Differential effects of donor T-cell cytokines on outcome with continuous bortezomib administration after allogeneic bone marrow transplantation
- 15 August 2008
- journal article
- Published by American Society of Hematology in Blood
- Vol. 112 (4), 1522-1529
- https://doi.org/10.1182/blood-2008-03-143461
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-α (TNFα) and interferon-γ (IFNγ) 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 TNFα but not IFNγ 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 IFNγ. 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 TNFα.Keywords
This publication has 42 references indexed in Scilit:
- CD8+ but not CD4+ T cells require cognate interactions with target tissues to mediate GVHD across only minor H antigens, whereas both CD4+ and CD8+ T cells require direct leukemic contact to mediate GVLBlood, 2008
- Shared biology of GVHD and GVT effects: Potential methods of separationCritical Reviews in Oncology/Hematology, 2006
- Graft-Versus-Host Disease in the 21st Century: New Perspectives on an Old ProblemSeminars in Hematology, 2006
- NF-κB as a target for the prevention of graft-versus-host disease: comparative efficacy of bortezomib and PS-1145Blood, 2006
- Pathophysiology of Graft-Versus-Host DiseaseSeminars in Hematology, 2006
- 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 toxicityBlood, 2005
- Role of tumor necrosis factor-α in graft-versus-host disease and graft-versus-leukemia responsesTransplantation and Cellular Therapy, 2003
- Donor-derived interferon γ separates graft-versus-leukemia effects and graft-versus-host disease induced by donor CD8 T cellsBlood, 2002
- Cytolytic pathways in haematopoietic stem-cell transplantationNature Reviews Immunology, 2002
- Major histocompatibility complex–mismatched allogeneic bone marrow transplantation using perforin and/or Fas ligand double-defective CD4+ donor T cells: involvement of cytotoxic function by donor lymphocytes prior to graft-versus-host disease pathogenesisBlood, 2001