title: Exposure of FVIII in the Presence of Phosphatidyl Serine Reduces Generation of Memory B-Cells and Induces Regulatory T-Cell-Mediated Hyporesponsiveness in Hemophilia A Mice.
abstract: A major complication of replacement therapy with Factor VIII (FVIII) for hemophilia A (HA) is the development of unwanted immune responses. Previous studies showed that administration of FVIII in the presence of phosphatidyl serine (PS) reduced the development of anti-FVIII antibodies in HA mice. However, the impact of PS-mediated effects on immunological memory, such as generation of memory B-cells, is not clear. The effect of PS on memory B-cells was therefore investigated using adoptive transfer approach in FVIII(-/-) HA mice. Adoptive transfer of memory B-cells from a PS-FVIII-treated group to naïve mice followed by challenge of the recipient mice with FVIII showed a significantly reduced anti-FVIII antibody response in the recipient mice, compared with animals that received memory B-cells from free FVIII and FVIII-charge matched phosphatidyl glycerol (PG) group. The decrease in memory B-cell response is accompanied by an increase in FoxP3 expressing regulatory T-cells (Tregs). Flow cytometry studies showed that the generation of Tregs is higher in PS-treated animals as compared with FVIII and FVIII-PG treated animals. The PS-mediated hyporesponsiveness was found to be antigen-specific. The PS-FVIII immunization showed hyporesponsiveness toward FVIII rechallenge but not against ovalbumin (OVA) rechallenge, an unrelated antigen. This demonstrates that PS reduces immunologic memory of FVIII and induces antigen-specific peripheral tolerance in HA mice.
authors.affiliation: Department of Pharmaceutical Sciences, University at Buffalo, The State University of New York, Buffalo, New York, 14215.
authors.forename: Radha
authors.initials: R
authors.lastname: Ramakrishnan
authors.affiliation: Department of Pharmaceutical Sciences, University at Buffalo, The State University of New York, Buffalo, New York, 14215.
authors.forename: Andrew
authors.initials: A
authors.lastname: Davidowitz
authors.affiliation: Department of Pharmaceutical Sciences, University at Buffalo, The State University of New York, Buffalo, New York, 14215.
authors.forename: Sathy V
authors.initials: SV
authors.lastname: Balu-Iyer
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000032:analysis / Q000096:biosynthesis; D000918:Antibody Specificity; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology; D004342:Drug Hypersensitivity / Q000517:prevention & control; D005169:Factor VIII / Q000008:administration & dosage* / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use; D051858:Forkhead Transcription Factors / Q000097:blood / Q000378:metabolism; D006397:Hematinics / Q000008:administration & dosage* / Q000009:adverse effects / Q000378:metabolism / Q000627:therapeutic use; D006467:Hemophilia A / Q000097:blood / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects*; D007156:Immunologic Memory / Q000187:drug effects*; D008081:Liposomes; D018345:Mice, Knockout; D008822:Mice, Transgenic; D014677:Pharmaceutical Vehicles / Q000737:chemistry*; D010715:Phosphatidylglycerols / Q000737:chemistry; D010718:Phosphatidylserines / Q000737:chemistry*; D011994:Recombinant Proteins / Q000378:metabolism / Q000627:therapeutic use; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology / Q000378:metabolism
chemical_list: D057134:Antibodies, Neutralizing; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D006397:Hematinics; D008081:Liposomes; D014677:Pharmaceutical Vehicles; D010715:Phosphatidylglycerols; D010718:Phosphatidylserines; D011994:Recombinant Proteins; C078147:F8 protein, human; D005169:Factor VIII
keywords: immunology; lipids; memory B cells; phosphatidyl serine; protein delivery; regulatory T cells