Inhalative Nanoparticulate CpG Immunotherapy in Severe Equine Asthma: An Innovative Therapeutic Concept and Potential Animal Model for Human Asthma Treatment

SIMPLE SUMMARY: Severe equine asthma is the most common globally widespread non-infectious equine respiratory disease (together with its mild and moderate form), which is associated with exposure to hay dust and mold spores, has certain similarities to human asthma, and continues to represent a therapeutic problem. Immunomodulatory DNA sequences (CpG) bound to nanoparticles were successfully administered by inhalation to severe asthmatic horses in several studies. It was possible to demonstrate a significant, sustained, one-to-eight-week improvement in important clinical parameters: partial oxygen pressure in the blood, quantity and viscosity of tracheal mucus secretion in the airways, and the amount of inflammatory cells in the respiratory tracts of severe asthmatic horses. The immunotherapy with CpG is performed independent of specific allergens. At an immunological level, the treatment leads to decreases in allergic and inflammatory parameters. This innovative therapeutic concept thus opens new perspectives in severe equine asthma treatment and possibly also in human asthma treatment. ABSTRACT: Severe equine asthma is the most common globally widespread non-infectious equine respiratory disease (together with its mild and moderate form), which is associated with exposure to hay dust and mold spores, has certain similarities to human asthma, and continues to represent a therapeutic problem. Immunomodulatory CpG-ODN, bound to gelatin nanoparticles as a drug delivery system, were successfully administered by inhalation to severe equine asthmatic patients in several studies. It was possible to demonstrate a significant, sustained, and allergen-independent one-to-eight-week improvement in key clinical parameters: the arterial partial pressure of oxygen, the quantity and viscosity of tracheal mucus, and neutrophilic inflammatory cells in the respiratory tracts of the severe equine asthmatic subjects. At the immunological level, an upregulation of the regulatory antiallergic and anti-inflammatory cytokine IL-10 as well as a downregulation of the proallergic IL-4 and proinflammatory IFN-γ in the respiratory tracts of the severe equine asthmatic patients were identified in the treatment groups. CD4(+) T lymphocytes in the respiratory tracts of the asthmatic horses were demonstrated to downregulate the mRNA expression of Tbet and IL-8. Concentrations of matrix metalloproteinase-2 and -9 and tissue inhibitors of metalloproteinase-2 were significantly decreased directly after the treatment as well as six weeks post-treatment. This innovative therapeutic concept thus opens new perspectives in the treatment of severe equine asthma and possibly also that of human asthma.