MATRIX-BOUND NANOVESICLES AS SELECTIVE MODULATORS OF THE IMMUNE RESPONSE
Introduction: Matrix bound nanovesicles (MBV) have recently been identified as an inherent component of the extracellular matrix (ECM) and possess the ability to mitigate the proinflammatory activation state of macrophages. While the “anti-inflammatory” properties of MBV have several potential clinical applications, it is unknown if there is an associated compromise of the broader immune system. Stated differently, the systemic effects of MBV, and more specifically the effects of MBV upon the adaptive immune system and the ability to mount a protective immune response to pathogens is unknown and has not been explored.
Objective: To investigate the effects of MBV at systemic level and upon the adaptative immune response to pathogens.
Methodology: Biodistribution of MBV was assessed by fluorescence tracking after systemic administration intraperitoneally (IP) and intravenously (IV) in mice. Antibody and blood work analysis were carried out to assess biosafety. MBV modulation of pro-inflammatory activation was assessed in vitro in macrophages and in vivo in a psoriasis model in mice.
To assess the effect of MBV on the immune humoral response to pathogenic infection, mice were vaccinated with the pneumococcal vaccine PneumoVax™23 at day 0. Then, for 5 weeks, MBV (1012/mouse) were injected IP weekly, while a weekly dose of methotrexate was used as immunosuppressor control. Anti-pneumococcal polysaccharide IgG and IgM antibody titers were measured at days 7 and 28. At week 5 mice were infected with Streptococcus pneumoniae and the survival of the animals was recorded over 2 weeks.
Results: Antibody levels and bloodwork in healthy animals treated with MBV showed no relevant fluctuations nor biosafety concerns, whereas biodistribution showed accumulation in depurating organs such as liver, kidneys and spleen. MBV downregulated inflammatory markers in pro-inflammatory macrophages in vitro and meliorated the symptoms of imiquimod-induced psoriasis in mice corresponding with a downregulation of the IL-17/IL-23 axis, which corroborated the anti-inflammatory properties of MBV.
Pneumococcal vaccine-immunized mice with and without MBV treatment presented similar anti-S. pneumoniae polysaccharide IgG and IgM titers at days 7 and 28, demonstrating that MBV do not compromise the adaptative immune response. Contrary, immunized mice treated with methotrexate showed lower IgG and IgM titers. The functionality of the humoral immune response was further confirmed with the higher survival in vaccinated mice with and without MBV treatment, conversely to unvaccinated and methotrexate treated animals. Interestingly, when infected with a lethal dose of S. pneumoniae (107 CFU/mouse), 50% of mice treated with MBV after vaccination presented complete recovery after 14 days, whereas the rest of the groups showed no survival after 2 days of infection. These results suggest a boosting effect on the adaptative immune response elicited by MBV.
Conclusion: The anti-inflammatory properties of MBV do not compromise the ability of the adaptative immune system to build up a response against pathogens. Moreover, preliminary results suggest that MBV could further enhance the humoral immune response.