2005 Jun 16.

Abstract

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 1beta (IL-1beta), 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Acute Disease
  • Animals
  • Bone Marrow Transplantation
  • Boronic Acids / administration & dosage
  • Boronic Acids / adverse effects
  • Boronic Acids / pharmacology*
  • Bortezomib
  • Enzyme Inhibitors / pharmacology
  • Female
  • Gastrointestinal Tract / drug effects*
  • Gastrointestinal Tract / metabolism*
  • Graft vs Host Disease / chemically induced*
  • Graft vs Host Disease / genetics
  • Graft vs Host Disease / metabolism
  • Mice
  • Proteasome Endopeptidase Complex / metabolism*
  • Proteasome Inhibitors*
  • Pyrazines / administration & dosage
  • Pyrazines / adverse effects
  • Pyrazines / pharmacology*
  • RNA, Messenger / genetics
  • Receptors, Tumor Necrosis Factor, Type I / genetics

Substances

  • Boronic Acids
  • Enzyme Inhibitors
  • Proteasome Inhibitors
  • Pyrazines
  • RNA, Messenger
  • Receptors, Tumor Necrosis Factor, Type I
  • Bortezomib
  • Proteasome Endopeptidase Complex