title: Therapeutic targeting of endothelial ligands for L-selectin (PNAd) in a sheep model of asthma.
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.
authors.affiliation: Department of Anatomy, University of California, San Francisco, CA 94143-0452, USA. sdr@itsa.ucsf.edu
authors.forename: Steven D
authors.initials: SD
authors.lastname: Rosen
authors.forename: Durwin
authors.initials: D
authors.lastname: Tsay
authors.forename: Mark S
authors.initials: MS
authors.lastname: Singer
authors.forename: Stefan
authors.initials: S
authors.lastname: Hemmerich
authors.forename: William M
authors.initials: WM
authors.lastname: Abraham
mesh_terms: D000818:Animals; D000954:Antigens, Surface / Q000737:chemistry*; D001249:Asthma / Q000378:metabolism* / Q000628:therapy*; D018893:Bronchoalveolar Lavage; D002217:Carbachol / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000473:pathology*; D004797:Enzyme-Linked Immunosorbent Assay; D000939:Epitopes / Q000737:chemistry; D007150:Immunohistochemistry; D007249:Inflammation; D019041:L-Selectin / Q000378:metabolism*; D007962:Leukocytes / Q000378:metabolism; D008024:Ligands; D008565:Membrane Proteins; D009077:Mucins / Q000737:chemistry; D019087:Selectins; D012680:Sensitivity and Specificity; D012756:Sheep; D052116:Sialomucins; D015238:Sulfotransferases / Q000737:chemistry; D013997:Time Factors; D000097811:Carbohydrate Sulfotransferases
chemical_list: D000954:Antigens, Surface; D002217:Carbachol; D000939:Epitopes; D019041:L-Selectin; D008024:Ligands; D008565:Membrane Proteins; D009077:Mucins; D019087:Selectins; D052116:Sialomucins; D015238:Sulfotransferases; D000097811:Carbohydrate Sulfotransferases; C069886:L-selectin counter-receptors
references.citation: J Exp Med. 1999 Oct 4;190(7):935-42
references.pmid: 10510083
references.citation: Immunity. 1999 Jul;11(1):79-89
references.pmid: 10435581
references.citation: Proc Am Thorac Soc. 2004;1(1):54-61
references.pmid: 16113413
references.citation: Am J Respir Crit Care Med. 2000 Aug;162(2 Pt 1):603-11
references.pmid: 10934094
references.citation: Am J Respir Cell Mol Biol. 2000 Oct;23(4):492-8
references.pmid: 11017914
references.citation: J Allergy Clin Immunol. 2000 Nov;106(5):817-28
references.pmid: 11080701
references.citation: Lancet. 2000 Dec 23-30;356(9248):2144-8
references.pmid: 11191542
references.citation: Immunol Rev. 2001 Feb;179:5-15
references.pmid: 11292027
references.citation: J Allergy Clin Immunol. 2001 Jun;107(6):1019-24
references.pmid: 11398079
references.citation: Glycoconj J. 2000 Oct;17(10):735-40
references.pmid: 11425194
references.citation: Cell. 2001 Jun 29;105(7):957-69
references.pmid: 11439191
references.citation: Am J Pathol. 2001 Aug;159(2):671-81
references.pmid: 11485925
references.citation: Immunity. 2001 Aug;15(2):237-47
references.pmid: 11520459
references.citation: Am J Respir Cell Mol Biol. 2001 Nov;25(5):533-7
references.pmid: 11713093
references.citation: J Biol Chem. 2002 Jan 4;277(1):424-31
references.pmid: 11679593
references.citation: Nat Rev Immunol. 2001 Nov;1(2):108-16
references.pmid: 11905818
references.citation: Am J Pathol. 2002 Aug;161(2):543-50
references.pmid: 12163379
references.citation: J Immunol. 2002 Aug 15;169(4):2120-5
references.pmid: 12165540
references.citation: Science. 2003 Jan 17;299(5605):405-8
references.pmid: 12532021
references.citation: J Exp Med. 2003 May 5;197(9):1153-63
references.pmid: 12732657
references.citation: Blood. 2003 Jun 1;101(11):4245-52
references.pmid: 12609846
references.citation: J Exp Med. 2003 May 19;197(10):1255-67
references.pmid: 12756264
references.citation: J Exp Med. 2003 Nov 3;198(9):1289-300
references.pmid: 14597732
references.citation: Am J Respir Crit Care Med. 2004 Jan 1;169(1):97-104
references.pmid: 14578216
references.citation: Clin Exp Allergy. 2004 Jan;34(1):77-84
references.pmid: 14720266
references.citation: J Biol Chem. 2004 Jan 23;279(4):3058-67
references.pmid: 14593101
references.citation: Annu Rev Immunol. 2004;22:129-56
references.pmid: 15032576
references.citation: Annu Rev Immunol. 2004;22:789-815
references.pmid: 15032597
references.citation: Am J Pathol. 2004 May;164(5):1635-44
references.pmid: 15111310
references.citation: Nat Rev Immunol. 2004 May;4(5):325-35
references.pmid: 15122198
references.citation: J Biol Chem. 2004 Aug 13;279(33):35001-8
references.pmid: 15175329
references.citation: Virology. 2004 Sep 1;326(2):310-6
references.pmid: 15302215
references.citation: J Cell Biol. 1988 Nov;107(5):1853-62
references.pmid: 2460470
references.citation: J Cell Biol. 1991 Jul;114(2):343-9
references.pmid: 1712790
references.citation: J Clin Invest. 1991 Oct;88(4):1407-11
references.pmid: 1717514
references.citation: Cell. 1991 Dec 20;67(6):1033-6
references.pmid: 1760836
references.citation: Immunol Today. 1992 Apr;13(4):119-22
references.pmid: 1580992
references.citation: Cell. 1994 Jan 28;76(2):301-14
references.pmid: 7507411
references.citation: J Clin Invest. 1994 Feb;93(2):776-87
references.pmid: 8113411
references.citation: Clin Exp Immunol. 1994 Apr;96(1):110-5
references.pmid: 7512004
references.citation: J Biol Chem. 1994 Jul 22;269(29):18794-813
references.pmid: 8034632
references.citation: Int Arch Allergy Immunol. 1995 Jan;106(1):69-77
references.pmid: 7529075
references.citation: Am J Pathol. 1995 Aug;147(2):412-21
references.pmid: 7543735
references.citation: J Cell Biol. 1995 Oct;131(1):261-70
references.pmid: 7559783
references.citation: Glycobiology. 1996 Mar;6(2):191-208
references.pmid: 8727791
references.citation: Clin Exp Allergy. 1997 May;27 Suppl 1:71-86
references.pmid: 9179449
references.citation: J Appl Physiol (1985). 1997 Sep;83(3):681-7
references.pmid: 9292449
references.citation: J Immunol. 1998 Jun 1;160(11):5629-36
references.pmid: 9605169
references.citation: J Biol Chem. 1998 Aug 28;273(35):22577-83
references.pmid: 9712885
references.citation: Physiol Rev. 1999 Jan;79(1):181-213
references.pmid: 9922371
references.citation: Am J Respir Crit Care Med. 1999 Apr;159(4 Pt 1):1205-14
references.pmid: 10194167
references.citation: J Cell Biol. 1999 May 17;145(4):899-910
references.pmid: 10330415
references.citation: Annu Rev Immunol. 1999;17:255-81
references.pmid: 10358759
references.citation: Am J Pathol. 1999 Oct;155(4):1013-20
references.pmid: 10514381