Cell-based immunotherapy with suppressor CD8+ T cells in rheumatoid arthritis.
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.
Davila
Eduardo
E
Department of Medicine, Kathleen B. and Mason I. Lowance Center for Human Immunology, Emory University School of Medicine, Atlanta, GA 30322, USA.
Kang
Young Mo
YM
Park
Yong Wook
YW
Sawai
Hirokazu
H
He
Xiaowen
X
Pryshchep
Sergey
S
Goronzy
Jörg J
JJ
Weyand
Cornelia M
CM
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*
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