Differential effects of donor T-cell cytokines on outcome with continuous bortezomib administration after allogeneic bone marrow transplantation.
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 (TNFalpha) and interferon-gamma (IFNgamma) 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 TNFalpha but not IFNgamma 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 IFNgamma. 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 TNFalpha.
Department of Microbiology and Immunology, University of Nevada, School of Medicine, Reno, NV 89557, USA.
Kai
K
Sun
Minghui
M
Li
Thomas J
TJ
Sayers
Lisbeth A
LA
Welniak
William J
WJ
Murphy
D000818:Animals; D016026:Bone Marrow Transplantation / Q000009:adverse effects / Q000379:methods*; D001897:Boronic Acids / Q000008:administration & dosage*; D000069286:Bortezomib; D016207:Cytokines / Q000378:metabolism*; D005260:Female; D020544:Graft vs Leukemia Effect; D020350:Graft vs Tumor Effect; D007371:Interferon-gamma; D008212:Lymphocyte Depletion; D051379:Mice; D011719:Pyrazines / Q000008:administration & dosage*; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000637:transplantation*; D014184:Transplantation, Homologous; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D001897:Boronic Acids; D016207:Cytokines; D011719:Pyrazines; D014409:Tumor Necrosis Factor-alpha; D000069286:Bortezomib; D007371:Interferon-gamma