This study compares the effect of recombinant Factor VIII Fc fusion protein (rFVIII-Fc) with recombinant FVIII (rFVIII) on monocyte-derived dendritic cells (moDC's). Cells treated with rFVIII-Fc showed morphological changes typical for cell activation, had a significant up-regulation of cell activation markers and produced higher levels of pro-inflammatory cytokines. Even after stimulation with Lipopolysaccharides, the addition of rFVIII-Fc led to increased expression of activation markers, indicating that rFVIII-Fc is capable of amplifying the maturation signal. On the contrary, cultivation of moDC's with rFVIII did not alter cell morphology or increase surface activation marker expression and pro-inflammatory cytokine production. The binding of the Fc domain to the activating Fc gamma receptor IIa (Fc gamma RIIa) can cause cell activation. Therefore, the effect of rFVIII-Fc on Fc gamma RIIa was analyzed in detail. Cultivation of moDC's with rFVIII-Fc led to increased phosphorylation of Fc gamma RIIa, which was not detected for rFVIII. Blocking Fc gamma RIIa prior to the cultivation with rFVIII-Fc significantly reduced the activating effect of rFVIII-Fc, indicating that rFVIII-Fc-induced moDC activation was caused by Fc gamma RIIa. Moreover, rFVIII-Fc bound to FCGR2A-transfected human embryonic kidney 293 cells. Taken together, our data present a new mechanism of moDC activation by rFVIII-Fc via Fc gamma RIIa.
机构:
Univ Calif Davis, Davis, CA 95616 USAUniv Witwatersrand, Fac Hlth Sci, Haemophilia Comprehens Care Ctr, Johannesburg, South Africa
Powell, Jerry S.
Ragni, Margaret V.
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Univ Pittsburgh, Pittsburgh, PA USA
Hemophilia Ctr Western Penn, Pittsburgh, PA USAUniv Witwatersrand, Fac Hlth Sci, Haemophilia Comprehens Care Ctr, Johannesburg, South Africa
Ragni, Margaret V.
Chowdary, Pratima
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Royal Free Hosp, Katharine Dormandy Haemophilia Ctr, London NW3 2QG, England
Royal Free Hosp, Thrombosis Unit, London NW3 2QG, EnglandUniv Witwatersrand, Fac Hlth Sci, Haemophilia Comprehens Care Ctr, Johannesburg, South Africa
Chowdary, Pratima
Josephson, Neil C.
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Puget Sound Blood Ctr, Seattle, WA 98104 USAUniv Witwatersrand, Fac Hlth Sci, Haemophilia Comprehens Care Ctr, Johannesburg, South Africa
Josephson, Neil C.
Pabinger, Ingrid
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Med Univ Wien, Univ Klin Innere Med 1, Vienna, AustriaUniv Witwatersrand, Fac Hlth Sci, Haemophilia Comprehens Care Ctr, Johannesburg, South Africa
Pabinger, Ingrid
Hanabusa, Hideji
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Ogikubo Hosp, Dept Hematol, Suginami Ku, Tokyo, JapanUniv Witwatersrand, Fac Hlth Sci, Haemophilia Comprehens Care Ctr, Johannesburg, South Africa
Hanabusa, Hideji
Gupta, Naresh
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Maulana Azad Med Coll, Haemophilia Ctr, New Delhi, India
Maulana Azad Med Coll, Dept Med, New Delhi, India
Associated Lok Nayak Jai Prakash Narayan Hosp, New Delhi, IndiaUniv Witwatersrand, Fac Hlth Sci, Haemophilia Comprehens Care Ctr, Johannesburg, South Africa
Gupta, Naresh
Kulkarni, Roshni
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Michigan State Univ, Dept Pediat & Human Dev, E Lansing, MI 48824 USAUniv Witwatersrand, Fac Hlth Sci, Haemophilia Comprehens Care Ctr, Johannesburg, South Africa
Kulkarni, Roshni
Fogarty, Patrick
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Hosp Univ Penn, Penn Comprehens Hemostasis & Thrombosis Program, Philadelphia, PA 19104 USAUniv Witwatersrand, Fac Hlth Sci, Haemophilia Comprehens Care Ctr, Johannesburg, South Africa
Fogarty, Patrick
Perry, David
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Addenbrookes Hosp, Cambridge Haemophilia & Thrombosis Ctr, Cambridge, EnglandUniv Witwatersrand, Fac Hlth Sci, Haemophilia Comprehens Care Ctr, Johannesburg, South Africa
