PMCCPMCCPMCC

Search tips
Search criteria 

Advanced

 
Logo of jcinvestThe Journal of Clinical InvestigationCurrent IssueArchiveSubscriptionAbout the Journal
 
J Clin Invest. 1997 December 15; 100(12): 3083–3092.
PMCID: PMC508521

Blockade of CD49d (alpha4 integrin) on intrapulmonary but not circulating leukocytes inhibits airway inflammation and hyperresponsiveness in a mouse model of asthma.

Abstract

Immunized mice after inhalation of specific antigen have the following characteristic features of human asthma: airway eosinophilia, mucus and Th2 cytokine release, and hyperresponsiveness to methacholine. A model of late-phase allergic pulmonary inflammation in ovalbumin-sensitized mice was used to address the role of the alpha4 integrin (CD49d) in mediating the airway inflammation and hyperresponsiveness. Local, intrapulmonary blockade of CD49d by intranasal administration of CD49d mAb inhibited all signs of lung inflammation, IL-4 and IL-5 release, and hyperresponsiveness to methacholine. In contrast, CD49d blockade on circulating leukocytes by intraperitoneal CD49d mAb treatment only prevented the airway eosinophilia. In this asthma model, a CD49d-positive intrapulmonary leukocyte distinct from the eosinophil is the key effector cell of allergen-induced pulmonary inflammation and hyperresponsiveness.

