title: The cyclin dependent kinase inhibitor (R)-roscovitine mediates selective suppression of alloreactive human T cells but preserves pathogen-specific and leukemia-specific effectors.
abstract: Graft versus host disease (GvHD), mediated by donor T cells, remains the primary cause of non-relapse mortality after allogeneic hematopoietic stem cell transplantation and novel therapeutic approaches are required. Cdk2 is a critical node of signal integration and programming of T cell responses towards immunity versus anergy but is dispensable for hematopoiesis and thymocyte development. We examined the effects of pharmacologic Cdk2 inhibition on alloreactive human T cells. Inhibition of Cdk2 blocked expansion of alloreactive T cells upon culture with HLA-mismatched dendritic cells and prevented generation of IFN-γ-producing alloantigen-specific effectors. In contrast, Cdk2 inhibition preserved effectors specific for Wilms' tumor 1 (WT1) leukemia antigen and for CMV as determined by WT1-specific and CMV-specific pentamers. Cdk2 inhibition preserved Treg cells, which have the ability to prevent GvHD while maintaining GvL. Thus, Cdk inhibitors may improve allogeneic HSCT by reducing alloreactivity and GvHD without loss of pathogen-specific and leukemia-specific immunity.
authors.affiliation: Department of Medicine, Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
authors.forename: Anoma
authors.initials: A
authors.lastname: Nellore
authors.affiliation: Department of Medicine, Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
authors.forename: Bianling
authors.initials: B
authors.lastname: Liu
authors.affiliation: Department of Medicine, Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Patsoukis
authors.affiliation: Department of Medicine, Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. Electronic address: vboussio@bidmc.harvard.edu.
authors.forename: Vassiliki A
authors.initials: VA
authors.lastname: Boussiotis
authors.affiliation: Department of Medicine, Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
authors.forename: Lequn
authors.initials: L
authors.lastname: Li
mesh_terms: D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D018920:Coculture Techniques; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors*; D003713:Dendritic Cells / Q000276:immunology; D000071221:Enhancer of Zeste Homolog 2 Protein; D006086:Graft vs Host Disease / Q000188:drug therapy / Q000276:immunology* / Q000517:prevention & control; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D063151:Polycomb Repressive Complex 2 / Q000096:biosynthesis / Q000276:immunology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011687:Purines / Q000494:pharmacology*; D000077546:Roscovitine; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology*; D014184:Transplantation, Homologous; D025721:WT1 Proteins / Q000276:immunology
chemical_list: D047428:Protein Kinase Inhibitors; D011687:Purines; D025721:WT1 Proteins; C583751:WT1 protein, human; D000077546:Roscovitine; D007371:Interferon-gamma; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2; D051357:Cyclin-Dependent Kinase 2
keywords: Cdk2; Graft versus host disease; T cells; T regulatory cells