Selective elimination of synovial inflammatory macrophages in rheumatoid arthritis by an Fcgamma receptor I-directed immunotoxin

Arthritis Rheum. 2003 May;48(5):1229-38. doi: 10.1002/art.10940.


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.

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.

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.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Antibody-Dependent Cell Cytotoxicity / drug effects*
  • Apoptosis / drug effects
  • Arthritis, Rheumatoid
  • Cell Death / drug effects
  • Cells, Cultured
  • Endocytosis / drug effects
  • Humans
  • Immunotoxins / immunology
  • Immunotoxins / toxicity*
  • Macrophage Activation / drug effects
  • Macrophages / cytology
  • Macrophages / drug effects*
  • Macrophages / metabolism
  • Middle Aged
  • Outpatients
  • Receptors, IgG / immunology
  • Receptors, IgG / metabolism*
  • Ricin / immunology
  • Ricin / toxicity*
  • Synovial Fluid / cytology
  • Synovial Membrane / drug effects*
  • Synovial Membrane / metabolism
  • Synovial Membrane / pathology


  • Immunotoxins
  • Receptors, IgG
  • Ricin