Therapeutic effects of cysteine protease inhibition in allergic lung inflammation: Inhibition of allergen-specific T lymphocyte migration

Objective and design: We have evaluated the effects of the broad-spectrum c ysteine protease inhibitor E64 on allergic lung inflammation in the mouse o valbumin model of human asthma. We have also characterised membrane-associa ted cathepsin enzyme activity on a range of cell types. Materials: Balb/C mice, E64 and CA074. various cell lines. Treatment: E64 was administered by subcutaneous minipump into ovalbumin-sen sitised mice prior to intranasal ovalbumin challenge. The effect of E64 on ovalbumin-induced inflammation in vivo and ovalbumin-specific T cell prolif eration in vitro and ex vivo was examined. Membrane-associated cathepsin ac tivity on various cell types was measured. Results: E64 treatment (0.36-0.48 mg/day) led to a significant reduction in eosinophil numbers and lung weights in the mouse model. Histological exami nation of lungs confirmed the anti-inflammatory effect. E64 greatly reduced ovalbumin-specific T cell numbers in the lymph nodes draining the lung fol lowing intranasal challenge whilst an accumulation of these T cells was fou nd in the 'priming' lymph nodes. An analysis of various cells involved in l ymphocyte priming and migration revealed that monocytes. dendritic cells an d endothelial cells express high levels of membrane-associated cathepsin B activity. Conclusions: Since E64 is not cell permeable and does not inhibit antigen-i nduced T cell proliferation in vitro or in vivo., the data indicate that me mbrane-associated cysteine proteases. possibly cathepsin B. may regulate T lymphocyte migration in vivo.