Therapeutic targeting of endothelial ligands for L-selectin (PNAd) in a sheep model of asthma

Steven D. Rosen, Durwin Tsay, Mark S. Singer, Stefan Hemmerich, William M. Abraham

Research output: Contribution to journalArticle

44 Citations (Scopus)

Abstract

The homing of lymphocytes to peripheral lymph nodes is initiated by an adhesive interaction between L-selectin on lymphocytes and PNAd, a set of sialomucins that are constitutively displayed on high endothelial venules of lymph nodes. PNAd is defined by monoclonal antibody MECA-79 that recognizes a sulfated oligosaccharide carried by the sialomucins. This epitope overlaps with 6-sulfo sialyl Lewis x, a recognition determinant for L-selectin. Previous work has shown that administration of a L-selectin monoclonal antibody blocks both late-phase airway responses and airway hyperresponsiveness in a sheep model of asthma. We show here that airway-associated lymphoid collections from lungs of allergic sheep exhibited PNAd+ venules as detected by immunostaining with MECA-79. The same vessels also expressed a GlcNAc-6-O-sulfotransferase known as HEC-GlcNAc6ST, which is known to contribute to the formation of the MECA-79 epitope in high endothelial venules of mouse lymph nodes. Intravenous administration of MECA-79 to allergic sheep significantly blunted both the late-phase airway response and airway hyperresponsiveness induced by airway allergen challenge. Furthermore, MECA-79 inhibited the accumulation of all classes of leukocytes in bronchoalveolar lavage fluid. These findings represent the first demonstration that targeting of PNAd has therapeutic efficacy in an inflammatory disease.

Original languageEnglish
Pages (from-to)935-944
Number of pages10
JournalAmerican Journal of Pathology
Volume166
Issue number3
StatePublished - Mar 1 2005
Externally publishedYes

Fingerprint

L-Selectin
Sheep
Asthma
Venules
Ligands
Sialomucins
Lymph Nodes
Epitopes
Monoclonal Antibodies
Lymphocytes
Therapeutics
Bronchoalveolar Lavage Fluid
Oligosaccharides
Intravenous Administration
Adhesives
Allergens
Leukocytes
L-selectin counter-receptors
Lung

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Rosen, S. D., Tsay, D., Singer, M. S., Hemmerich, S., & Abraham, W. M. (2005). Therapeutic targeting of endothelial ligands for L-selectin (PNAd) in a sheep model of asthma. American Journal of Pathology, 166(3), 935-944.

Therapeutic targeting of endothelial ligands for L-selectin (PNAd) in a sheep model of asthma. / Rosen, Steven D.; Tsay, Durwin; Singer, Mark S.; Hemmerich, Stefan; Abraham, William M.

In: American Journal of Pathology, Vol. 166, No. 3, 01.03.2005, p. 935-944.

Research output: Contribution to journalArticle

Rosen, SD, Tsay, D, Singer, MS, Hemmerich, S & Abraham, WM 2005, 'Therapeutic targeting of endothelial ligands for L-selectin (PNAd) in a sheep model of asthma', American Journal of Pathology, vol. 166, no. 3, pp. 935-944.
Rosen SD, Tsay D, Singer MS, Hemmerich S, Abraham WM. Therapeutic targeting of endothelial ligands for L-selectin (PNAd) in a sheep model of asthma. American Journal of Pathology. 2005 Mar 1;166(3):935-944.
Rosen, Steven D. ; Tsay, Durwin ; Singer, Mark S. ; Hemmerich, Stefan ; Abraham, William M. / Therapeutic targeting of endothelial ligands for L-selectin (PNAd) in a sheep model of asthma. In: American Journal of Pathology. 2005 ; Vol. 166, No. 3. pp. 935-944.
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