Biodegradable antigen-associated PLG nanoparticles tolerize Th2-mediated allergic airway inflammation pre- and postsensitization.
Specific immunotherapy (SIT) is the most widely used treatment for allergic diseases that directly targets the T helper 2 (Th2) bias underlying allergy. However, the most widespread clinical applications of SIT require a long period of dose escalation with soluble antigen (Ag) and carry a significant risk of adverse reactions, particularly in highly sensitized patients who stand to benefit most from a curative treatment. Thus, the development of safer, more efficient methods to induce Ag-specific immune tolerance is critical to advancing allergy treatment. We hypothesized that antigen-associated nanoparticles (Ag-NPs), which we have used to prevent and treat Th1/Th17-mediated autoimmune disease, would also be effective for the induction of tolerance in a murine model of Th2-mediated ovalbumin/alum-induced allergic airway inflammation. We demonstrate here that antigen-conjugated polystyrene (Ag-PS) NPs, although effective for the prophylactic induction of tolerance, induce anaphylaxis in presensitized mice. Antigen-conjugated NPs made of biodegradable poly(lactide-co-glycolide) (Ag-PLG) are similarly effective prophylactically, are well tolerated by sensitized animals, but only partially inhibit Th2 responses when administered therapeutically. PLG NPs 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 toward PLG(Ag) as a biodegradable Ag carrier platform for the safe and effective inhibition of allergic airway inflammation without the need for nonspecific immunosuppression in animals with established Th2 sensitization.
Department of Microbiology-Immunology and Interdepartmental Immunobiology Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611; Translational Research Program, Benaroya Research Institute at Virginia Mason, Seattle, WA 98101;
Charles B
CB
Smarr
Department of Chemical and Biological Engineering, Northwestern University, Evanston, IL 60208;
Woon Teck
WT
Yap
Department of Microbiology-Immunology and Interdepartmental Immunobiology Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611;
Tobias P
TP
Neef
Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109.
Ryan M
0000-0002-7857-0973
RM
Pearson
Department of Microbiology-Immunology and Interdepartmental Immunobiology Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611;
Zoe N
ZN
Hunter
Department of Microbiology-Immunology and Interdepartmental Immunobiology Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611;
Igal
I
Ifergan
Department of Microbiology-Immunology and Interdepartmental Immunobiology Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611;
Daniel R
DR
Getts
Department of Microbiology-Immunology and Interdepartmental Immunobiology Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611;
Paul J
PJ
Bryce
Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109 ldshea@umich.edu s-d-miller@northwestern.edu.
Lonnie D
LD
Shea
Department of Microbiology-Immunology and Interdepartmental Immunobiology Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611; ldshea@umich.edu s-d-miller@northwestern.edu.
Stephen D
SD
Miller
D020341:Absorbable Implants; D000818:Animals; D000941:Antigens / Q000008:administration & dosage* / Q000276:immunology*; D001249:Asthma / Q000175:diagnosis / Q000276:immunology* / Q000628:therapy*; D004343:Drug Implants / Q000008:administration & dosage*; D005260:Female; D007114:Immunization / Q000379:methods; D007275:Injections, Intravenous; D051379:Mice; D008807:Mice, Inbred BALB C; D053769:Nanocapsules / Q000008:administration & dosage*; D010316:Particle Size; D011098:Polyglactin 910 / Q000008:administration & dosage / Q000737:chemistry; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology*; D016896:Treatment Outcome
D000941:Antigens; D004343:Drug Implants; D053769:Nanocapsules; D011098:Polyglactin 910
Th2 cells; allergy; immunotherapy; nanoparticles; tolerance