title: The protection and therapy effects of bortezomib in murine acute graft-versus-host disease.
abstract: Acute graft-versus-host disease (aGVHD) remains a life-threatening complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). The proteasome inhibitor bortezomib exhibits potent antitumor activity with anti-inflammatory and immunomodulatory effects. However, the effects of bortezomib on aGVHD are unclear. In this study, we assessed the effects of bortezomib on aGVHD in the C57BL/6 (H-2b+) donor to BALB/c (H-2d+) recipient major histocompatibility complex-mismatched model. Two bortezomib doses (1 mg/kg each) on days 0 and +1 after transplantation, significantly increased survival rate and attenuated clinical signs of aGVHD without altering donor reconstitution. However, GVHD-associated mortality was significantly increased when bortezomib administration was delayed to day +2 posttransplantation. Furthermore, a single dose of bortezomib on day 0 or day +1 after transplantation also decreased the GVHD protective effect. Consistent with the above data, serum cytokine levels of IL-2, IFN-γ and TNF-α were significantly decreased at day +7 posttransplantation after two doses of bortezomib compared with aGVHD control group. Moreover, two administrations of bortezomib reduced donor T-cell expansion at days +3 and +4 posttransplantation and enhanced donor CD4(+)T-cell differentiation into the T help cell 17 subset at day +7 after transplantation in spleens. These results indicated that the protective effects of bortezomib on aGVHD were dependent on the time and the frequency of bortezomib administration.
authors: Department of Hematology, The Affiliated Hospital of Xuzhou Medical College, Xuzhou, China.
authors: Z
authors: Z
authors: Li
authors: Q
authors: Q
authors: Wu
authors: Z
authors: Z
authors: Yan
authors: D
authors: D
authors: Li
authors: G
authors: G
authors: Lu
authors: W
authors: W
authors: Mou
authors: S
authors: S
authors: Wu
authors: X
authors: X
authors: Pan
authors: Q
authors: Q
authors: Lu
authors: K
authors: K
authors: Xu
mesh_terms: D000208:Acute Disease; D000818:Animals; D015415:Biomarkers / Q000097:blood; D016026:Bone Marrow Transplantation / Q000009:adverse effects*; D001897:Boronic Acids / Q000008:administration & dosage*; D000069286:Bortezomib; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D006086:Graft vs Host Disease / Q000097:blood / Q000209:etiology / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D018836:Inflammation Mediators / Q000097:blood; D007371:Interferon-gamma / Q000097:blood; D007376:Interleukin-2 / Q000097:blood; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D011719:Pyrazines / Q000008:administration & dosage*; D058504:Th17 Cells / Q000187:drug effects / Q000276:immunology; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
chemical_list: D015415:Biomarkers; D001897:Boronic Acids; D007166:Immunosuppressive Agents; D018836:Inflammation Mediators; D007376:Interleukin-2; D011719:Pyrazines; D014409:Tumor Necrosis Factor-alpha; D000069286:Bortezomib; D007371:Interferon-gamma