title: Cell-based immunotherapy with suppressor CD8+ T cells in rheumatoid arthritis.
abstract: The chronic persistence of rheumatoid synovitis, an inflammation driven by activated T cells, macrophages, and fibroblasts causing irreversible joint damage, suggests a failure in physiologic mechanisms that down-regulate and terminate chronic immune responses. In vitro CD8(+)CD28(-)CD56(+) T cells tolerize APCs, prevent the priming of naive CD4(+) T cells, and suppress memory CD4(+) T cell responses. Therefore, we generated CD8(+)CD28(-)CD56(+) T cell clones from synovial tissues, expanded them in vitro, and adoptively transferred them into NOD-SCID mice engrafted with synovial tissues from patients with rheumatoid arthritis. Adoptively transferred CD8(+)CD28(-)CD56(+) T cells displayed strong anti-inflammatory activity. They inhibited production of IFN-gamma, TNF-alpha, and chemokines in autologous and HLA class I-matched heterologous synovitis. Down-regulation of costimulatory ligands CD80 and CD86 on synovial fibroblasts was identified as one mechanism of immunosuppression. We propose that rheumatoid synovitis can be suppressed by cell-based immunotherapy with immunoregulatory CD8(+) T cells.
authors.affiliation: Department of Medicine, Kathleen B. and Mason I. Lowance Center for Human Immunology, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Davila
authors.forename: Young Mo
authors.initials: YM
authors.lastname: Kang
authors.forename: Yong Wook
authors.initials: YW
authors.lastname: Park
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Sawai
authors.forename: Xiaowen
authors.initials: X
authors.lastname: He
authors.forename: Sergey
authors.initials: S
authors.lastname: Pryshchep
authors.forename: Jörg J
authors.initials: JJ
authors.lastname: Goronzy
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: Weyand
mesh_terms: D019264:Adoptive Transfer / Q000379:methods*; D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000378:metabolism; D015703:Antigens, CD / Q000096:biosynthesis; D001172:Arthritis, Rheumatoid / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D051940:B7-2 Antigen; D018106:CD28 Antigens / Q000096:biosynthesis / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D019002:CD56 Antigen / Q000096:biosynthesis; D002450:Cell Communication / Q000276:immunology; D002460:Cell Line; D045744:Cell Line, Tumor; D002999:Clone Cells; D015536:Down-Regulation / Q000276:immunology; D005347:Fibroblasts / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D015789:HLA-A2 Antigen / Q000276:immunology; D006801:Humans; D016130:Immunophenotyping; D008213:Lymphocyte Activation / Q000276:immunology; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D013583:Synovial Membrane / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation*
chemical_list: D015703:Antigens, CD; D051940:B7-2 Antigen; D018106:CD28 Antigens; D019002:CD56 Antigen; C497964:CD86 protein, human; C497965:Cd86 protein, mouse; D015789:HLA-A2 Antigen; D008562:Membrane Glycoproteins