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Semerano L.,University of Paris 13 | Semerano L.,Assistance Publique Hopitaux Of Paris Ap Hp Groupe Hospitalier Avicenne Jean Verdier Rene Muret | Duvallet E.,University of Paris 13 | Belmellat N.,University of Paris 13 | And 15 more authors.
Angiogenesis | Year: 2016

Objectives: Inflammation and angiogenesis are two tightly linked processes in arthritis, and therapeutic targeting of pro-angiogenic factors may contribute to control joint inflammation and synovitis progression. In this work, we explored whether vaccination against vascular endothelial growth factor (VEGF) ameliorates collagen-induced arthritis (CIA). Methods: Anti-VEGF vaccines were heterocomplexes consisting of the entire VEGF cytokine (or a VEGF-derived peptide) linked to the carrier protein keyhole limpet hemocyanin (KLH). Two kinds of vaccines were separately tested in two independent experiments of CIA. In the first, we tested a kinoid of the murine cytokine VEGF (VEGF-K), obtained by conjugating VEGF-A to KLH. For the second, we selected two VEGF-A-derived peptide sequences to produce heterocomplexes (Vpep1-K and Vpep2-K). DBA/1 mice were immunized with either VEGF-K, Vpep1-K, or Vpep2-K, before CIA induction. Clinical and histological scores of arthritis, anti-VEGF, anti-Vpep Ab titers, and anti-VEGF Abs neutralizing capacity were determined. Results: Both VEGF-K and Vpep1-K significantly ameliorated clinical arthritis scores and reduced synovial inflammation and joint destruction at histology. VEGF-K significantly reduced synovial vascularization. None of the vaccines reduced anti-collagen Ab response in mice. Both VEGF-K and Vpep1-K induced persistently high titers of anti-VEGF Abs capable of inhibiting VEGF-A bioactivity. Conclusion: Vaccination against the pro-angiogenic factor VEGF-A leads to the production of anti-VEGF polyclonal Abs and has a significant anti-inflammatory effect in CIA. Restraining Ab response to a single peptide sequence (Vpep1) with a peptide vaccine effectively protects immunized mice from joint inflammation and destruction. © 2015, Springer Science+Business Media Dordrecht.

Semerano L.,French Institute of Health and Medical Research | Semerano L.,University of Paris 13 | Semerano L.,Assistance Publique Hopitaux Of Paris Ap Hp Groupe Hospitalier Avicenne Jean Verdier Rene Muret | Minichiello E.,University of Paris 13 | And 6 more authors.
Trends in Molecular Medicine | Year: 2016

Rheumatoid arthritis (RA) is the most common inflammatory rheumatic disease. It leads to irreversible joint damage, physical handicap, and reduced life expectancy. The past two decades have seen considerable therapeutic advances with the development of biologic treatments to block proinflammatory cytokines or modulate lymphocyte function, followed by the development of small molecules to target intracellular signaling. Nevertheless, only a minority of patients can achieve disease remission, especially long term, warranting further investigation into newer therapeutic options. Targeting single proinflammatory pathways may not be sufficient, as suggested by variable results with T helper (Th)-17-related cytokine blockade. Multilevel information from 'omics' techniques along with data from mechanistic studies might facilitate the identification of pivotal checkpoints in RA disease pathogenesis and the subsequent development of new effective treatments. Current standard therapeutic options for RA involve targeting proinflammatory cytokines [such as tumor necrosis factor (TNF)-α and interleukin (IL)-6] or intracellular signaling pathways, depleting B cells, and controlling T cell activation.Several novel specific inhibitors of Janus kinase (JAK) isoforms and new biologics targeting IL-6 or IL-6 receptor (IL-6R) may enrich the therapeutic armamentarium in the near future.Initial targeting of most Th17 cytokines may have been deceptive, but blockade of cytokines, such as granulocyte-macrophage colony-stimulating factor (GM-CSF), have provided good clinical results. However, further testing is required. In vivo expansion of regulatory T cells by different means is being tested in clinical trials, although this approach remains challenging and controversial. © 2016.

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