IM Richards, KP Kolbasa, CA Hatfield, GE Winterrowd, SL Vonderfecht, SF Fidler, RL Griffin, JR Brashler, RF Krzesicki, LM Sly, KA Ready, ND Staite and JE Chin
Pharmacia and Upjohn, Inc., Kalamazoo, Michigan 49001, USA.

We used flow cytometry and treatment in vivo with a monoclonal antibody (mAb), TA-2, to the alpha 4 integrin to investigate the role of alpha 4 beta 1, CD49d/CD29 (VLA-4) in antigen-induced lung inflammation in Brown Norway (BN) rats. Ovalbumin (OVA) inhalation induced an accumulation of eosinophils and lymphocytes in the lungs and bronchoalveolar lavage (BAL) fluid of sensitized BN rats at 24 h after challenge. Phenotypic analyses demonstrated that the percentages of T cells expressing detectable alpha 4 and CD25 in the bronchial lumen after antigen challenge were dramatically increased compared with blood and lymph node T cells. The mean channel fluorescence values of alpha 4 expression were also increased on BAL T cells compared with blood or lymph node T cells. Treatment of OVA-sensitized rats in vivo with total cumulative doses of 0.75 to 6 mg/kg TA-2 mAb intraperitoneally produced dose-related increases in circulating TA-2 and a peripheral blood lymphocytosis, basophilia, and eosinophilia. Flow cytometric analysis of the peripheral blood T cells after in vivo TA-2 mAb administration showed decreases in detectable alpha 4 when these cells were examined ex vivo. Treatment with TA-2, but not an isotype-matched control mouse immunoglobulin G1 mAb, markedly inhibited the OVA-induced recruitment of lymphocytes and eosinophils into the airway lumen. Very few CD3+CD49d+ cells migrated into BAL fluid following anti-alpha 4 mAb treatment in vivo. Treatment with TA-2 also significantly attenuated OVA-induced inflammatory histopathology. We conclude that VLA-4 is a critically important adhesion molecule involved in antigen-specific lung inflammation in sensitized BN rats.

This article has been cited by other articles:

				S. R. Barthel, M. W. Johansson, D. M. McNamee, and D. F. Mosher Roles of integrin activation in eosinophil function and the eosinophilic inflammation of asthma J. Leukoc. Biol., January 1, 2008; 83(1): 1 - 12. [Abstract] [Full Text] [PDF]

				J. P. Abonia, J. Hallgren, T. Jones, T. Shi, Y. Xu, P. Koni, R. A. Flavell, J. A. Boyce, K. F. Austen, and M. F. Gurish Alpha-4 integrins and VCAM-1, but not MAdCAM-1, are essential for recruitment of mast cell progenitors to the inflamed lung Blood, September 1, 2006; 108(5): 1588 - 1594. [Abstract] [Full Text] [PDF]

				G. R. Stenton, M. Ulanova, R. E. Dery, S. Merani, M.-K. Kim, M. Gilchrist, L. Puttagunta, S. Musat-Marcu, D. James, A. D. Schreiber, et al. Inhibition of Allergic Inflammation in the Airways Using Aerosolized Antisense to Syk Kinase J. Immunol., July 15, 2002; 169(2): 1028 - 1036. [Abstract] [Full Text] [PDF]

				E. Kudlacz, C. Whitney, C. Andresen, A. Duplantier, G. Beckius, L. Chupak, A. Klein, K. Kraus, and A. Milici Pulmonary Eosinophilia in a Murine Model of Allergic Inflammation Is Attenuated by Small Molecule alpha 4beta 1 Antagonists J. Pharmacol. Exp. Ther., May 1, 2002; 301(2): 747 - 752. [Abstract] [Full Text] [PDF]

				J. A. Boyce, E. A. Mellor, B. Perkins, Y.-C. Lim, and F. W. Luscinskas Human mast cell progenitors use alpha 4-integrin, VCAM-1, and PSGL-1 E-selectin for adhesive interactions with human vascular endothelium under flow conditions Blood, April 15, 2002; 99(8): 2890 - 2896. [Abstract] [Full Text] [PDF]

