Treatment with cathepsin L inhibitor potentiates T(h)2-type immune response in Leishmania major-infected BALB/c mice

Prior to the activation of CD4(+) T cells, exogenous proteins must be diges ted by endo/lysosomal enzymes in antigen-presenting cells (APC) to produce antigenic peptides that are able to be presented on class II molecules of t he MHC. Studies described here inspect the functional significance of cathe psin L inhibition for antigen processing and T(h)1/T(h)2 differentiation in experimental leishmaniasis. We first demonstrated using in vitro systems t hat cathepsin L is one of the candidate endo/lysosomal enzymes in processin g of soluble Leishmania antigen (SLA) and that its specific inhibitor, CLIK 148, modulated the processing of SLA. BALB/c mice are known to be susceptib le to infection with Leishmania major Interestingly, treatment of BALB/c mi ce with CLIK148 exacerbated the infection by enhancing the development of S LA-specific T(h)2-type response such as production of IL-4 and generation o f T(h)2-dependent specific IgE/IgG1 antibodies. Moreover, addition of CLIK1 48 in incubation of a SLA-specific CD4(+) T cell line with APC upregulated the production of IL-4. However, CLIK148 did not exert any direct influence on the function of T cells themselves. Taken together, these findings sugg est that treatment of host mice with CLIK148 affects the processing of SLA in APC, resulting in the potentiation of Th-2-type immune responses and thu s leading to exacerbation of the infection. Furthermore, endo/lysosomal cat hepsin L was found to be functionally distinct from previously described ca thepsins B and D.