Exposure to Factor VIII Protein in the Presence of Phosphatidylserine Induces Hypo-responsiveness toward Factor VIII Challenge in Hemophilia A Mice
Year: 2013
Type: article
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. Background: Phosphatidylserine (PS) reduces immunogenicity of FVIII by possibly inducing tolerance. Results: FVIII-PS exposure leads to hypo-responsiveness in hemophilia A mice to FVIII challenge but responds normally to ovalbumin. Conclusion: Exposure of FVIII in the presence of PS leads to hypo-responsiveness/tolerance. Significance: An innovative reverse/inverse vaccination could desensitize the patients to antigen.
Source: Journal of Biological Chemistry
Authors: Puneet Gaitonde, Radha Ramakrishnan, Jamie Chin, Raymond J. Kelleher, Richard B. Bankert, Sathy V. Balu-Iyer
Institution: University at Buffalo, State University of New York
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $3,430
OpenAlex ID: W2002826770