Abstract:
:The extracellular matrix in asthmatic lungs contains abundant low-molecular-weight hyaluronan, and this is known to promote antigen presentation and allergic responses. Conversely, high-molecular-weight hyaluronan (HMW-HA), typical of uninflamed tissues, is known to suppress inflammation. We investigated whether HMW-HA can be adapted to promote tolerance to airway allergens. HMW-HA was thiolated to prevent its catabolism and was tethered to allergens via thiol linkages. This platform, which we call "XHA," delivers antigenic payloads in the context of antiinflammatory costimulation. Allergen/XHA was administered intranasally to mice that had been sensitized previously to these allergens. XHA prevents allergic airway inflammation in mice sensitized previously to either ovalbumin or cockroach proteins. Allergen/XHA treatment reduced inflammatory cell counts, airway hyperresponsiveness, allergen-specific IgE, and T helper type 2 cell cytokine production in comparison with allergen alone. These effects were allergen specific and IL-10 dependent. They were durable for weeks after the last challenge, providing a substantial advantage over the current desensitization protocols. Mechanistically, XHA promoted CD44-dependent inhibition of nuclear factor-κB signaling, diminished dendritic cell maturation, and reduced the induction of allergen-specific CD4 T-helper responses. XHA and other potential strategies that target CD44 are promising alternatives for the treatment of asthma and allergic sinusitis.
journal_name
Am J Respir Cell Mol Biolauthors
Gebe JA,Yadava K,Ruppert SM,Marshall P,Hill P,Falk BA,Sweere JM,Han H,Kaber G,Harten IA,Medina C,Mikecz K,Ziegler SF,Balaji S,Keswani SG,Perez VA,Butte MJ,Nadeau K,Altemeier WA,Fanger N,Bollyky PLdoi
10.1165/rcmb.2016-0111OCsubject
Has Abstractpub_date
2017-01-01 00:00:00pages
109-120issue
1eissn
1044-1549issn
1535-4989journal_volume
56pub_type
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