Submitted March 4, 2008
Accepted May 20, 2008
Differential effects of donor T cell cytokines on outcome with continuous bortezomib administration following allogeneic bone marrow transplantation
Kai Sun, Minghui Li, Thomas J Sayers, Lisbeth A Welniak, and William J Murphy*
Microbiology & Immunology, University of Nevada, Reno, Reno, NV, United States
Laboratory of Experimental Immunology, SAIC at Frederick, Frederick, MD, United States
* Corresponding author; email: wmurphy{at}medicine.nevada.edu.
Dissociating graft-vs.-tumor (GVT) effect from acute graft-versus-host disease (GVHD) still remains a great challenge in allogeneic bone marrow transplantation (allo-BMT). Bortezomib, a proteasome inhibitor, has shown impressive efficacy as a single agent in patients with hematologic malignancies but can result in toxicity when administered late after allogeneic transplant in murine models of GVHD. In the current study, the effects of T cell subsets and their associated cytokines on the efficacy of bortezomib in murine allogeneic BMT were investigated. Increased levels of serum TNF
and IFN
were observed after allo-BMT and continuous bortezomib administration. Bortezomib induced GVHD dependent mortality was preventable by depletion of CD4+ but not CD8+ T cells from the donor graft. The improved survival correlated with markedly reduced serum TNF but not IFN levels. Transfer of Tnf-/- T cells also protected recipients from bortezomib induced GVHD-dependent toxicity. Importantly, prolonged administration of bortezomib following transplantation of purified CD8+ T cells resulted in enhanced GVT response, which was dependent on donor CD8+ T cell-derived IFN. These results indicate that decreased toxicity and increased efficacy of bortezomib in murine allo-BMT can be achieved by removal of CD4+ T cells from the graft or by inhibiting TNF.
