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

Abstract

Inhibitors to 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 non-inhibitor 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 mediated B-cell depletion. In naïve HA mice, prophylactic anti-BAFF therapy prior to FVIII immunization prevented inhibitors 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.

BAFF rs9514828 gene polymorphism and the risk of the development of inhibitors in children with severe haemophilia A

“…Interestingly, BAFF rs9514828 SNP was significantly associated with FVIII inhibitor titre and circulating BAFF levels suggesting that BAFF rs9514828 SNP contributing to elevated BAFF levels could be an independent risk factor for FVIII inhibitor development. In accordance with our results, a recent work performed by Doshi et al 28 observed that the circulating BAFF levels were higher in paediatric HA patients with inhibitors compared to those without inhibitors and these levels were significantly correlated with FVIII antibody titres. Quite near to our findings, several studies reported a significant association between -871 C > T SNP (BAFF rs9514828) and serum BAFF levels in primary Sjogren's syndrome, 25 SLE in Egypt, 31 and in ITP.…”

“…27 Recently, Doshi et al found that plasma BAFF levels were significantly higher in both paediatric and adult HA patients with inhibitors compared to those with no inhibitors revealing that BAFF may regulate the generation and maintenance of FVIII inhibitors. 28 Given the implication of BAFF rs9514828 gene polymorphism in the pathophysiology of SLE and several autoimmune diseases, considering the pathogenic similarities between the development of SLE and inhibitors formation, we hypothesized that BAFF rs9514828 gene polymorphism and its plasma level may be important in the pathogenesis of the development of FVIII inhibitors.…”

A review of existing strategies for designing long-acting parenteral formulations: Focus on underlying mechanisms, and future perspectives

“…While we have highlighted many successful examples of LAPFs ( Table 1 20 , 46 , 56 , 161 , 162 , 163 , 164 , 165 , 166 , 167 , 168 , 169 , 170 , 171 , 172 ), challenges still remain in many areas of their application. Improved technologies still need to solve the potential issues of current strategies.…”

On the road to eliminating long‐lived plasma cells—“are we there yet?”

“…Upon replacement therapy with exogenous FVIII protein, approximately 30% of patients with severe FVIII deficiency form anti‐FVIII antibodies, termed inhibitors, which neutralized the therapeutic effect of subsequent FVIII administration 67 . B‐cell depletion using rituximab has had limited success at depleting FVIII inhibitors in both mice and humans 68‐70 . Emerging PC‐directed therapies, discussed below, may prove more effective, particularly when combined with B cells targeted therapy to eliminate pathogenic clones in the B mem pool.…”

“…Reciprocally, blocking the BAFF‐BAFF‐R axis during B‐cell regeneration could serve to restrict development of new autoreactive clones. Indeed, B‐cell depletion, regardless of the method, results in compensatory increase in serum BAFF levels and BAFF blockade to increase stringency of B‐cell selection may be a crucial to preventing disease relapse due to new pathogenic clones 53,68,174 . In the transplant setting as well, B‐cell regeneration in the context of a new allograft combined with BAFF inhibition may result in allograft tolerance, the holy grail of transplantation.…”