α4 and β2 integrins have nonredundant roles for asthma development, but for optimal allergen sensitization only α4 is critical

Objective. Recruitment of effector cell subsets to inflammatory lung, together with airway resident cells responsive to secreted products, play pivotal roles in developing and maintaining asthma. Differential use of adhesion molecules dictates the recruitment patterns of specific cell subsets, yet a clear understanding of the distinctive adhesive molecular pathways guiding them to lung is lacking. To provide further insight into the role of alpha 4 beta 1/VCAM-1 pathway and to compare this to the role of beta 2 integrin in the development of acute asthma phenotype, we used genetically deficient mice, in contrast to previous studies with anti-functional antibodies yielding ambiguous results. Methods. Allergen-dependent airway inflammation and hyperresponsiveness was induced in conditional alpha 4(Delta/Delta), VCAM-1(-/-), and beta 2(-/-) mice. Cytology, immunocytochemistry, cytokine and immunoglobulin measurements, and cell type accumulation in lung, BAL fluid, plasma, and hemopoietic tissues were carried out. Results. Asthma phenotype was totally abrogated in alpha 4- or beta 2-deficient mice. Adoptive transfer of sensitized alpha 4(Delta/Delta) CD4(+) cells into challenged normal mice failed to induce asthma, whereas alpha 4(+/+) CD4+ cells were able to induce asthma in challenged alpha 4(Delta/Delta) mice. Parallel studies with beta 2(-/-) or VCAM-1(-/-) mice uncovered novel mechanistic insights in primary sensitization and into redundant or unique functional roles of these adhesion pathways in allergic asthma. Conclusions. The lack of alpha 4 integrin not only impedes the migration of all white cell subsets to lung and airways, but also prevents upregulation of vascular cell adhesion molecule-1 (VCAM-1) in inflamed lung vasculature and, unlike beta 2, attenuates optimal sensitization and ovalbumin-specific IgE production in vivo. As VCAM-1 deficiency did not protect mice from asthma, interactions of alpha 4 beta 1(+) or alpha 4 beta 7(+) cells with other ligands are suggested. (c) 2007 International Society for Experimental Hematology. Published by Elsevier Inc.