BACKGROUND: Monocytes/macrophages have an important and versatile role in joint inflammation and destruction in rheumatoid arthritis (RA). OBJECTIVE: To determine the efficiency of monocyte/macrophage elimination by a new drug conjugated antibody (CD64-calicheamicin (CD64-CaMi)) directed to the high affinity receptor for IgG (FcgammaRI). METHODS: Mononuclear cells from peripheral blood and synovial fluid of patients with RA were cultured in the presence of CD64-CaMi. Cell death of monocytes/macrophages was measured by analysis of phenotypic changes (light scatter patterns, CD14 expression, and FcgammaRI expression) and nuclear DNA fragmentation. The selectivity of CD64-CaMi was checked by using FcgammaRI deficient and FcgammaRI transfected cell lines. In addition, the indirect effect of CD64-CaMi-induced macrophage cell death on arthritogenic T(h1) cell activity was determined. RESULTS: Inflammatory macrophages from RA synovial fluid, expressing increased FcgammaRI levels, were efficiently killed by CD64-CaMi through induction of DNA fragmentation. CD64-CaMi-induced cell death of monocytes/macrophages from peripheral blood of patients with RA proved less efficient. Induction of synovial macrophage death by CD64-CaMi was accompanied by efficient inhibition of proinflammatory T(h1) cytokine production. CONCLUSION: Together, the presented data suggest that elimination of macrophages through a new FcgammaRI directed CD64-CaMi is feasible. Because monocytes from peripheral blood are also eliminated by this immunoconjugate, additional experimental studies should validate its potential for local (intra-articular) application in the treatment of RA.
BACKGROUND: Monocytes/macrophages have an important and versatile role in joint inflammation and destruction in rheumatoid arthritis (RA). OBJECTIVE: To determine the efficiency of monocyte/macrophage elimination by a new drug conjugated antibody (CD64-calicheamicin (CD64-CaMi)) directed to the high affinity receptor for IgG (FcgammaRI). METHODS: Mononuclear cells from peripheral blood and synovial fluid of patients with RA were cultured in the presence of CD64-CaMi. Cell death of monocytes/macrophages was measured by analysis of phenotypic changes (light scatter patterns, CD14 expression, and FcgammaRI expression) and nuclear DNA fragmentation. The selectivity of CD64-CaMi was checked by using FcgammaRI deficient and FcgammaRI transfected cell lines. In addition, the indirect effect of CD64-CaMi-induced macrophage cell death on arthritogenic T(h1) cell activity was determined. RESULTS: Inflammatory macrophages from RA synovial fluid, expressing increased FcgammaRI levels, were efficiently killed by CD64-CaMi through induction of DNA fragmentation. CD64-CaMi-induced cell death of monocytes/macrophages from peripheral blood of patients with RA proved less efficient. Induction of synovial macrophage death by CD64-CaMi was accompanied by efficient inhibition of proinflammatory T(h1) cytokine production. CONCLUSION: Together, the presented data suggest that elimination of macrophages through a new FcgammaRI directed CD64-CaMi is feasible. Because monocytes from peripheral blood are also eliminated by this immunoconjugate, additional experimental studies should validate its potential for local (intra-articular) application in the treatment of RA.
Authors: I A Heijnen; M J van Vugt; N A Fanger; R F Graziano; T P de Wit; F M Hofhuis; P M Guyre; P J Capel; J S Verbeek; J G van de Winkel Journal: J Clin Invest Date: 1996-01-15 Impact factor: 14.808