Treatment with cathepsin L inhibitor potentiates Th2-type immune response in Leishmania major-infected BALB/c mice

• Published in: International immunology 2001-08, Vol.13 (8), p.975-982
• Main Authors: Zhang, Tianqian, Maekawa, Yoichi, Sakai, Tohru, Nakano, Yoko, Ishii, Kazunari, Hisaeda, Hajime, Dainichi, Teruki, Asao, Tetsuji, Katunuma, Nobuhiko, Himeno, Kunisuke
• Format: Article
• Language: English
• Subjects: Adjuvants, Immunologic - administration & dosage; Adjuvants, Immunologic - pharmacology; Animals; Antigen Presentation - drug effects; antigen processing; Antigens, Protozoan - immunology; Antigens, Protozoan - metabolism; APC antigen-presenting cell; Cathepsin L; Cathepsins - antagonists & inhibitors; Cell Differentiation - drug effects; Cell Differentiation - immunology; Cell Line; Con A concanavalin A; Cysteine Endopeptidases; Cysteine Proteinase Inhibitors - pharmacology; Dipeptides - administration & dosage; Dipeptides - pharmacology; Endosomes - enzymology; Epoxy Compounds - administration & dosage; Epoxy Compounds - pharmacology; Female; Ii invariant chain; Injections, Intraperitoneal; Leishmania major - drug effects; Leishmania major - immunology; Leishmaniasis, Cutaneous - enzymology; Leishmaniasis, Cutaneous - etiology; Leishmaniasis, Cutaneous - immunology; LN lymph node; lysosomal proteases; Lysosomes - enzymology; Mice; Mice, Inbred BALB C; ML mitochondria and lysosome; protozoan parasites; Pyridines - administration & dosage; Pyridines - pharmacology; SLA soluble Leishmania antigen; Solubility; T h 1; T h 2; Th2 Cells - cytology; Th2 Cells - drug effects; Th2 Cells - immunology
• ISSN: 0953-8178; 1460-2377
• DOI: 10.1093/intimm/13.8.975

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.