title: Antibody-mediated immune suppression of erythrocyte alloimmunization can occur independently from red cell clearance or epitope masking in a murine model.
abstract: Anti-D can prevent immunization to the RhD Ag on RBCs, a phenomenon commonly termed Ab-mediated immune suppression (AMIS). The most accepted theory to explain this effect has been the rapid clearance of RBCs. In mouse models using SRBC, these xenogeneic cells are always rapidly cleared even without Ab, and involvement of epitope masking of the SRBC Ags by the AMIS-inducing Ab (anti-SRBC) has been suggested. To address these hypotheses, we immunized mice with murine transgenic RBCs expressing the HOD Ag (hen egg lysozyme [HEL], in sequence with ovalbumin, and the human Duffy transmembrane protein) in the presence of polyclonal Abs or mAbs to the HOD molecule. The isotype, specificity, and ability to induce AMIS of these Abs were compared with accelerated clearance as well as steric hindrance of the HOD Ag. Mice made IgM and IgG reactive with the HEL portion of the molecule only. All six of the mAbs could inhibit the response. The HEL-specific Abs (4B7, IgG1; GD7, IgG2b; 2F4, IgG1) did not accelerate clearance of the HOD-RBCs and displayed partial epitope masking. The Duffy-specific Abs (MIMA 29, IgG2a; CBC-512, IgG1; K6, IgG1) all caused rapid clearance of HOD RBCs without steric hindrance. To our knowledge, this is the first demonstration of AMIS to erythrocytes in an all-murine model and shows that AMIS can occur in the absence of RBC clearance or epitope masking. The AMIS effect was also independent of IgG isotype and epitope specificity of the AMIS-inducing Ab.
authors.affiliation: The Canadian Blood Services, Ottawa, Ontario K1G 4J5, Canada; Department of Anesthesiology, Tongji Hospital, Huazhong University of Science and Technology, 430030 Wuhan, China; Department of Laboratory Medicine, Keenan Research Centre, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario M5B 1W8, Canada;
authors.forename: Honghui
authors.initials: H
authors.lastname: Yu
authors.affiliation: Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322;
authors.forename: Sean R
authors.initials: SR
authors.lastname: Stowell
authors.affiliation: The Canadian Blood Services, Ottawa, Ontario K1G 4J5, Canada; Department of Laboratory Medicine, 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: Department of Laboratory Medicine, Yale University, New Haven, CT 06520;
authors.forename: Jeanne E
authors.initials: JE
authors.lastname: Hendrickson
authors.affiliation: Puget Sound Blood Center Research Institute, Seattle, WA 98102;
authors.forename: James C
authors.initials: JC
authors.lastname: Zimring
authors.affiliation: Department of Laboratory Medicine, 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: Kanto-Koshinetsu Block Blood Center, Japanese Red Cross, Koto-ku, Tokyo, Japan 135-8639;
authors.forename: Makoto
authors.initials: M
authors.lastname: Uchikawa
authors.affiliation: The Canadian Blood Services, Ottawa, Ontario K1G 4J5, Canada; Department of Laboratory Medicine, 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: D064591:Allografts / Q000276:immunology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D004375:Duffy Blood-Group System / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D000939:Epitopes / Q000276:immunology*; D017707:Erythrocyte Transfusion; D004912:Erythrocytes / Q000276:immunology*; D007108:Immune Tolerance / Q000276:immunology; D007074:Immunoglobulin G / Q000276:immunology*; D007075:Immunoglobulin M / Q000276:immunology; D007518:Isoantibodies / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D009113:Muramidase / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D010047:Ovalbumin / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D011956:Receptors, Cell Surface / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D023001:Transplantation Tolerance / Q000276:immunology*
chemical_list: C473745:ACKR1 protein, human; D000911:Antibodies, Monoclonal; D004375:Duffy Blood-Group System; D000939:Epitopes; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D007518:Isoantibodies; D011956:Receptors, Cell Surface; D010047:Ovalbumin; C421864:hen egg lysozyme; D009113:Muramidase