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 Blood, 15 August 2008, Vol. 112, No. 4, pp. 1522-1529.
Prepublished online as a Blood First Edition Paper on June 6, 2008; DOI 10.1182/blood-2008-03-143461.

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TRANSPLANTATION

Differential effects of donor T-cell cytokines on outcome with continuous bortezomib administration after allogeneic bone marrow transplantation

Kai Sun1, Minghui Li1, Thomas J. Sayers2, Lisbeth A. Welniak1, and William J. Murphy1

1 Departments of Microbiology and Immunology, University of Nevada at Reno; and 2 Basic Sciences Program, SAIC-Frederick, Laboratory of Experimental Immunology, Cancer and Inflammation Program, National Cancer Institute-Frederick, Frederick, MD

Dissociating graft-versus-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 transplantation 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 tumor necrosis factor-{alpha} (TNF{alpha}) and interferon-{gamma} (IFN{gamma}) 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{alpha} but not IFN{gamma} levels. Transfer of Tnf–/– T cells also protected recipients from bortezomib-induced GVHD-dependent toxicity. Importantly, prolonged administration of bortezomib after transplantation of purified CD8+ T cells resulted in enhanced GVT response, which was dependent on donor CD8+ T cell–derived IFN{gamma}. 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{alpha}.


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