International Immunology, Vol. 13, No. 8, 975-982,
August 2001
© 2001 Japanese Society for Immunology
Treatment with cathepsin L inhibitor potentiates Th2-type immune response in Leishmania major-infected BALB/c mice
Department of Parasitology and Immunology, The University of Tokushima School of Medicine, 3 Kuramoto-cho, Tokushima 770-8503, Japan
1 Chemistry Laboratory, Taiho Pharmaceutical Co., Misugidai 1-27, Hanno 357, Japan
2 Institute for Health Sciences, Tokushima Bunri University, Tokushima 770–8514, Japan
Correspondence to: Y. Maekawa
Prior to the activation of CD4 + T cells, exogenous proteins must be digested by endo/lysosomal enzymes in antigen-presenting cells (APC) to produce antigenic peptides that are able to be presented on class II molecules of the MHC. Studies described here inspect the functional significance of cathepsin L inhibition for antigen processing and T h 1/T h 2 differentiation in experimental leishmaniasis. We first demonstrated using in vitro systems that cathepsin L is one of the candidate endo/lysosomal enzymes in processing of soluble Leishmania antigen (SLA) and that its specific inhibitor, CLIK148, modulated the processing of SLA. BALB/c mice are known to be susceptible to infection with Leishmania major . Interestingly, treatment of BALB/c mice with CLIK148 exacerbated the infection by enhancing the development of SLA-specific T h 2-type response such as production of IL-4 and generation of T h 2-dependent specific IgE/IgG1 antibodies. Moreover, addition of CLIK148 in incubation of a SLA-specific CD4 + T cell line with APC up-regulated the production of IL-4. However, CLIK148 did not exert any direct influence on the function of T cells themselves. Taken together, these findings suggest that treatment of host mice with CLIK148 affects the processing of SLA in APC, resulting in the potentiation of T h 2-type immune responses and thus leading to exacerbation of the infection. Furthermore, endo/lysosomal cathepsin L was found to be functionally distinct from previously described cathepsins B and D.
Keywords: antigen processing, lysosomal proteases, protozoan parasites, T h 1, T h 2
Transmitting editor: T. Watanabe
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