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A1.36 Active immunisation against peptides of vegf improves joint inflammation and destruction in collagen-induced arthritis
  1. Luca Semerano1,2,3,
  2. Emilie Duvallet1,2,
  3. Nadia Belmellat1,2,
  4. Nicolas Schall4,
  5. Maëlle Monteil5,
  6. Anna Starzec1,2,
  7. Marc Lecouvey5,
  8. Sylviane Muller4,
  9. Marie-Christophe Boisser1,2,3,
  10. Eric Assier1,2
  1. 1Inserm UMR 1125, 93017 Bobigny France
  2. 2Sorbonne Paris Cité Université Paris 13, 93017 Bobigny France
  3. 3Assistance Publique – Hôpitaux de Paris (AP-HP) Groupe hospitalier Avicenne – Jean Verdier – René Muret, Service de Rhumatologie, 93017 Bobigny France
  4. 4CNRS, Institut de Biologie Moléculaire et Cellulaire, 67084 Strasbourg, France
  5. 5Sorbonne Paris Cité Université Paris 13 UMR7244, 93017 Bobigny France

Abstract

Background Angiogenesis is a key pathophysiological process in rheumatoid arthritis (RA). VEGF-A is considered the major player in both physiological and pathological angiogenesis. VEGF–VEGFR system blockade delays synovitis onset and ameliorates collagen-induced arthritis (CIA). We previously demonstrated the effectiveness of active anti-cytokine immunisation in RA models, with a class of therapeutics called kinoids. The kinoids (heterocomplexes consisting of a cytokine conjugated to a carrier protein, the keyhole limpet hemocyanin, KLH) induce the endogenous production of polyclonal anti-cytokine Abs. Here we tested the effectiveness in CIA of two distinct peptidic vaccines obtained by conjugation of one of two different VEGF-derived peptides to KLH.

Objectives To demonstrate the inhibitory effect on CIA of sustained VEGF blockade by vaccines based on VEGF-derived peptides linked to KLH (Vpep-K).

Materials and Methods Two peptides were chosen in the sequence of the VEGF murine isoformVEGF-A164 (90% identity and 93% homology with the human VEGF-A165): Vpep1 (16 aminoacids (aa), position 98-113) localised in the region cleaved by the plasmin between the exons 4 and 5, and Vpep2 (77 carboxy-terminal aa) which comprises the Arginine 164, essential for binding of VEGF to Neuropilin-1 (NRP1). Each peptide was linked to keyhole limpet hemocyanin (KLH) to form Vpep1-kinoid (Vpep1-K) and Vpep2-kinoid (Vpep2-K), respectively. CIA was induced in 48 DBA/1 male mice with two injections of 100µg of bovine collagen type II (day 0 and 21). Mice were divided in 4 groups to receive one of the following: Vpep1-K, Vpep2-K, KLH or PBS emulsified in Incomplete Freund Adjuvant (IFA, 5 intra muscular injections at days -36, -22, -8, 7 and 37). Sera were sampled from each mouse three times during the experiment (days -44, -2, 48).

Results Vpep1-K group showed lower arthritic scores compared to KLH and PBS groups (p<0.05). At histological analysis, inflammation and destruction scores of the paws were lower in Vpep1-K group versus KLH and PBS group (p<0.005). Vpep1-K and Vpep2-K groups showed anti-VEGF Ab production as assessed by ELISA at day -2 and sacrifice.

Conclusions Active immunotherapy with the kinoid of a single VEGF-derived peptide (Vpep1-K) induces anti-VEGF antibodies and ameliorates collagen-induced arthritis. Active anti-angiogenic immunotherapy based on peptidic vaccines might be a potential strategy to control chronic inflammation.

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