Abstract
Background: Insect bite hypersensitivity (IBH) is an eosinophilic allergic dermatitis of horses caused by type I/IVb reactions against mainly Culicoides bites. The vaccination of IBH-affected horses with equine IL-5 coupled to the Cucumber mosaic virus-like particle (eIL-5-CuMVTT) induces IL-5-specific auto-antibodies, resulting in a significant reduction in eosinophil levels in blood and clinical signs. Objective: the preclinical and clinical safety of the eIL-5-CuMVTT vaccine. Methods: The B cell responses were assessed by longitudinal measurement of IL-5- and CuMVTT-specific IgG in the serum and plasma of vaccinated and unvaccinated horses. Further, peripheral blood mononuclear cells (PBMCs) from the same horses were re-stimulated in vitro for the proliferation and IFN-γ production of specific T cells. In addition, we evaluated longitudinal kidney and liver parameters and the general blood status. An endogenous protein challenge was performed in murine IL-5-vaccinated mice. Results: The vaccine was well tolerated as assessed by serum and cellular biomarkers and also induced reversible and neutralizing antibody titers in horses and mice. Endogenous IL-5 stimulation was unable to re-induce anti-IL-5 production. The CD4+ T cells of vaccinated horses produced significantly more IFN-γ and showed a stronger proliferation following stimulation with CuMVTT as compared to the unvaccinated controls. Re-stimulation using E. coli-derived proteins induced low levels of IFNγ+CD4+ cells in vaccinated horses; however, no IFN-γ and proliferation were induced following the HEK-eIL-5 re-stimulation. Conclusions: Vaccination using eIL-5-CuMVTT induces a strong B-cell as well as CuMVTT-specific T cell response without the induction of IL-5-specific T cell responses. Hence, B-cell unresponsiveness against self-IL-5 can be bypassed by inducing CuMVTT carrier-specific T cells, making the vaccine a safe therapeutic option for IBH-affected horses.
Highlights
Insect bite hypersensitivity (IBH) is a type I/IVb hypersensitivity to mainly Culicoides salivary gland proteins characterized by the induction of IgE, activation of mast cells and basophils and late-phase eosinophil accumulation in the skin [1,2]
We recently presented IL-5 to be a suitable target for treating IBH-affected horses and developed a therapeutic vaccine consisting of equine
Cell responses, as all the horses were previously vaccinated against tetanus by their owners and with an unrelated E. coli expressed E. coli-mGM-CSF as an irrelevant protein
Summary
Insect bite hypersensitivity (IBH) is a type I/IVb hypersensitivity to mainly Culicoides salivary gland proteins characterized by the induction of IgE, activation of mast cells and basophils and late-phase eosinophil accumulation in the skin [1,2]. The vaccine induces IL-5-specific auto-antibodies, thereby significantly reducing the levels of eosinophils and clinical signs of IBH [7,8]. Coupling a non-immunogenic soluble self-protein to a highly immunogenic VLP forms hapten-carrier-like conjugates. T cell-dependent long-lasting IgG antibody responses are developed against both the carrier VLP and the hapten self-molecule, hapten-specific T cell responses are absent. Important for the control of auto-reactive B cell responses are the reversibility of the IgG antibody response and the lack of their activation through endogenous protein other than by the vaccine. The vaccination of IBH-affected horses with equine IL-5 coupled to the Cucumber mosaic virus-like particle (eIL-5-CuMVTT ) induces IL-5-specific auto-antibodies, resulting in a significant reduction in eosinophil levels in blood and clinical signs
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