Depletion of synovial macrophages in rheumatoid arthritis by an anti-FcgammaRI-calicheamicin immunoconjugate.
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.


CONCLUSIONS
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.
van Roon
J A G
JA
Department of Rheumatology and Clinical Immunology, University Medical Centre Utrecht, F02.127, PO Box 85500, 3508 GA Utrecht, The Netherlands. J.vanRoon@azu.nl
Bijlsma
J W J
JW
van de Winkel
J G J
JG
Lafeber
F P J G
FP
D000368:Aged; D000369:Aged, 80 and over; D000617:Aminoglycosides / Q000627:therapeutic use; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D053938:DNA Fragmentation / Q000187:drug effects; D053281:Enediynes; D006801:Humans; D018796:Immunoconjugates / Q000627:therapeutic use*; D016130:Immunophenotyping; D008213:Lymphocyte Activation; D008264:Macrophages / Q000276:immunology / Q000473:pathology*; D008875:Middle Aged; D009000:Monocytes / Q000473:pathology; D017452:Receptors, IgG / Q000276:immunology / Q000378:metabolism; D013582:Synovial Fluid / Q000166:cytology / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology
D000617:Aminoglycosides; D053281:Enediynes; C489017:FCGR1A protein, human; D018796:Immunoconjugates; D017452:Receptors, IgG; C055955:calicheamicin gamma(1)I