A Cellular Viewpoint of Anti-FVIII Immune Response in Hemophilia A

Abstract

A large proportion of hemophilia A patients who receive replacement therapy, develop an immune response toward the infused factor VIII (FVIII). In this review, we discuss recent progress in several aspects of the anti-FVIII immune response, focusing on the sites of FVIII endocytosis (marginal zone of the spleen and bleeding site), the type of antigen-presenting cells (dendritic cells, macrophages and B cells) and endocytic receptors, implicated in FVIII presentation to T cells during primary and secondary immune response. Although it is becoming increasingly clear that regulatory T cells are involved in FVIII tolerance in healthy subjects and potentially in patients without inhibitors, we would like to demonstrate that little is known about the different T cells subsets and the cytokines network, which are also crucial for the development of allo- and autoimmune diseases. As more information on these issues becomes available, a better understanding of the role of each immune cells compartment in promoting FVIII tolerance or inhibitors development might lead to new strategies to promote FVIII tolerance in hemophilia A patients.

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

“…S1B) showed reduction (not significant) in the effector T cell populations in mice receiving cytokineconditioned DCs versus mice receiving control DCs, but at levels similar to those in OVA-only mice. Blood-borne antigens are filtered by the spleen, which provides the ideal environment for initiation and amplification of the immune responses (Lacroix-Desmazes et al, 2008;Andre et al, 2009). Mice were killed 1 week after the second OVA challenge (week 6), and splenocytes were analyzed ex vivo.…”

“…Normally, when therapeutic proteins are administered intravenously, antigen presentation is expected to take place largely in the spleen (Andre et al, 2009;Waters and Lillicrap, 2009). In the marginal zone of the spleen, antigen is endocytosed and processed by antigen-presenting cells (APCs).…”

“…During the ensuing germinal center reaction, antigen-specific T and B cells costimulate each other, leading to B cell expansion and differentiation of B cells into terminally differentiated antibody-producing plasma cells, or into memory B cells. Once started, repeated administration of antigen in the form of therapeutic protein will drive additional rounds of B cell proliferation and increasingly higher titers of neutralizing antibodies (Lacroix-Desmazes et al, 2008;Andre et al, 2009;Waters and Lillicrap, 2009).…”

Role of B Cells in Breaking and Maintaining Tolerance to Clotting Factor VIII in Congenital and Acquired Hemophilia A

“…Indeed, the severity of the F8 gene mutation has the greatest influence on a patient's risk for developing inhibitors. Patients with large deletions, nonsense mutations, and chromosomal inversions have the highest incidence of severe inhibitor formation [26]. Further experimental evidence for the necessity of FVIII expression during lymphocyte development was provided by gene therapy studies in animal models that showed that stable expression of FVIII protein in thymus or bone marrow correlated with tolerance to FVIII [27,28].…”

FVIII proteins with a modified immunodominant T-cell epitope exhibit reduced immunogenicity and normal FVIII activity

“…[6][7][8][9][10] Binding of antigenic peptides to a particular MHCII is dictated by polymorphisms in 4 or 5 major pockets within its peptide-binding groove. Peptide side chains at relative "anchor" positions 1, 4, 6, 7, and 9 bind to these pockets, with size, shape, and charge or hydrophobic complementarity determining their affinity.…”