title: Exposure to factor VIII protein in the presence of phosphatidylserine induces hypo-responsiveness toward factor VIII challenge in hemophilia A mice.
abstract: Administration of recombinant factor VIII (FVIII), an important co-factor in blood clotting cascade, elicits unwanted anti-FVIII antibodies in hemophilia A (HA) patients. Previously, FVIII associated with phosphatidylserine (PS) showed significant reduction in the anti-FVIII antibody response in HA mice. The reduction in the immune response to FVIII-PS could be due either to a failure of the immune system to recognize the antigen (i.e. immunological ignorance) or to an active induction of an antigen-specific nonresponsiveness (i.e. immunological tolerance). If it were a result of tolerance, one would predict that pre-exposure to FVIII-PS would render the mice hypo-responsive to a subsequent FVIII challenge. Here, we have demonstrated that naive HA mice that were pretreated with FVIII-PS showed a significantly reduced FVIII immune response to further challenge with native FVIII and that this decreased responsiveness could be adoptively transferred to other mice. An increase in number of FoxP3-expressing CD4(+) regulatory T-cells (Treg) was observed for the FVIII-PS-immunized group as compared with animals that received FVIII alone, suggesting the involvement of Treg in PS-mediated hypo-responsiveness. The PS-mediated reduction in antibody response was reversed by the co-administration of function-blocking anti-TGF-β antibody with FVIII-PS. The decreased response to FVIII induced by FVIII-PS was determined to be antigen-specific because the immune response to another non-cross-reactive antigen (ovalbumin) was not altered. These results are consistent with the notion that FVIII-PS is tolerogenic and suggest that immunization with this tolerogenic form of the protein could be a useful treatment option to minimize immunogenicity of FVIII and other protein-based therapeutics.
authors: Department of Pharmaceutical Sciences, University at Buffalo, The State University of New York, Buffalo, New York 14214, USA.
authors: Puneet
authors: P
authors: Gaitonde
authors: Radha
authors: R
authors: Ramakrishnan
authors: Jamie
authors: J
authors: Chin
authors: Raymond J
authors: RJ
authors: Kelleher
authors: Richard B
authors: RB
authors: Bankert
authors: Sathy V
authors: SV
authors: Balu-Iyer
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage; D019264:Adoptive Transfer; D000818:Animals; D057134:Antibodies, Neutralizing / Q000097:blood; D005169:Factor VIII / Q000008:administration & dosage / Q000276:immunology*; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006467:Hemophilia A / Q000276:immunology / Q000628:therapy*; D006801:Humans; D007108:Immune Tolerance; D051379:Mice; D018345:Mice, Knockout; D010718:Phosphatidylserines / Q000008:administration & dosage / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism / Q000637:transplantation
chemical_list: D000276:Adjuvants, Immunologic; D057134:Antibodies, Neutralizing; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D010718:Phosphatidylserines; D005169:Factor VIII
keywords: Biotechnology; Blood Coagulation Factors; Dendritic Cells; Factor VIII; GFP-FoxP3; Immunological Tolerance; Immunosuppression; Phosphatidylserine; Regulatory T-cell; Reverse/Inverse Vaccination
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