Therapeutic effect of IVIG on inflammatory arthritis in mice is dependent on the Fc portion and independent of sialylation or basophils.
High-dose i.v. Ig (IVIG) is used to treat various autoimmune and inflammatory diseases; however, the mechanism of action remains unclear. Based on the K/BxN serum transfer arthritis model in mice, IVIG suppression of inflammation has been attributed to a mechanism involving basophils and the binding of highly sialylated IgG Fc to DC-SIGN-expressing myeloid cells. The requirement for sialylation was examined in the collagen Ab-induced arthritis (CAbIA) and K/BxN serum transfer arthritis models in mice. High-dose IVIG (1-2 g/kg body weight) suppressed inflammatory arthritis when given prophylactically. The same doses were also effective in the CAbIA model when given subsequent to disease induction. In this therapeutic CAbIA model, the anti-inflammatory effect of IVIG was dependent on IgG Fc but not F(ab')2 fragments. Removal of sialic acid residues by neuraminidase had no impact on the anti-inflammatory activity of IVIG or Fc fragments. Treatment of mice with basophil-depleting mAbs did not abrogate the suppression of either CAbIA or K/BxN arthritis by IVIG. Our data confirm the therapeutic benefit of IVIG and IgG Fc in Ab-induced arthritis but fail to support the significance of sialylation and basophil involvement in the mechanism of action of IVIG therapy.
CSL Ltd., Bio21 Institute, Parkville, Victoria 3010, Australia;
Ian K
IK
Campbell
CSL Behring, Research and Development, CH-3000 Bern, Switzerland;
Sylvia
S
Miescher
Canadian Blood Services, Centre for Innovation, Toronto, Ontario K1G 4J5, Canada; Department of Medicine, University of Toronto, Toronto, Ontario M5G 2M1, Canada; and.
Donald R
DR
Branch
Canadian Blood Services, Centre for Innovation, Toronto, Ontario K1G 4J5, Canada; Keenan Research Centre, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario M5B 1W8, Canada.
Patrick J
PJ
Mott
Canadian Blood Services, Centre for Innovation, Toronto, Ontario K1G 4J5, Canada; Keenan Research Centre, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario M5B 1W8, Canada.
Alan H
AH
Lazarus
Canadian Blood Services, Centre for Innovation, Toronto, Ontario K1G 4J5, Canada; Keenan Research Centre, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario M5B 1W8, Canada.
Dongji
D
Han
CSL Ltd., Bio21 Institute, Parkville, Victoria 3010, Australia;
Eugene
E
Maraskovsky
CSL Ltd., Bio21 Institute, Parkville, Victoria 3010, Australia; CSL Behring, Research and Development, CH-3000 Bern, Switzerland;
Adrian W
AW
Zuercher
Canadian Blood Services, Centre for Innovation, Toronto, Ontario K1G 4J5, Canada; Department of Medicine, University of Toronto, Toronto, Ontario M5G 2M1, Canada; and.
Anton
A
Neschadim
Canadian Blood Services, Centre for Innovation, Toronto, Ontario K1G 4J5, Canada; Department of Medicine, University of Toronto, Toronto, Ontario M5G 2M1, Canada; and.
Danila
D
Leontyev
CSL Ltd., Bio21 Institute, Parkville, Victoria 3010, Australia;
Brent S
BS
McKenzie
CSL Behring, Research and Development, CH-3000 Bern, Switzerland; Fabian.Kaesermann@cslbehring.com.
Fabian
F
Käsermann
D000818:Animals; D001168:Arthritis / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D001491:Basophils / Q000276:immunology* / Q000473:pathology; D004195:Disease Models, Animal; D007141:Immunoglobulin Fc Fragments / Q000276:immunology*; D016756:Immunoglobulins, Intravenous / Q000276:immunology / Q000494:pharmacology*; D007155:Immunologic Factors / Q000276:immunology / Q000494:pharmacology*; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D019158:N-Acetylneuraminic Acid / Q000276:immunology*
D007141:Immunoglobulin Fc Fragments; D016756:Immunoglobulins, Intravenous; D007155:Immunologic Factors; D019158:N-Acetylneuraminic Acid