Back to Search
Start Over
Selective elimination of synovial inflammatory macrophages in rheumatoid arthritis by an Fcgamma receptor I-directed immunotoxin.
- Source :
-
Arthritis and rheumatism [Arthritis Rheum] 2003 May; Vol. 48 (5), pp. 1229-38. - Publication Year :
- 2003
-
Abstract
- Objective: To determine whether monocyte/macrophages from rheumatoid arthritis (RA) patients can be selectively eliminated by a toxin-conjugated antibody CD64-ricin A (CD64-RiA) directed toward the high-affinity receptor for IgG (FcgammaRI), exploiting the capacity of FcgammaRI to efficiently endocytose antibody which it has bound.<br />Methods: Mononuclear cells from peripheral blood (PB) and synovial fluid (SF) obtained from RA patients were cultured in the presence of CD64-RiA. Cell death of monocyte/macrophages was measured by phenotypic changes (light-scatter patterns and CD14 and FcgammaRI expression) and apoptosis (nuclear DNA fragmentation). We then tested whether CD64-RiA-induced cell death of macrophages affected their capacity to stimulate antigen-induced lymphocyte proliferation and to secrete cytokines. Additionally, the capacity of CD64-RiA to inhibit proinflammatory activity and cartilage degradation by RA synovial tissue explants was evaluated.<br />Results: Inflammatory macrophages from RA SF expressed elevated levels of FcgammaRI and were selectively eliminated by CD64-RiA via apoptotic cell death. Monocyte/macrophages from RA PB, which had lower levels of FcgammaRI expression, were much less affected. Induction of SF macrophage apoptosis was associated with efficient inhibition of antigen-induced lymphocyte proliferation and a reduction in tumor necrosis factor alpha (TNFalpha) release. Consistent with these effects on SF macrophages, CD64-RiA also inhibited TNFalpha production, interleukin-1beta production, and cartilage-degrading activity of RA synovial tissue explants.<br />Conclusion: Together, these data underscore the crucial role of synovial macrophages in RA joint inflammation and indicate that selective elimination of these cells through FcgammaRI-directed immunotoxins could be a novel approach to the treatment of RA.
- Subjects :
- Aged
Aged, 80 and over
Apoptosis drug effects
Arthritis, Rheumatoid
Cell Death drug effects
Cells, Cultured
Endocytosis drug effects
Humans
Immunotoxins immunology
Macrophage Activation drug effects
Macrophages cytology
Macrophages metabolism
Middle Aged
Outpatients
Receptors, IgG immunology
Ricin immunology
Synovial Fluid cytology
Synovial Membrane metabolism
Synovial Membrane pathology
Antibody-Dependent Cell Cytotoxicity drug effects
Immunotoxins toxicity
Macrophages drug effects
Receptors, IgG metabolism
Ricin toxicity
Synovial Membrane drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 0004-3591
- Volume :
- 48
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Arthritis and rheumatism
- Publication Type :
- Academic Journal
- Accession number :
- 12746896
- Full Text :
- https://doi.org/10.1002/art.10940