| Allergic diseases such as allergic asthma are an increasing health concern in developed nations. Specific immunotherapy (SIT) is the only treatment for allergic diseases that directly targets the Th2 bias underlying allergy. However, the most widespread clinical applications of SIT require a long period of dose escalation with soluble antigen and carry a significant risk of adverse reactions, particularly in highly sensitized patients who stand to benefit most from a curative treatment. Therefore, the development of safer, more efficient methods to induce antigen-specific immune tolerance is critical to advancing allergy treatment.;We have previously identified ECDI-fixed, antigen-coupled cells (Ag-SP) and antigen-associated nanoparticles (Ag-NP) as effective and safe inducers of tolerance for the prevention and treatment of Th1/Th17-mediated autoimmune disease. We hypothesized that these antigen carriers would be similarly effective in a Th2-mediated OVA/alum-induced murine model of allergic airway inflammation. We demonstrate here that Ag-SP induce tolerance to prevent alum-induced sensitization. Ag-SP are well tolerated in pre-sensitized mice and inhibit T cell responses but not airway inflammation. Inhibition studies of common immunosuppressive factors found that the induction of tolerance by Ag-SP did not require Tregs, IL-10, PD-L1, PD-L2 or IDO activity.;Although effective for the induction of prophylactic tolerance, Ag-SP incompletely inhibit disease in sensitized mice. Furthermore, complex isolation and manipulation of leukocytes present impediments to clinical applications of Ag-SP. Therefore, we investigated synthetic antigen carriers that can be produced under good manufacturing practices to substitute for and improve upon Ag-SP tolerance. We found that antigen-conjugated polystyrene nanoparticles (Ag-PS), while effective for the prophylactic induction of tolerance, present antigen in an anaphylactic fashion to pre-sensitized mice. Antigen-conjugated nanoparticles made of biodegradable poly(lactide-co-glycolide) (Ag-PLG) are similarly effective prophylactically and are well tolerated by sensitized animals, but only partially inhibit Th2 responses when administered therapeutically. PLG nanoparticles containing encapsulated antigen [PLG(Ag)], however, were well tolerated and effectively inhibited Th2 responses and airway inflammation both prophylactically and therapeutically. Thus, we illustrate progression towards PLG(Ag) as a biodegradable antigen carrier platform for the safe and effective inhibition of allergic airway inflammation in animals with established Th2 sensitization. |
