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Journal of Pharmacology and Experimental Therapeutics

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Research ArticleINFLAMMATION, IMMUNOPHARMACOLOGY, AND ASTHMA

Inhaled CD86 Antisense Oligonucleotide Suppresses Pulmonary Inflammation and Airway Hyper-Responsiveness in Allergic Mice

Jeffrey R. Crosby, Mausumee Guha, David Tung, Doreen A. Miller, Brianna Bender, Thomas P. Condon, Cathie York-DeFalco, Richard S. Geary, Brett P. Monia, James G. Karras and Susan A. Gregory
Journal of Pharmacology and Experimental Therapeutics June 2007, 321 (3) 938-946; DOI: https://doi.org/10.1124/jpet.106.119214
Jeffrey R. Crosby
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Mausumee Guha
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David Tung
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Doreen A. Miller
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Brianna Bender
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Thomas P. Condon
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Cathie York-DeFalco
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Richard S. Geary
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Brett P. Monia
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James G. Karras
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Susan A. Gregory
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Abstract

The B7-family molecule CD86, expressed on the surface of pulmonary and thoracic lymph node antigen-presenting cells, delivers essential costimulatory signals for T-cell activation in response to inhaled allergens. CD86-CD28 signaling is involved in priming allergen-specific T cells, but it is unclear whether these interactions play a role in coordinating memory T-helper 2 cell responses. In the ovalbumin (OVA)-induced mouse model of asthma, administration of CD86-specific antibody before systemic sensitization suppresses inhaled OVA-induced pulmonary inflammation and airway hyper-responsiveness (AHR). In previously OVA-sensitized mice, systemic and intranasal coadministration of CD86 antibody is required to produce these effects. To directly assess the importance of pulmonary CD86 expression in secondary immune responses to inhaled allergens, mice were sensitized and locally challenged with nebulized OVA before treatment with an inhaled aerosolized CD86 antisense oligonucleotide (ASO). CD86 ASO treatment suppressed OVA-induced up-regulation of CD86 protein expression on pulmonary dendritic cells and macrophages as well as on recruited eosinophils. Suppression of CD86 protein expression correlated with decreased methacholine-induced AHR, airway inflammation, and mucus production following rechallenge with inhaled OVA. CD86 ASO treatment reduced BAL eotaxin levels, but it did not reduce CD86 protein on cells in the draining lymph nodes of the lung, and it had no effect on serum IgE levels, suggesting a local and not a systemic effect. These results demonstrate that CD86 expression on pulmonary antigen-presenting cells plays a vital role in regulating pulmonary secondary immune responses and suggest that treatment with an inhaled CD86 ASO may have utility in asthma and other chronic inflammatory lung conditions.

Footnotes

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

  • doi:10.1124/jpet.106.119214.

  • ABBREVIATIONS: APC, antigen-presenting cell; MHC, major histocompatibility complex; Th, T-helper; AHR, airway hyper-responsiveness; T reg, regulatory CD4+CD25+ T cell; IL, interleukin; ASO, antisense oligonucleotide; 2′-MOE, 2′-O-methoxyethylribose; PCR, polymerase chain reaction; ELISA, enzyme-linked immunosorbent assay; BAL, bronchoalveolar lavage; PBS, phosphate-buffered saline; Penh, enhanced pause; RL, resistance; CL, compliance; PAS, periodic acid-Schiff's reagent; FITC, fluorescein isothiocyanate; PerCP, peridinin chlorophyll a protein; PE, phycoerythrin; MFI, mean fluorescence intensity; RANTES, regulated on activation normal T cell expressed and secreted; DC, dendritic cell; MM, mismatch.

    • Received December 27, 2006.
    • Accepted March 22, 2007.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 387 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 387, Issue 1
1 Oct 2023
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Research ArticleINFLAMMATION, IMMUNOPHARMACOLOGY, AND ASTHMA

Inhaled CD86 Antisense Oligonucleotide Suppresses Pulmonary Inflammation and Airway Hyper-Responsiveness in Allergic Mice

Jeffrey R. Crosby, Mausumee Guha, David Tung, Doreen A. Miller, Brianna Bender, Thomas P. Condon, Cathie York-DeFalco, Richard S. Geary, Brett P. Monia, James G. Karras and Susan A. Gregory
Journal of Pharmacology and Experimental Therapeutics June 1, 2007, 321 (3) 938-946; DOI: https://doi.org/10.1124/jpet.106.119214

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Research ArticleINFLAMMATION, IMMUNOPHARMACOLOGY, AND ASTHMA

Inhaled CD86 Antisense Oligonucleotide Suppresses Pulmonary Inflammation and Airway Hyper-Responsiveness in Allergic Mice

Jeffrey R. Crosby, Mausumee Guha, David Tung, Doreen A. Miller, Brianna Bender, Thomas P. Condon, Cathie York-DeFalco, Richard S. Geary, Brett P. Monia, James G. Karras and Susan A. Gregory
Journal of Pharmacology and Experimental Therapeutics June 1, 2007, 321 (3) 938-946; DOI: https://doi.org/10.1124/jpet.106.119214
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