Effects of chronic anti-interleukin-5 monoclonal antibody treatment in a murine model of pulmonary inflammation

The maturation of eosinophils in bone marrow, their migration to pulmonary tissue, and their subsequent degranulation and release of toxic granule pro teins contributes to the pathophysiology observed in asthma. Interleukin-5 (IL-5) is essential for these processes to occur. Therefore, much emphasis has been placed on attempts to inhibit the production or activity of IL-5 i n order to attenuate the inflammatory aspect of asthma. In this report, the immunological consequences of long-term exposure to an antibody recognizin g IL-5 (TRFK-5) were studied in a murine pulmonary inflammation model. A si ngle dose of TRFK-5 (1 mg/ kg intraperitoneally) reversibly inhibited antig en-dependent lung eosinophilia in mice for at least 12 wk and inhibited the release of eosinophils from bone marrow fur at least 8 wk. Normal response s to aerosol challenge were attained after 24 wk. In mice treated acutely w ith antibody (2 h before challenge), 50% inhibition of pulmonary eosinophil ia occurred when 0.06 mg/kg TRFK-5 was administered (intraperitoneally; ED5 0), resulting in 230 ng/ml (IC50) in serum. In mice treated with one dose o f TRFK-5 (1 mg/kg) and rested before challenge, the antibody exhibited a ha lf-life of 2.4 wk. After 18 to 19 wk, antigen challenge-induced eosinophili a was inhibited by 50% and serum levels of TRFK-5 were 25 ng/ml. TRFK-5 rem aining in mice 8 wk after a single injection of TRFK-5 was sufficient to in hibit at least 50% of the eosinophilia induced in blood 3 h after injection of recombinant murine IL-5 (10 mu g/kg, intravenously). To assess the biol ogic effect of long-term exposure of mice to antibody, several parameters o f immune-cell function were measured. Throughout the extended period of act ivity of TRFK-5 (greater than or equal to 12 wk) there were no gross effect s on antigen-dependent increases in T-cell recruitment into bronchoalveolar fluid (BALF), in IL-4 and IL-5 steady-state mRNA levels in lung tissue, or in immunoglobulin E (IgE) and IgG levels in serum. There was a small incre ase in IL-5 steady-state mRNA production in TRFK-5-treated mice after 2 h o r 2 wk, but this was not observed at other times examined. In untreated mic e, IL-5 steady-state mRNA production in response to antigen challenge decre ased > 6-fold with age, although at all time points there was an increase i n mRNA levels following challenge. Therefore, at later times, 25 ng/ml rath er than 230 ng/ml of TRFK-5 inhibited BALF eosinophilia, probably because o f reduced IL-5 levels. Twenty-four weeks after treatment with TRFK-5, when challenge-induced eosinophilia was restored, there was an excess of CD4(+) T cells in BALF from challenged mice. However, these T cells had no measura ble effects on other responses to challenge, including cytokine production, B-cell accumulation, and immunoglobulin production in serum. Thus, the bio logic duration of TRFK-5 was several months, and its activity was due to th e presence of antibody above a therapeutic threshold rather than to any pro found effect on the immune system.