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

  1. Author:
    Sun, K.
    Li, M. H.
    Sayers, T. J.
    Welniak, L. A.
    Murphy, W. J.

  2. Author Address

    Sayers, Thomas J.] NCI, Basic Sci Program, SAIC Frederick, Expt Immunol Lab,Canc & Inflammat Program, Frederick, MD 21701 USA. [Sun, Kai, Li, Minghui, Welniak, Lisbeth A.; Murphy, William J.] Univ Nevada, Sch Med, Dept Microbiol, Reno, NV 89557 USA. [Sun, Kai, Li, Minghui, Welniak, Lisbeth A.; Murphy, William J.] Univ Nevada, Sch Med, Dept Immunol, Reno, NV 89557 USA.
    1. Year: 2008
  2. Journal: Blood
    1. 112
    2. 4
    3. Pages: 1522-1529
  4. Type of Article: Article
  1. Abstract:

    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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