Rational design of FVIII sialylated peptides to target Siglec-3 and Siglec-9 and improve peptide formulations for reverse vaccines

TL;DR

This study shows that adding sialic acid to FVIII peptides can help induce tolerance in immune cells, potentially improving treatments for allergies and hemophilia A.

Contribution

The paper introduces a novel method for designing sialylated FVIII peptides to target Siglec receptors and enhance tolerogenic immune responses.

Findings

Sialic acid modification of FVIII peptides targets Siglec-3 and -9 on dendritic cells.

Modified peptides increase IL-10 secretion, promoting tolerogenic responses.

The approach may help re-establish tolerance in hemophilia A patients with anti-FVIII antibodies.

Abstract

Reverse vaccine formulations have shown their potential for the treatment of allergies and other autoimmune diseases by the design of antigens that modify dendritic cell function towards tolerogenic responses. We here demonstrate that modification of an immunodominant peptide from factor VIII (FVIII) with a tolerizing molecule, sialic acid, improves existing peptide formulations towards the induction of tolerogenic cytokine secretion by DCs. Sialic acids are the end-standing moiety of mammalian N- and O- glycans, which are naturally recognized as self-associated molecular pattern. In this paper we show that sialic acid modified FVIII peptides target Siglec-3 and -9 on DCs and increase IL-10 secretion. Our work proposes a method to select, synthetize and test sialylated immunodominant peptides with the aim of ameliorating the efficacy of peptide immunotherapy. Based on our results, we propose that the sialylated FVIII peptide designed in this study may be useful for re-establishing tolerance to FVIII in hemophilia A patients who developed neutralizing antibodies following treatment.

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