Engagement of alpha(4)beta(7) integrins by monoclonal antibodies or ligands enhances survival of human eosinophils in vitro

Asthma is characterized by an airway inflammatory infiltrate that is rich i n eosinophilic leukocytes, Cellular fibronectin and VCAM-1, ligands for alp ha(4) integrins, are enriched in the fluid of airways of allergic patients subjected to Ag challenge. We therefore hypothesized that ligands of alpha( 4) integrins can promote eosinophil survival independent of cell adhesion. Cellular fibronectin and VCAM-1 increased viability of human peripheral blo od eosinophil in a dose- and time-dependant manner whether the ligand was c oated on the culture well or added to the medium at the beginning of the as say. Eosinophils cultured with cellular fibronectin were not adherent to th e bottom of culture wells after 3 days. Treatment with mAb Fib 30 to beta(7 ), but not mAb P4C10 or TS2/16 to beta(1), increased eosinophil survival. T he increased survival of eosinophils incubated with Fib 30 was blocked by F ab fragments of another anti-beta(7) mAb, Fib 504, Eosinophils incubated wi th soluble cellular fibronectin or mAb Fib 30 for 6 h demonstrated a higher level of GM-CSF mRNA than eosinophils incubated with medium alone, Additio n of neutralizing mAb to GM-CSF during incubation, but not mAbs to IL-3 or IL-5, reduced the enhancement of eosinophil survival by soluble cellular fi bronectin or mAb Fib 30 to control levels. Thus, viability of eosinophils i ncubated with cellular fibronectin or VCAM-1 is due to engagement, probably followed by cross-linking, of alpha(4)beta(7) by soluble ligand (or mAb) t hat stimulates autocrine production of GM-CSF and promotes eosinophil survi val.