Modified High-Molecular-Weight Hyaluronan Promotes Allergen-Specific Immune Tolerance.
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.
1 Benaroya Research Institute, Seattle, Washington.
John A
JA
Gebe
2 Division of Infectious Diseases and Geographic Medicine, Department of Medicine.|3 Stanford Immunology, and.
Koshika
K
Yadava
2 Division of Infectious Diseases and Geographic Medicine, Department of Medicine.|3 Stanford Immunology, and.
Shannon M
SM
Ruppert
3 Stanford Immunology, and.
Payton
P
Marshall
4 Virtici, LLC, Seattle, Washington.
Paul
P
Hill
3 Stanford Immunology, and.
Ben A
BA
Falk
2 Division of Infectious Diseases and Geographic Medicine, Department of Medicine.|3 Stanford Immunology, and.
Johanna M
JM
Sweere
1 Benaroya Research Institute, Seattle, Washington.
Hongwei
H
Han
2 Division of Infectious Diseases and Geographic Medicine, Department of Medicine.
Gernot
G
Kaber
Ingrid A
IA
Harten
2 Division of Infectious Diseases and Geographic Medicine, Department of Medicine.|3 Stanford Immunology, and.
Carlos
C
Medina
5 Department of Orthopedic Surgery, Rush University Medical Center, Chicago, Illinois.
Katalin
K
Mikecz
1 Benaroya Research Institute, Seattle, Washington.
Steven F
SF
Ziegler
6 Division of Pediatric Surgery, Baylor College of Medicine, Houston, Texas; and.
Swathi
S
Balaji
6 Division of Pediatric Surgery, Baylor College of Medicine, Houston, Texas; and.
Sundeep G
SG
Keswani
7 Division of Pulmonary and Critical Care, Stanford University Medical Center, Stanford University School of Medicine, Stanford, California.
Vinicio A de Jesus
VA
Perez
3 Stanford Immunology, and.
Manish J
MJ
Butte
7 Division of Pulmonary and Critical Care, Stanford University Medical Center, Stanford University School of Medicine, Stanford, California.
Kari
K
Nadeau
8 Division of Pulmonary and Critical Care Medicine, University of Washington, Seattle, Washington.
William A
WA
Altemeier
4 Virtici, LLC, Seattle, Washington.
Neil
N
Fanger
1 Benaroya Research Institute, Seattle, Washington.|2 Division of Infectious Diseases and Geographic Medicine, Department of Medicine.|3 Stanford Immunology, and.
Paul L
PL
Bollyky
D000485:Allergens / Q000276:immunology*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D001854:Bone Marrow Cells / Q000166:cytology; D002454:Cell Differentiation / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D003432:Cross-Linking Reagents / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects; D018960:Hyaluronan Receptors / Q000378:metabolism; D006820:Hyaluronic Acid / Q000737:chemistry* / Q000494:pharmacology*; D007108:Immune Tolerance / Q000187:drug effects*; D007114:Immunization; D016753:Interleukin-10; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008970:Molecular Weight; D016328:NF-kappa B / Q000378:metabolism; D011014:Pneumonia / Q000276:immunology / Q000473:pathology / Q000503:physiopathology; D021381:Protein Transport / Q000187:drug effects; D013438:Sulfhydryl Compounds / Q000378:metabolism
D000485:Allergens; D000893:Anti-Inflammatory Agents; D003432:Cross-Linking Reagents; D018960:Hyaluronan Receptors; D016328:NF-kappa B; D013438:Sulfhydryl Compounds; D016753:Interleukin-10; D006820:Hyaluronic Acid
T cell; allergy; dendritic cell; hyaluronan; tolerance