title: Post-transplant cyclophosphamide and bortezomib inhibit dendritic cell maturation and function and alter their IκB and NFκB.
abstract: Impairing dendritic cell (DC) function to prevent graft versus host disease (GvHD) is an appealing concept. DC antigen presentation is NF-κB pathway-dependent and bortezomib might therefore play a role in preventing alloreactivity. We obtained DC from the blood of patients enrolled in a phase I study using post-transplant cyclophosphamide and bortezomib for prevention of GvHD. Control samples were obtained from patients receiving standard GvHD prevention regimen. Pre-treatment samples were also collected from enrolled patients. DC isolated on days +1, +4, and +7 showed progressive decrease in the expression of maturation markers in comparison to control. In a DC-CD4+ mixed lymphocyte reaction (MLR) where DC isolated from the recipient blood before graft infusion were the stimulator cells, T cell proliferation measured by bromodeoxyuridine (BrdU) integration was decreased in samples obtained on days +14 and +21 in comparison to control group. Finally, measured by real-time PCR, the expression of IκB progressively increased while the expression of NF-κB decreased in DC on days +1, +4, and +7, in comparison to pre-treatment paired controls. We conclude that our data further justify exploring the role of bortezomib in GvHD prevention and propose a novel mechanism of action of bortezomib in DC.
authors.affiliation: Division of Adult Blood and Marrow Transplantation, Spectrum Health, and Michigan State University, College of Human Medicine, Grand Rapids, MI, USA. Electronic address: Ahmad.Al-Homsi@SpectrumHealth.org.
authors.forename: Ahmad Samer
authors.initials: AS
authors.lastname: Al-Homsi
authors.affiliation: Division of Hematological Malignancies and Blood and Marrow Transplantation, Roger Williams Medical Center, Providence, RI, USA.
authors.forename: Zhongbin
authors.initials: Z
authors.lastname: Lai
authors.affiliation: Division of Adult Blood and Marrow Transplantation, Spectrum Health, and Michigan State University, College of Human Medicine, Grand Rapids, MI, USA.
authors.forename: Tara S
authors.initials: TS
authors.lastname: Roy
authors.affiliation: Division of Hematological Malignancies and Blood and Marrow Transplantation, Roger Williams Medical Center, Providence, RI, USA; Boston University, School of Medicine, Boston, MA, USA.
authors.forename: M Monzr
authors.initials: MM
authors.lastname: Al-Malki
authors.affiliation: Division of Hematological Malignancies and Blood and Marrow Transplantation, Roger Williams Medical Center, Providence, RI, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Kouttab
authors.affiliation: Department of Surgical Research, Roger Williams Medical Center, Providence, RI, USA; Boston University, School of Medicine, Boston, MA, USA.
authors.forename: Richard P
authors.initials: RP
authors.lastname: Junghans
mesh_terms: D017951:Antigen Presentation / Q000187:drug effects / Q000276:immunology; D001897:Boronic Acids / Q000008:administration & dosage; D000069286:Bortezomib; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation; D002478:Cells, Cultured; D003520:Cyclophosphamide / Q000008:administration & dosage; D003713:Dendritic Cells / Q000276:immunology*; D005786:Gene Expression Regulation / Q000187:drug effects; D006086:Graft vs Host Disease / Q000276:immunology / Q000517:prevention & control*; D006801:Humans; D020672:I-kappa B Proteins / Q000235:genetics / Q000378:metabolism*; D007166:Immunosuppressive Agents / Q000008:administration & dosage; D008213:Lymphocyte Activation; D007959:Lymphocyte Culture Test, Mixed; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D011182:Postoperative Care; D011719:Pyrazines / Q000008:administration & dosage
chemical_list: D001897:Boronic Acids; C083487:I kappa B beta protein; D020672:I-kappa B Proteins; D007166:Immunosuppressive Agents; D016328:NF-kappa B; D011719:Pyrazines; D000069286:Bortezomib; D003520:Cyclophosphamide
keywords: Bortezomib; Cyclophosphamide; DC; GvHD; IκB; NF-κB