title: IgG-Mediated Immune Suppression to Erythrocytes by Polyclonal Antibodies Can Occur in the Absence of Activating or Inhibitory Fcγ Receptors in a Full Mouse Model.
abstract: Polyclonal anti-D has been used to prevent RhD-negative mothers from becoming immunized against RhD positive fetal erythrocytes, and this mechanism has been referred as Ab or IgG-mediated immune suppression (AMIS). Although anti-D has been highly successful, the inhibitory mechanisms remain poorly understood. Two major theories behind AMIS involve the binding of IgG to activating or inhibitory FcγR, which can induce either erythrocyte clearance or immune inhibition, respectively. In this work, we explored the absolute role of activating and inhibitory FcγR in the AMIS mechanism using the HOD mouse model of RBC immunization. HOD mice contain a RBC-specific recombinant protein composed of hen egg lysozyme (HEL), OVA and human transmembrane Duffy Ag, and erythrocytes from HOD mice can stimulate an immune response to HEL. To assess the contribution of activating and inhibitory FcγR to AMIS, C57BL/6 versus FcRγ-chain(-/-) or FcγRIIB(-/-) mice were used as recipients of HOD-RBC alone or together with anti-HEL Abs (i.e., AMIS) and the resulting immune response to HEL evaluated. We show that anti-HEL polyclonal Abs induce the same degree of AMIS effect in mice lacking these IgG binding receptors as compared with wild-type mice. In agreement with this, F(ab')2 fragments of the AMIS Ab also significantly reduced the Ab response to the HOD cells. In conclusion, successful inhibition of in vivo Ab responses to HOD-RBC by polyclonal IgG can occur independently of activating or inhibitory FcγR involvement. These results may have implications for the understanding of RhD prophylaxis.
authors.affiliation: Canadian Blood Services, Ottawa, Ontario K1G 4J5, Canada; Department of Laboratory Medicine, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario M5B 1W8, Canada; Keenan Research Centre, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario M5B 1W8, Canada;
authors.forename: Lidice
authors.initials: L
authors.lastname: Bernardo
authors.affiliation: Canadian Blood Services, Ottawa, Ontario K1G 4J5, Canada; Department of Laboratory Medicine, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario M5B 1W8, Canada; Keenan Research Centre, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario M5B 1W8, Canada; Department of Anesthesiology, Tongji Hospital, Huazhong University of Science and Technology, 430030 Wuhan, China;
authors.forename: Honghui
authors.initials: H
authors.lastname: Yu
authors.affiliation: Department of Laboratory Medicine, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario M5B 1W8, Canada; Keenan Research Centre, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario M5B 1W8, Canada;
authors.forename: Alaa
authors.initials: A
authors.lastname: Amash
authors.affiliation: Bloodworks Northwest Research Institute, South Lake Union, Seattle, WA 98102;
authors.forename: James C
authors.initials: JC
authors.lastname: Zimring
authors.affiliation: Canadian Blood Services, Ottawa, Ontario K1G 4J5, Canada; Department of Laboratory Medicine, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario M5B 1W8, Canada; Keenan Research Centre, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario M5B 1W8, Canada; Department of Medicine, University of Toronto, Toronto, Ontario M5S 1A1, Canada; and Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5S 1A1, Canada lazarusa@smh.ca.
authors.forename: Alan H
authors.initials: AH
authors.lastname: Lazarus
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D004375:Duffy Blood-Group System / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D004912:Erythrocytes / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007108:Immune Tolerance / Q000235:genetics / Q000276:immunology*; D007074:Immunoglobulin G / Q000276:immunology*; D007075:Immunoglobulin M / Q000276:immunology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018448:Models, Immunological; D009113:Muramidase / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D010047:Ovalbumin / Q000276:immunology; D017452:Receptors, IgG / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D012204:Rh-Hr Blood-Group System / Q000276:immunology; D018029:Rho(D) Immune Globulin / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D004375:Duffy Blood-Group System; C080571:Fc gamma receptor IIB; D007074:Immunoglobulin G; D007075:Immunoglobulin M; C061961:RHO(D) antibody; D017452:Receptors, IgG; D012204:Rh-Hr Blood-Group System; D018029:Rho(D) Immune Globulin; C026410:Rho(D) antigen; D010047:Ovalbumin; C421864:hen egg lysozyme; D009113:Muramidase