Modified High-Molecular-Weight Hyaluronan Promotes Allergen-Specific Immune Tolerance
In: American Journal of Respiratory Cell and Molecular Biology, Jg. 56 (2017), S. 109-120
Online
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Zugriff:
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.
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Modified High-Molecular-Weight Hyaluronan Promotes Allergen-Specific Immune Tolerance
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Autor/in / Beteiligte Person: | Hill, Paul ; Nadeau, Kari C. ; Vinicio A. de Jesus Perez ; Sweere, Johanna M. ; Balaji, Swathi ; Ziegler, Steven F. ; Harten, Ingrid A. ; Keswani, Sundeep G. ; Altemeier, William A. ; Falk, Ben A. ; Medina, Carlos ; Fanger, Neil A. ; Gebe, John A. ; Yadava, Koshika ; Butte, Manish J. ; Bollyky, Paul L. ; Kaber, Gernot ; Mikecz, Katalin ; Ruppert, Shannon M. ; Han, Hongwei ; Marshall, Payton L. |
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Zeitschrift: | American Journal of Respiratory Cell and Molecular Biology, Jg. 56 (2017), S. 109-120 |
Veröffentlichung: | American Thoracic Society, 2017 |
Medientyp: | unknown |
ISSN: | 1535-4989 (print) ; 1044-1549 (print) |
DOI: | 10.1165/rcmb.2016-0111oc |
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