Effect of B-cell depletion using anti-CD20 therapy on inhibitory antibody formation to human FVIII in hemophilia A mice

Abstract

We herein tested the effect of B-cell depletion on tolerance induction to factor VIII (FVIII) in a mouse model of hemophilia A. Two subclasses of anti–mouse CD20 monoclonal antibodies with differential depletion effects were used. Thus, IgG1 anti-CD20 selectively depleted follicular B cells and spared marginal zone B cells, whereas IgG2a anti-CD20 efficiently depleted both. In FVIII primed mice, a single dose of either IgG1 or IgG2a anti-CD20 pretreatment prevented the increase in inhibitor formation in the majority of treated mice by subsequent daily, high-dose FVIII intravenous injection as a model for immune tolerance induction. However, the IgG1, but not the IgG2a, anti-CD20 pretreatment led to a significant increase of regulatory T cells in the spleen. Importantly, 3 months after the partial B-cell depletion with IgG1 anti-CD20, the FVIII-specific hyporesponsive state remained. We suggest a tolerogenic role of the remaining marginal zone B cells as a potential mechanism for anti-CD20 therapy.

Cytokine-Conditioned Dendritic Cells Induce Humoral Tolerance to Protein Therapy in Mice

“…They enhance the ability of DCs to promote a more active form of tolerance by the generation of Tregs (Zahorchak et al, 2007;Zapata-Gonzalez et al, 2007;Zhang et al, 2010;Moghimi et al, 2011). In addition, anti-CD20 antibody or rituximab treatment resulted in reduction of inhibitory antibodies (Franchini et al, 2008;Zhang et al, 2011). Our findings, along with the reports by TorresAguilar and colleagues and Sato and colleagues, indicate the translational potential of cytokine-conditioned DC therapy for the induction of tolerance (Sato et al, 2003a,b;Torres-Aguilar et al, 2010b).…”

Adjuvant facilitates tolerance induction to factor VIII in hemophilic mice through a Foxp3-independent mechanism that relies on IL-10

“…39 Concerning nondepleting anti-CD4, there is, however, one special case of successful induction of long-term tolerance to foreign proteins in the absence of adjuvant: it is when the foreign protein is an immunoglobulin. In fact, in some of the earliest demonstrations that nondepleting anti-CD4 can induce tolerance to foreign antigens, immunoglobulins from different animal species were used as the tolerizing antigen.…”

Alloantibodies to therapeutic factor VIII in hemophilia A: the role of von Willebrand factor in regulating factor VIII immunogenicity

“…Interestingly, the presence of VWF prolonged the residence of FVIII in the splenic marginal zone, which is the main microenvironment of specialized subsets of myeloid (CD11b + /CD11c + ) DCs and B cells with immune-regulatory (tolerance inducing) characteristics. [76][77][78][79] In contrast, in the absence of VWF (parallel experiment with VWF-deficient mice), only trace amounts of exogenous rFVIII were transiently detected in this important splenic zone. Taken together, the authors proposed that the inhibition of FVIII uptake by antigenpresenting cells, and possibly the facilitation of its contact with tolerogenic splenic DCs, are mechanisms by which VWF may reduce the immunogenicity of rFVIII in hemophilic mice.…”