Modified High-Molecular-Weight Hyaluronan Promotes Allergen-Specific Immune Tolerance.

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.

• Authors: John A Gebe, Koshika Yadava, Shannon M Ruppert, Payton Marshall, Paul Hill, Ben A Falk, Johanna M Sweere, Hongwei Han, Gernot Kaber, Ingrid A Harten, Carlos Medina, Katalin Mikecz, Steven F Ziegler, Swathi Balaji, Sundeep G Keswani, Vinicio A de Jesus Perez, Manish J Butte, Kari Nadeau, William A Altemeier, Neil Fanger, Paul L Bollyky
• Journal: American journal of respiratory cell and molecular biology (Am J Respir Cell Mol Biol) Vol. 56 Issue 1 Pg. 109-120 (01 2017) ISSN: 1535-4989 [Electronic] United States
• PMID: 27598620 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Allergens
• Anti-Inflammatory Agents
• Cross-Linking Reagents
• Hyaluronan Receptors
• NF-kappa B
• Sulfhydryl Compounds
• Interleukin-10
• Hyaluronic Acid

Topics

• Allergens (immunology)
• Animals
• Anti-Inflammatory Agents (pharmacology)
• Bone Marrow Cells (cytology)
• Cell Differentiation (drug effects)
• Cell Nucleus (drug effects, metabolism)
• Cell Proliferation (drug effects)
• Cross-Linking Reagents (metabolism)
• Dendritic Cells (drug effects)
• Hyaluronan Receptors (metabolism)
• Hyaluronic Acid (chemistry, pharmacology)
• Immune Tolerance (drug effects)
• Immunization
• Interleukin-10
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Mice, Transgenic
• Molecular Weight
• NF-kappa B (metabolism)
• Pneumonia (immunology, pathology, physiopathology)
• Protein Transport (drug effects)
• Sulfhydryl Compounds (metabolism)