T. Zhang et al., Treatment with cathepsin L inhibitor potentiates T(h)2-type immune response in Leishmania major-infected BALB/c mice, INT IMMUNOL, 13(8), 2001, pp. 975-982
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.