A CD1d-dependent antagonist inhibits the activation of invariant NKT cells and prevents development of allergen-induced airway hyperreactivity.

Abstract

The prevalence of asthma continues to increase in westernized countries, and optimal treatment remains a significant therapeutic challenge. Recently, CD1d-restricted invariant NKT (iNKT) cells were found to play a critical role in the induction of airway hyperreactivity (AHR) in animal models and are associated with asthma in humans. To test whether iNKT cell-targeted therapy could be used to treat allergen-induced airway disease, mice were sensitized with OVA and treated with di-palmitoyl-phosphatidyl-ethanolamine polyethylene glycol (DPPE-PEG), a CD1d-binding lipid antagonist. A single dose of DPPE-PEG prevented the development of AHR and pulmonary infiltration of lymphocytes upon OVA challenge, but had no effect on the development of OVA-specific Th2 responses. In addition, DPPE-PEG completely prevented the development of AHR after administration of alpha-galactosylceramide (alpha-GalCer) intranasally. Furthermore, we demonstrate that DPPE-PEG acts as antagonist to alpha-GalCer and competes with alpha-GalCer for binding to CD1d. Finally, we show that DPPE-PEG completely inhibits the alpha-GalCer-induced phosphorylation of ERK tyrosine kinase in iNKT cells, suggesting that DPPE-PEG specifically blocks TCR signaling and thus activation of iNKT cells. Because iNKT cells play a critical role in the development of AHR, the inhibition of iNKT activation by DPPE-PEG suggests a novel approach to treat iNKT cell-mediated diseases such as asthma.

• Authors: Vincent Lombardi, Philippe Stock, Abinav K Singh, Jerome Kerzerho, Wen Yang, Barbara A Sullivan, Xiangming Li, Takayuki Shiratsuchi, Nathan E Hnatiuk, Amy R Howell, Karl O A Yu, Steven A Porcelli, Moriya Tsuji, Mitchell Kronenberg, S Brian Wilson, Omid Akbari
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 184 Issue 4 Pg. 2107-15 (Feb 15 2010) ISSN: 1550-6606 [Electronic] United States
• PMID: 20083656 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Allergens
• Antigens, CD1d
• CD1D protein, human
• Cd1d1 protein, mouse
• DPPE-PEG2000
• Galactosylceramides
• Immunosuppressive Agents
• Phosphatidylethanolamines
• alpha-galactosylceramide
• Polyethylene Glycols
• Ovalbumin

Topics

• Allergens (administration & dosage, immunology)
• Animals
• Antigens, CD1d (metabolism, physiology)
• Binding, Competitive (immunology)
• Bronchial Hyperreactivity (immunology, prevention & control)
• Cell Line
• Disease Models, Animal
• Female
• Galactosylceramides (administration & dosage, antagonists & inhibitors)
• Humans
• Immunosuppressive Agents (antagonists & inhibitors, pharmacology)
• Lymphocyte Activation (drug effects, immunology)
• Mice
• Mice, Inbred BALB C
• Natural Killer T-Cells (immunology)
• Ovalbumin (administration & dosage, immunology)
• Phosphatidylethanolamines (administration & dosage, pharmacology)
• Polyethylene Glycols (administration & dosage, pharmacology)