Full Text

The Full Text of this article is available as a PDF (346K).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Carlos TM, Harlan JM. Leukocyte-endothelial adhesion molecules. Blood. 1994 Oct 1;84(7):2068–2101. [PubMed]
  • Berlin C, Berg EL, Briskin MJ, Andrew DP, Kilshaw PJ, Holzmann B, Weissman IL, Hamann A, Butcher EC. Alpha 4 beta 7 integrin mediates lymphocyte binding to the mucosal vascular addressin MAdCAM-1. Cell. 1993 Jul 16;74(1):185–195. [PubMed]
  • Erle DJ, Briskin MJ, Butcher EC, Garcia-Pardo A, Lazarovits AI, Tidswell M. Expression and function of the MAdCAM-1 receptor, integrin alpha 4 beta 7, on human leukocytes. J Immunol. 1994 Jul 15;153(2):517–528. [PubMed]
  • Lobb RR, Hemler ME. The pathophysiologic role of alpha 4 integrins in vivo. J Clin Invest. 1994 Nov;94(5):1722–1728. [PMC free article] [PubMed]
  • Weg VB, Williams TJ, Lobb RR, Nourshargh S. A monoclonal antibody recognizing very late activation antigen-4 inhibits eosinophil accumulation in vivo. J Exp Med. 1993 Feb 1;177(2):561–566. [PMC free article] [PubMed]
  • Richards IM, Kolbasa KP, Hatfield CA, Winterrowd GE, Vonderfecht SL, Fidler SF, Griffin RL, Brashler JR, Krzesicki RF, Sly LM, et al. Role of very late activation antigen-4 in the antigen-induced accumulation of eosinophils and lymphocytes in the lungs and airway lumen of sensitized brown Norway rats. Am J Respir Cell Mol Biol. 1996 Aug;15(2):172–183. [PubMed]
  • Abraham WM, Sielczak MW, Ahmed A, Cortes A, Lauredo IT, Kim J, Pepinsky B, Benjamin CD, Leone DR, Lobb RR, et al. Alpha 4-integrins mediate antigen-induced late bronchial responses and prolonged airway hyperresponsiveness in sheep. J Clin Invest. 1994 Feb;93(2):776–787. [PMC free article] [PubMed]
  • Nakajima H, Sano H, Nishimura T, Yoshida S, Iwamoto I. Role of vascular cell adhesion molecule 1/very late activation antigen 4 and intercellular adhesion molecule 1/lymphocyte function-associated antigen 1 interactions in antigen-induced eosinophil and T cell recruitment into the tissue. J Exp Med. 1994 Apr 1;179(4):1145–1154. [PMC free article] [PubMed]
  • Pretolani M, Ruffié C, Lapa e Silva JR, Joseph D, Lobb RR, Vargaftig BB. Antibody to very late activation antigen 4 prevents antigen-induced bronchial hyperreactivity and cellular infiltration in the guinea pig airways. J Exp Med. 1994 Sep 1;180(3):795–805. [PMC free article] [PubMed]
  • Fryer AD, Costello RW, Yost BL, Lobb RR, Tedder TF, Steeber DA, Bochner BS. Antibody to VLA-4, but not to L-selectin, protects neuronal M2 muscarinic receptors in antigen-challenged guinea pig airways. J Clin Invest. 1997 Apr 15;99(8):2036–2044. [PMC free article] [PubMed]
  • Laberge S, Rabb H, Issekutz TB, Martin JG. Role of VLA-4 and LFA-1 in allergen-induced airway hyperresponsiveness and lung inflammation in the rat. Am J Respir Crit Care Med. 1995 Mar;151(3 Pt 1):822–829. [PubMed]
  • Rabb HA, Olivenstein R, Issekutz TB, Renzi PM, Martin JG. The role of the leukocyte adhesion molecules VLA-4, LFA-1, and Mac-1 in allergic airway responses in the rat. Am J Respir Crit Care Med. 1994 May;149(5):1186–1191. [PubMed]
  • Henderson WR, Jr, Lewis DB, Albert RK, Zhang Y, Lamm WJ, Chiang GK, Jones F, Eriksen P, Tien YT, Jonas M, et al. The importance of leukotrienes in airway inflammation in a mouse model of asthma. J Exp Med. 1996 Oct 1;184(4):1483–1494. [PMC free article] [PubMed]
  • Corry DB, Folkesson HG, Warnock ML, Erle DJ, Matthay MA, Wiener-Kronish JP, Locksley RM. Interleukin 4, but not interleukin 5 or eosinophils, is required in a murine model of acute airway hyperreactivity. J Exp Med. 1996 Jan 1;183(1):109–117. [PMC free article] [PubMed]
  • Mauser PJ, Pitman A, Witt A, Fernandez X, Zurcher J, Kung T, Jones H, Watnick AS, Egan RW, Kreutner W, et al. Inhibitory effect of the TRFK-5 anti-IL-5 antibody in a guinea pig model of asthma. Am Rev Respir Dis. 1993 Dec;148(6 Pt 1):1623–1627. [PubMed]
  • Zhang Y, Lamm WJ, Albert RK, Chi EY, Henderson WR, Jr, Lewis DB. Influence of the route of allergen administration and genetic background on the murine allergic pulmonary response. Am J Respir Crit Care Med. 1997 Feb;155(2):661–669. [PubMed]
  • Burkly LC, Jakubowski A, Hattori M. Protection against adoptive transfer of autoimmune diabetes mediated through very late antigen-4 integrin. Diabetes. 1994 Apr;43(4):529–534. [PubMed]
  • Tsuyuki S, Bertrand C, Erard F, Trifilieff A, Tsuyuki J, Wesp M, Anderson GP, Coyle AJ. Activation of the Fas receptor on lung eosinophils leads to apoptosis and the resolution of eosinophilic inflammation of the airways. J Clin Invest. 1995 Dec;96(6):2924–2931. [PMC free article] [PubMed]
