B cell–activating factor modulates the factor VIII immune response in hemophilia A

• Type of Material: Article
• Authors: Bhavya S. Doshi, University of Pennsylvania; Jyoti Rana, Indiana University; Giancarlo Castaman, Careggi University; Mostafa A. Shaheen, Children’s Hospital of Philadelphia; Radoslaw Kaczmarek, Indiana University; John S. S. Butterfield, Indiana University; Shannon Meeks, Emory University; Cindy Leissinger, Tulane University; Moanaro Biswas, Indiana University; Valder R. Arruda, University of Pennsylvania
• Language: English
• Date: 2021-04-15
• Publisher: American Society for Clinical Investigation
• Publication Version: Final Published Version
• Copyright Statement: © 2021 Doshi et al.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1172/JCI142906
• Title of Journal or Parent Work: JOURNAL OF CLINICAL INVESTIGATION
• Volume: 131
• Issue: 8
• Grant/Funding Information: This work was supported by grants from the Bayer Hemophilia Awards Program (to BSD), American Society of Hematology (to BSD), National Hemophilia Foundation (to MB), Hemophilia of Georgia (to SLM), and National Heart, Lung, and Blood Institute grants U54 HL112309 (to SLM) and U54-HL142012 (to VRA). BAFF antibody for animal studies at Indiana University was a gift from GlaxoSmithKline.
• Keywords: Hematology; Coagulation; Cytokines
• Research Categories: Biology, Cell; Health Sciences, Immunology; Health Sciences, Medicine and Surgery

Abstract

Inhibitors of factor VIII (FVIII) remain the most challenging complication of FVIII protein replacement therapy in hemophilia A (HA). Understanding the mechanisms that guide FVIII-specific B cell development could help identify therapeutic targets. The B cell–activating factor (BAFF) cytokine family is a key regulator of B cell differentiation in normal homeostasis and immune disorders. Thus, we used patient samples and mouse models to investigate the potential role of BAFF in modulating FVIII inhibitors. BAFF levels were elevated in pediatric and adult HA inhibitor patients and decreased to levels similar to those of noninhibitor controls after successful immune tolerance induction (ITI). Moreover, elevations in BAFF levels were seen in patients who failed to achieve FVIII tolerance with anti-CD20 antibody–mediated B cell depletion. In naive HA mice, prophylactic anti-BAFF antibody therapy prior to FVIII immunization prevented inhibitor formation and this tolerance was maintained despite FVIII exposure after immune reconstitution. In preimmunized HA mice, combination therapy with anti-CD20 and anti-BAFF antibodies dramatically reduced FVIII inhibitors via inhibition of FVIII-specific plasma cells. Our data suggest that BAFF may regulate the generation and maintenance of FVIII inhibitors and/or anti-FVIII B cells. Finally, anti-CD20/anti-BAFF combination therapy may be clinically useful for ITI.