pepstatin and Leishmaniasis--Cutaneous

We previously reported that CA074, a specific inhibitor of cathepsin B, significantly deviated immune responses from the disease-promoting Th2 type to the protective Th1 type in BALB/c mice infected with Leishmania major. Herein, we found that pepstatin A-sensitive aspartic proteases (PSAP) in lysosomes seem to play a different role from that of cathepsin B in antigen-processing and Ii-degradation. That is, cathepsin B appears to digest 16-, 28-, and 31-kDa peptides of soluble leishmania antigen (SLA), whereas PSAP seems to process mainly 28-kDa peptides. Furthermore, the latter protease contributed to the degradation of Ii but cathepsin B did not. Following treatment with pepstatin A, both Th1 and Th2 responses were profoundly suppressed in resistant DBA/2 mice (H-2(d)) and in susceptible BALB/c mice (H-2(d)), and both strains of mice became markedly susceptible compared with the untreated groups, probably owing to failure in degradation of Ii and partly to failure in digestion of 28-kDa peptide.

Topics: Animals; Antibody Formation; Antigen Presentation; Antigen-Presenting Cells; Antigens, Differentiation, B-Lymphocyte; Antigens, Protozoan; Aspartic Acid Endopeptidases; Cathepsin B; CD4-Positive T-Lymphocytes; Cell Division; Cysteine Proteinase Inhibitors; Cytokines; Dipeptides; Disease Models, Animal; Female; Histocompatibility Antigens Class II; Leishmania major; Leishmaniasis, Cutaneous; Lymphocytes; Lysosomes; Mice; Mice, Inbred BALB C; Mice, Inbred DBA; Pepstatins; Th1 Cells; Th2 Cells