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

Abstract

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.

• Authors: T Zhang, Y Maekawa, T Sakai, Y Nakano, K Ishii, H Hisaeda, T Dainichi, T Asao, N Katunuma, K Himeno
• Journal: International immunology (Int Immunol) Vol. 13 Issue 8 Pg. 975-82 (Aug 2001) ISSN: 0953-8178 [Print] England
• PMID: 11470767 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adjuvants, Immunologic
• Antigens, Protozoan
• CA 074 methyl ester
• CLIK 148
• Cysteine Proteinase Inhibitors
• Dipeptides
• Epoxy Compounds
• Pyridines
• Cathepsins
• Cysteine Endopeptidases
• Cathepsin L
• Ctsl protein, mouse

Topics

• Adjuvants, Immunologic (administration & dosage, pharmacology)
• Animals
• Antigen Presentation (drug effects)
• Antigens, Protozoan (immunology, metabolism)
• Cathepsin L
• Cathepsins (antagonists & inhibitors)
• Cell Differentiation (drug effects, immunology)
• Cell Line
• Cysteine Endopeptidases
• Cysteine Proteinase Inhibitors (pharmacology)
• Dipeptides (administration & dosage, pharmacology)
• Endosomes (enzymology)
• Epoxy Compounds (administration & dosage, pharmacology)
• Female
• Injections, Intraperitoneal
• Leishmania major (drug effects, immunology)
• Leishmaniasis, Cutaneous (enzymology, etiology, immunology)
• Lysosomes (enzymology)
• Mice
• Mice, Inbred BALB C
• Pyridines (administration & dosage, pharmacology)
• Solubility
• Th2 Cells (cytology, drug effects, immunology)