INHIBITORS OF DIPEPTIDYL PEPTIDASE IV CD26 SUPPRESS ACTIVATION OF HUMAN MBP-SPECIFIC CD4+T CELL CLONES/

The ectoenzyme dipeptidyl peptidase IV (DP IV, EC 3.4.14.5, CD26) has been shown to play a crucial role in T cell activation. Specific inhib itors of DP IV suppress DNA synthesis as well as cytokine production ( IL-2, IL-10, IL-12, IFN-gamma) of stimulated human and mouse T cells s uggesting a potential application of these effecters in transplantatio ns and autoimmune diseases. In the present study, we have examined the expression of DP IV/CD26 on six myelin basic protein (MBP)(87-99)-spe cific, CD4 + T cell clones (TCC) derived from patients with multiple s clerosis (MS) as well as the biological effects of the two synthetic D P IV inhibitors Lys[Z(NO2)]-thiazolidide and Lys[Z(NO2)]-pyrrolidide o n the function of these cells. All TCC expressed high levels of DP IV/ CD26, as shown by flow cytometry and by enzymatic DP IV assay. Enzymat ic activity of resting TCC was found to be three to fourfold higher th an on resting peripheral blood T cells and close to that of T cells 48 h after PHA stimulation. The DP IV inhibitors suppress DNA synthesis and IFN-gamma, IL-4, and TNF-alpha production of the antigen-stimulate d TCC. These data suggest that CD26 plays a role in regulation of acti vation of autoreactive TCC. Further in-vivo investigations, first in e xperimental models, will clarify, whether the inhibition of the enzyma tic activity of DP TV could be a useful tool for therapeutic intervent ions in MS or other autoimmune diseases. (C) 1998 Elsevier Science B.V . All rights reserved.