  • AMDUR MO, MEAD J. Mechanics of respiration in unanesthetized guinea pigs. Am J Physiol. 1958 Feb;192(2):364–368. [PubMed]
  • Martin TR, Gerard NP, Galli SJ, Drazen JM. Pulmonary responses to bronchoconstrictor agonists in the mouse. J Appl Physiol (1985) 1988 Jun;64(6):2318–2323. [PubMed]
  • Levitt RC, Mitzner W. Expression of airway hyperreactivity to acetylcholine as a simple autosomal recessive trait in mice. FASEB J. 1988 Jul;2(10):2605–2608. [PubMed]
  • Su M, Chi EY, Bishop MJ, Henderson WR., Jr Lung mast cells increase in number and degranulate during pulmonary artery occlusion/reperfusion injury in dogs. Am Rev Respir Dis. 1993 Feb;147(2):448–456. [PubMed]
  • Thornton DJ, Holmes DF, Sheehan JK, Carlstedt I. Quantitation of mucus glycoproteins blotted onto nitrocellulose membranes. Anal Biochem. 1989 Oct;182(1):160–164. [PubMed]
  • Fung DC, Somerville M, Richardson PS, Sheehan JK. Mucus glycoconjugate complexes released from feline trachea by a bacterial toxin. Am J Respir Cell Mol Biol. 1995 Mar;12(3):296–306. [PubMed]
  • Logun C, Mullol J, Rieves D, Hoffman A, Johnson C, Miller R, Goff J, Kaliner M, Shelhamer J. Use of a monoclonal antibody enzyme-linked immunosorbent assay to measure human respiratory glycoprotein production in vitro. Am J Respir Cell Mol Biol. 1991 Jul;5(1):71–79. [PubMed]
  • Reiner SL, Zheng S, Corry DB, Locksley RM. Constructing polycompetitor cDNAs for quantitative PCR. J Immunol Methods. 1993 Sep 27;165(1):37–46. [PubMed]
  • Gavett SH, O'Hearn DJ, Li X, Huang SK, Finkelman FD, Wills-Karp M. Interleukin 12 inhibits antigen-induced airway hyperresponsiveness, inflammation, and Th2 cytokine expression in mice. J Exp Med. 1995 Nov 1;182(5):1527–1536. [PMC free article] [PubMed]
  • Maraskovsky E, Brasel K, Teepe M, Roux ER, Lyman SD, Shortman K, McKenna HJ. Dramatic increase in the numbers of functionally mature dendritic cells in Flt3 ligand-treated mice: multiple dendritic cell subpopulations identified. J Exp Med. 1996 Nov 1;184(5):1953–1962. [PMC free article] [PubMed]
  • Pulendran B, Lingappa J, Kennedy MK, Smith J, Teepe M, Rudensky A, Maliszewski CR, Maraskovsky E. Developmental pathways of dendritic cells in vivo: distinct function, phenotype, and localization of dendritic cell subsets in FLT3 ligand-treated mice. J Immunol. 1997 Sep 1;159(5):2222–2231. [PubMed]
  • Gonzalo JA, Lloyd CM, Kremer L, Finger E, Martinez-A C, Siegelman MH, Cybulsky M, Gutierrez-Ramos JC. Eosinophil recruitment to the lung in a murine model of allergic inflammation. The role of T cells, chemokines, and adhesion receptors. J Clin Invest. 1996 Nov 15;98(10):2332–2345. [PMC free article] [PubMed]
  • Ishida K, Thomson RJ, Beattie LL, Wiggs B, Schellenberg RR. Inhibition of antigen-induced airway hyperresponsiveness, but not acute hypoxia nor airway eosinophilia, by an antagonist of platelet-activating factor. J Immunol. 1990 May 15;144(10):3907–3911. [PubMed]
  • Lilly CM, Chapman RW, Sehring SJ, Mauser PJ, Egan RW, Drazen JM. Effects of interleukin 5-induced pulmonary eosinophilia on airway reactivity in the guinea pig. Am J Physiol. 1996 Mar;270(3 Pt 1):L368–L375. [PubMed]
  • Rankin JA, Picarella DE, Geba GP, Temann UA, Prasad B, DiCosmo B, Tarallo A, Stripp B, Whitsett J, Flavell RA. Phenotypic and physiologic characterization of transgenic mice expressing interleukin 4 in the lung: lymphocytic and eosinophilic inflammation without airway hyperreactivity. Proc Natl Acad Sci U S A. 1996 Jul 23;93(15):7821–7825. [PubMed]
  • Elwood W, Lötvall JO, Barnes PJ, Chung KF. Effect of dexamethasone and cyclosporin A on allergen-induced airway hyperresponsiveness and inflammatory cell responses in sensitized Brown-Norway rats. Am Rev Respir Dis. 1992 Jun;145(6):1289–1294. [PubMed]
  • Foster PS, Hogan SP, Ramsay AJ, Matthaei KI, Young IG. Interleukin 5 deficiency abolishes eosinophilia, airways hyperreactivity, and lung damage in a mouse asthma model. J Exp Med. 1996 Jan 1;183(1):195–201. [PMC free article] [PubMed]
  • Hogan SP, Mould A, Kikutani H, Ramsay AJ, Foster PS. Aeroallergen-induced eosinophilic inflammation, lung damage, and airways hyperreactivity in mice can occur independently of IL-4 and allergen-specific immunoglobulins. J Clin Invest. 1997 Mar 15;99(6):1329–1339. [PMC free article] [PubMed]
