Study in collagen induced arthritis of strategies for active immunotherapies targeting: interleukin-23, vascular endothelial growth factor and tumor necrosis factor-a

La polyarthrite rhumatoïde (PR) est le rhumatisme inflammatoire le plus fréquent. Des immunothérapies passives utilisées pour le traitement de la PR, ciblent principalement les cytokines pro-inflammatoires majeures dans la PR. Ces traitements sont efficaces mais présentent de nombreux inconvénients (coût, perte d efficacité, infections et cancers), ce qui laisse la place pour le développement d une stratégie vaccinale anti-cytokine. Notre travail s est organisé en trois axes : - Cibler spécifiquement la cytokine pro-inflammatoire interleukine-23 par une approche vaccinale et rechercher les mécanismes impliqués dans l amélioration des arthrites. - Cibler l angiogenèse pathologique par une approche vaccinale anti-peptide du VEGF. - Etudier la faisabilité et la sécurité de la vaccination anti-TNF lorsqu elle est coadministrée avec des immunosuppresseurs. Nos résultats ont montré que bien que l inhibition des arthrites ne soit que partielle, la vaccination dirigée contre l IL-23 ou le VEGF permet de moduler les arthrites au niveau clinique, tout en diminuant nettement l inflammation et la destruction ostéo-articulaire au niveau histologique. De plus, l utilisation combinée d immunosuppresseurs avec un vaccin anti-TNF ne diminue pas l efficacité de ce dernier. Enfin, il est intéressant de noter que l utilisation de forte dose de cyclophosphamide neutralise l action du vaccin. Ainsi nous montrons que le VEGF et l IL-23 sont de bonnes cibles thérapeutiques potentielles dans l arthrite et que l approche vaccinale est compatible avec le maintien d un traitement de fond par des immunosuppresseurs.Rheumatoid arthritis (RA) is the most frequent inflammatory rheumatism. Passive immunotherapies used for the treatment of RA, mainly target the main pro-inflammatory cytokines in RA. These therapies are efficient but possess many drawbacks (cost, loss of efficacy, infections, and cancers), which lives some room for the development of a strategy by anti-cytokine vaccination. Our work was organized into three axes: - Specifically target the pro-inflammatory cytokine interleukine-23 through vaccination and look for the mechanisms implied in the arthritis decrease. - Target the pathological angiogenesis through a peptide-based anti-VEGF vaccination. - Study feasibility and safety of the anti-TNF vaccination when it is coadministered with immunosuppressive drugs. Our results showed that even of arthritis inhibition is partial, vaccination against IL-23 or VEGF can modulate arthritis at the clinical level while distinctly decreasing inflammation and osteo-articular destruction at the histological level. Additionally, the combined use of immunosuppressive drug with an anti-TNF vaccin does not decrease its efficiency. To finish, it is interresting to note that use an elevated dose of cyclophosphamide neutralize the vaccin s action. So we show that VEGF and IL-23 are potential therapeutic targets in arthritis and that vaccination is compatible with maintenance of disease-modifying drugs as immunosuppressive drugs.PARIS13-BU Sciences (930792102) / SudocSudocFranceF

Attractiveness and Specificity of Different Polyethylene Blue Screens on Stomoxys calcitrans (Diptera: Muscidae)

International audienceSimple Summary: The haematophagous fly Stomoxys calcitransis considered as a major pest of livestock worldwide. Insecticides have been extensively used to control this pest but resistance to these chemical compounds is now reported in many countries. Therefore, a more sustainable and efficient control is needed. New blue polyethylene sticky screens have been proved to be very attractant for stable flies. They are produced at a lower price than all blue fabric screens or traps. More than 70% of flies are captured on the lower half (30 to 60 cm above ground) of the screens. In our conditions, very few non-target fauna was captured as very few pollinators were caught by these screens. These results are highlighting the interest of these blue polyethylene screens to control stable flies in cattle farms, in comparison with more expensive blue fabrics. Stomoxys calcitrans is considered as a major pest of livestock worldwide. Insecticides have been extensively used to control this pest but resistance to these chemical compounds is now reported in many countries. Therefore, a more sustainable and efficient control is needed. Seven different types of blue screens, with reflectances around 460 nm, were tested during summer 2016 in southwestern France to evaluate their attractiveness and their specificity for stable flies. Height of the screen and orientation (east or west) of a blue screen were also considered. High levels of S. calcitrans captures were recorded during this study (from 141 to 7301 individuals per blue screen and per day) whereas the numbers of tabanids and pollinator insects remained extremely low (less than 10 individuals per screen and per day). No significant difference in attractiveness has been shown between the different types of blue screens. The lower half of the blue screens caught significantly more stable flies (70%) than the higher half (30%). The “east” side of the screen attracted 60% of stable flies but this was not significantly different from the west side. These results are highlighting the interest in these blue polyethylene screens for controlling stable flies in cattle farms, in comparison with more expensive blue fabrics

The repellency of lemongrass oil against stable flies, tested using video tracking

Lemongrass oil (Cymbopogon citratus) is an effective repellent against mosquitoes (Diptera: Culicidae) and house flies (Diptera: Muscidae). In this study, its effectiveness was assessed on stable flies (Diptera: Muscidae) in laboratory conditions. First, we demonstrated that lemongrass oil is an active substance for antennal olfactory receptor cells of Stomoxys calcitrans as indicated by a significant increase in the electroantennogram responses to increasing doses of lemongrass oil. Feeding-choice tests in a flight cage with stable flies having access to two blood-soaked sanitary pads, one of which was treated with lemongrass oil, showed that stable flies (n = 24) spent significantly more time in the untreated zone (median value = 218.4 s) than in the treated zone (median value = 63.7 s). No stable flies fed on the treated pad, whereas nine fed on the untreated pad. These results suggest that lemongrass oil could be used as an effective repellent against stable flies. Additional studies to confirm its spatial repellent and feeding deterrent effects are warranted

Exosome-driven transfer of tumor-associated Pioneer Translation Products (TA-PTPs) for the MHC class I cross-presentation pathway

Cellular immune reactions against non-self-epitopes require activation of cytotoxic CD8+ T-cells via cross-presentation of MHC class I-restricted peptides by professional antigen presenting cells (pAPCs), with the consequent detection and elimination of cells expressing the same antigens via the endogenous (direct) pathway. The source of peptides for the endogenous pathway is constituted of alternative mRNA translation products; however, it is still unclear which source of peptides is used for cross-presentation. Furthermore, the presentation of non-canonical translation products, produced during a non-conventional translation event, on class I molecules of tumor cells has been reported but how these peptides are generated, presented to pAPCs, and their capacity to stimulate CD8+ T cells is still not known. Here, we report that pioneer translation peptides (PTPs) derived from intron or exon pre-mRNAs can serve as tumor-associated antigens (TA-PTPs) and are delivered from the producing tumor cells to pAPCs via exosomes where they are processed by the cytosolic pathway. Injection of TA-PTPs and tumor-derived exosomes efficiently induce CD8+ T-cell proliferation and prevent tumor growth in mice. Our results show that TA-PTPs represent an efficient source of antigenic peptides for CD8+ T cell activation and that full-length proteins are not required for cross-presentation. These findings can have interesting implications for generating tolerance and for designing vectors to generate vaccines