				M. T. Borchers, J. Crosby, S. Farmer, J. Sypek, T. Ansay, N. A. Lee, and J. J. Lee Blockade of CD49d inhibits allergic airway pathologies independent of effects on leukocyte recruitment Am J Physiol Lung Cell Mol Physiol, April 1, 2001; 280(4): L813 - L821. [Abstract] [Full Text] [PDF]

				D. RAMOS-BARBÓN, M. SUZUKI, R. TAHA, S. MOLET, T. B. ISSEKUTZ, Q. HAMID, and J. G. MARTIN Effect of {alpha}4-Integrin Blockade on CD4+ Cell-driven Late Airway Responses in the Rat Am. J. Respir. Crit. Care Med., January 1, 2001; 163(1): 101 - 108. [Abstract] [Full Text]

				A. KANEHIRO, K. TAKEDA, A. JOETHAM, A. TOMKINSON, T. IKEMURA, C. G. IRVIN, and E. W. GELFAND Timing of Administration of Anti-VLA-4 Differentiates Airway Hyperresponsiveness in the Central and Peripheral Airways in Mice Am. J. Respir. Crit. Care Med., September 1, 2000; 162(3): 1132 - 1139. [Abstract] [Full Text]

				M. SCHUSTER, T. TSCHERNIG, N. KRUG, and R. PABST Lymphocytes Migrate from the Blood into the Bronchoalveolar Lavage and Lung Parenchyma in the Asthma Model of the Brown Norway Rat Am. J. Respir. Crit. Care Med., February 1, 2000; 161(2): 558 - 566. [Abstract] [Full Text]

				A. Papi and S. L. Johnston Respiratory Epithelial Cell Expression of Vascular Cell Adhesion Molecule-1 and Its Up-regulation by Rhinovirus Infection via NF-kappa B and GATA Transcription Factors J. Biol. Chem., October 15, 1999; 274(42): 30041 - 30051. [Abstract] [Full Text] [PDF]

				L. L. Perry and S. Hughes Chlamydial Colonization of Multiple Mucosae following Infection by Any Mucosal Route Infect. Immun., July 1, 1999; 67(7): 3686 - 3689. [Abstract] [Full Text] [PDF]

				T. Hisada, P. G. Hellewell, M. M. Teixeira, M. G. K. Malm, M. Salmon, T.-J. Huang, and K. Fan Chung alpha 4 Integrin-Dependent Eotaxin Induction of Bronchial Hyperresponsiveness and Eosinophil Migration in Interleukin-5 Transgenic Mice Am. J. Respir. Cell Mol. Biol., May 1, 1999; 20(5): 992 - 1000. [Abstract] [Full Text]

				T. Schneider, T. B. Issekutz, and A. C. Issekutz The Role of alpha 4 (CD49d) and beta 2 (CD18) Integrins in Eosinophil and Neutrophil Migration to Allergic Lung Inflammation in the Brown Norway Rat Am. J. Respir. Cell Mol. Biol., March 1, 1999; 20(3): 448 - 457. [Abstract] [Full Text]

				K. Blease, J. Seybold, I. M. Adcock, P. G. Hellewell, and A. Burke-Gaffney Interleukin-4 and Lipopolysaccharide Synergize to Induce Vascular Cell Adhesion Molecule-1 Expression in Human Lung Microvascular Endothelial Cells Am. J. Respir. Cell Mol. Biol., May 1, 1998; 18(5): 620 - 630. [Abstract] [Full Text]

				T. Schneider, D. van Velzen, R. Moqbel, and A. C. Issekutz Kinetics and Quantitation of Eosinophil and Neutrophil Recruitment to Allergic Lung Inflammation in a Brown Norway Rat Model Am. J. Respir. Cell Mol. Biol., December 1, 1997; 17(6): 702 - 712. [Abstract] [Full Text]

				B. M. Taylor, K. P. Kolbasa, J. E. Chin, I. M. Richards, W. E. Fleming, R. L. Griffin, S. F. Fidler, and F. F. Sun Roles of Adhesion Molecules ICAM-1 and alpha 4 Integrin in Antigen-induced Changes in Microvascular Permeability Associated with Lung Inflammation in Sensitized Brown Norway Rats Am. J. Respir. Cell Mol. Biol., December 1, 1997; 17(6): 757 - 766. [Abstract] [Full Text]