  • Brusselle GG, Kips JC, Tavernier JH, van der Heyden JG, Cuvelier CA, Pauwels RA, Bluethmann H. Attenuation of allergic airway inflammation in IL-4 deficient mice. Clin Exp Allergy. 1994 Jan;24(1):73–80. [PubMed]
  • Kung TT, Stelts D, Zurcher JA, Jones H, Umland SP, Kreutner W, Egan RW, Chapman RW. Mast cells modulate allergic pulmonary eosinophilia in mice. Am J Respir Cell Mol Biol. 1995 Apr;12(4):404–409. [PubMed]
  • Rochester CL, Rankin JA. Is asthma T-cell mediated? Am Rev Respir Dis. 1991 Nov;144(5):1005–1007. [PubMed]
  • Bentley AM, Menz G, Storz C, Robinson DS, Bradley B, Jeffery PK, Durham SR, Kay AB. Identification of T lymphocytes, macrophages, and activated eosinophils in the bronchial mucosa in intrinsic asthma. Relationship to symptoms and bronchial responsiveness. Am Rev Respir Dis. 1992 Aug;146(2):500–506. [PubMed]
  • Walker C, Kaegi MK, Braun P, Blaser K. Activated T cells and eosinophilia in bronchoalveolar lavages from subjects with asthma correlated with disease severity. J Allergy Clin Immunol. 1991 Dec;88(6):935–942. [PubMed]
  • Gratziou C, Carroll M, Walls A, Howarth PH, Holgate ST. Early changes in T lymphocytes recovered by bronchoalveolar lavage after local allergen challenge of asthmatic airways. Am Rev Respir Dis. 1992 Jun;145(6):1259–1264. [PubMed]
  • Robinson DS, Hamid Q, Ying S, Tsicopoulos A, Barkans J, Bentley AM, Corrigan C, Durham SR, Kay AB. Predominant TH2-like bronchoalveolar T-lymphocyte population in atopic asthma. N Engl J Med. 1992 Jan 30;326(5):298–304. [PubMed]
  • Gavett SH, Chen X, Finkelman F, Wills-Karp M. Depletion of murine CD4+ T lymphocytes prevents antigen-induced airway hyperreactivity and pulmonary eosinophilia. Am J Respir Cell Mol Biol. 1994 Jun;10(6):587–593. [PubMed]
  • Nakajima H, Iwamoto I, Tomoe S, Matsumura R, Tomioka H, Takatsu K, Yoshida S. CD4+ T-lymphocytes and interleukin-5 mediate antigen-induced eosinophil infiltration into the mouse trachea. Am Rev Respir Dis. 1992 Aug;146(2):374–377. [PubMed]
  • Steinman RM. The dendritic cell system and its role in immunogenicity. Annu Rev Immunol. 1991;9:271–296. [PubMed]
  • Schon-Hegrad MA, Oliver J, McMenamin PG, Holt PG. Studies on the density, distribution, and surface phenotype of intraepithelial class II major histocompatibility complex antigen (Ia)-bearing dendritic cells (DC) in the conducting airways. J Exp Med. 1991 Jun 1;173(6):1345–1356. [PMC free article] [PubMed]
  • Chvatchko Y, Kosco-Vilbois MH, Herren S, Lefort J, Bonnefoy JY. Germinal center formation and local immunoglobulin E (IgE) production in the lung after an airway antigenic challenge. J Exp Med. 1996 Dec 1;184(6):2353–2360. [PMC free article] [PubMed]
  • Grouard G, Durand I, Filgueira L, Banchereau J, Liu YJ. Dendritic cells capable of stimulating T cells in germinal centres. Nature. 1996 Nov 28;384(6607):364–367. [PubMed]
  • Hynes RO. Integrins: versatility, modulation, and signaling in cell adhesion. Cell. 1992 Apr 3;69(1):11–25. [PubMed]
  • Nojima Y, Humphries MJ, Mould AP, Komoriya A, Yamada KM, Schlossman SF, Morimoto C. VLA-4 mediates CD3-dependent CD4+ T cell activation via the CS1 alternatively spliced domain of fibronectin. J Exp Med. 1990 Oct 1;172(4):1185–1192. [PMC free article] [PubMed]
  • Davis LS, Oppenheimer-Marks N, Bednarczyk JL, McIntyre BW, Lipsky PE. Fibronectin promotes proliferation of naive and memory T cells by signaling through both the VLA-4 and VLA-5 integrin molecules. J Immunol. 1990 Aug 1;145(3):785–793. [PubMed]
  • Damle NK, Aruffo A. Vascular cell adhesion molecule 1 induces T-cell antigen receptor-dependent activation of CD4+T lymphocytes. Proc Natl Acad Sci U S A. 1991 Aug 1;88(15):6403–6407. [PubMed]
  • Lazaar AL, Albelda SM, Pilewski JM, Brennan B, Puré E, Panettieri RA., Jr T lymphocytes adhere to airway smooth muscle cells via integrins and CD44 and induce smooth muscle cell DNA synthesis. J Exp Med. 1994 Sep 1;180(3):807–816. [PMC free article] [PubMed]
  • Ruoslahti E, Reed JC. Anchorage dependence, integrins, and apoptosis. Cell. 1994 May 20;77(4):477–478. [PubMed]
  • Anwar AR, Moqbel R, Walsh GM, Kay AB, Wardlaw AJ. Adhesion to fibronectin prolongs eosinophil survival. J Exp Med. 1993 Mar 1;177(3):839–843. [PMC free article] [PubMed]
  • Koopman G, Keehnen RM, Lindhout E, Newman W, Shimizu Y, van Seventer GA, de Groot C, Pals ST. Adhesion through the LFA-1 (CD11a/CD18)-ICAM-1 (CD54) and the VLA-4 (CD49d)-VCAM-1 (CD106) pathways prevents apoptosis of germinal center B cells. J Immunol. 1994 Apr 15;152(8):3760–3767. [PubMed]

Articles from The Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation