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C. Bucolo, A.R. Qasem, M. Baiula, G. Farruggia, P. Govoni, S. Spampinato; Involvement of 4 Integrin in Experimental Allergic Conjunctivitis . Invest. Ophthalmol. Vis. Sci. 2006;47(13):4970.
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© ARVO (1962-2015); The Authors (2016-present)
Integrins α4ß1 and αLß2 play a critical role in allergic/inflammatory reactions acting at specific stages of leukocyte emigration from blood into tissues. On T lymphocytes, α4ß1 binds to VCAM–1 and integrin αLß2 binds to ICAM–1, resulting in enhanced leukocyte activation and release of inflammatory mediators. It has been suggested that antagonists of α4ß1 andαLß2 may have a beneficial effect in the treatment of ocular allergic diseases. The objective of this work was to use both antisense technology and pharmacological tool compounds to determine the relevance of the α4 subunit of α4ß1 integrin to the allergic eye disease in vitro and in an animal model of allergic conjunctivitis.
Animal procedures conformed to the ARVO resolution on the use of animals in research. Sensitized mice were pretreated prior to ovalbumin challenge with an antisense oligonucleotide against the α4 subunit of α4ß1 integrin (5’–TGGTACAGCAGTGCATTCTC–3’; 50µg/mouse i.p. for 7 days).
Antisense treatment reduced the levels of α4 subunit (evaluated by Western blot) as well as eosinophil infiltration in conjunctiva and clinical scores in ovalbumin–treated mice. Next, levocabastine, a selective H1 receptor antagonist used to treat ocular allergy, which also down regulates intercellular adhesion molecules, was used as a tool acting as α4 antagonist blocking cell emigration, adhesion and integrin expression in mouse conjunctiva. Levocabastine also significantly reduced conjunctival α4ß1 levels in sensitized mice. Furthermore, a cell–based adhesion assay to study the effect of potential integrin antagonists was developed. The adhesion of Jurkat cells which express α4ß1 and αLß2 to plates coated with the counter receptor for each integrin was blocked by levocabastine (IC50=280 µM) or by the purported antagonist BIO1211 (IC50=0.31 µM). Additionally, cell cytoflometry was used to demonstrate that pre–treatment of Jurkat cells with levocabastine or BIO1211 inhibited, in a concentration–dependent manner, the binding of a monoclonal antibody raised against the α4 subunit. Therefore, by modifying the fluorescence of the cells, these compounds act as antagonists of α4ß1 integrin.
In conclusion, these data support the concept that targeting α4 integrins may have therapeutic potential in allergic eye diseases.
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