Perry, David
Shapiro, Amy
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Indiana Hemophilia & Thrombosis Ctr, Dept Hematol, Indianapolis, IN USAUniv Witwatersrand, Fac Hlth Sci, Haemophilia Comprehens Care Ctr, Johannesburg, South Africa
Shapiro, Amy
Pasi, K. John
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Royal London Haemophilia Ctr, Barts & London Sch Med & Dent, London, EnglandUniv Witwatersrand, Fac Hlth Sci, Haemophilia Comprehens Care Ctr, Johannesburg, South Africa
Pasi, K. John
Apte, Shashikant
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Sahyadri Hosp, Dept Hematol, Mahara, IndiaUniv Witwatersrand, Fac Hlth Sci, Haemophilia Comprehens Care Ctr, Johannesburg, South Africa
Apte, Shashikant
Nestorov, Ivan
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机构:
Biogen Idec Hemophilia, Cambridge, MA USAUniv Witwatersrand, Fac Hlth Sci, Haemophilia Comprehens Care Ctr, Johannesburg, South Africa
Nestorov, Ivan
Jiang, Haiyan
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Biogen Idec Hemophilia, Cambridge, MA USAUniv Witwatersrand, Fac Hlth Sci, Haemophilia Comprehens Care Ctr, Johannesburg, South Africa
Jiang, Haiyan
Li, Shuanglian
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Biogen Idec Hemophilia, Cambridge, MA USAUniv Witwatersrand, Fac Hlth Sci, Haemophilia Comprehens Care Ctr, Johannesburg, South Africa
Li, Shuanglian
Neelakantan, Srividya
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Biogen Idec Hemophilia, Cambridge, MA USAUniv Witwatersrand, Fac Hlth Sci, Haemophilia Comprehens Care Ctr, Johannesburg, South Africa
Neelakantan, Srividya
Cristiano, Lynda M.
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Biogen Idec Hemophilia, Cambridge, MA USAUniv Witwatersrand, Fac Hlth Sci, Haemophilia Comprehens Care Ctr, Johannesburg, South Africa
Cristiano, Lynda M.
Goyal, Jaya
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机构:
Biogen Idec Hemophilia, Cambridge, MA USAUniv Witwatersrand, Fac Hlth Sci, Haemophilia Comprehens Care Ctr, Johannesburg, South Africa
Goyal, Jaya
Sommer, Jurg M.
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机构:
Biogen Idec Hemophilia, Cambridge, MA USAUniv Witwatersrand, Fac Hlth Sci, Haemophilia Comprehens Care Ctr, Johannesburg, South Africa
Sommer, Jurg M.
Dumont, Jennifer A.
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机构:
Biogen Idec Hemophilia, Cambridge, MA USAUniv Witwatersrand, Fac Hlth Sci, Haemophilia Comprehens Care Ctr, Johannesburg, South Africa
Dumont, Jennifer A.
Dodd, Nigel
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机构:
Biogen Idec Hemophilia, Cambridge, MA USAUniv Witwatersrand, Fac Hlth Sci, Haemophilia Comprehens Care Ctr, Johannesburg, South Africa
Dodd, Nigel
Nugent, Karen
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机构:
Biogen Idec Hemophilia, Cambridge, MA USAUniv Witwatersrand, Fac Hlth Sci, Haemophilia Comprehens Care Ctr, Johannesburg, South Africa
Nugent, Karen
Vigliani, Gloria
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Biogen Idec Hemophilia, Cambridge, MA USAUniv Witwatersrand, Fac Hlth Sci, Haemophilia Comprehens Care Ctr, Johannesburg, South Africa
Vigliani, Gloria
Luk, Alvin
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Biogen Idec Hemophilia, Cambridge, MA USAUniv Witwatersrand, Fac Hlth Sci, Haemophilia Comprehens Care Ctr, Johannesburg, South Africa
Luk, Alvin
Brennan, Aoife
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机构:
Biogen Idec Hemophilia, Cambridge, MA USAUniv Witwatersrand, Fac Hlth Sci, Haemophilia Comprehens Care Ctr, Johannesburg, South Africa
Brennan, Aoife
Pierce, Glenn F.
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机构:
Biogen Idec Hemophilia, Cambridge, MA USAUniv Witwatersrand, Fac Hlth Sci, Haemophilia Comprehens Care Ctr, Johannesburg, South Africa