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 inhibitors 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 suggesting a potential application of these effectors in transplantations and autoimmune diseases. In the present study, we have examined the expression of DP IV/CD26 on six myelin basic protein (MBP)(87-99)-specific, CD4+ T cell clones (TCC) derived from patients with multiple sclerosis (MS) as well as the biological effects of the two synthetic DP IV inhibitors Lys[Z(NO2)]-thiazolidide and Lys[Z(NO2)]-pyrrolidide on 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. Enzymatic activity of resting TCC was found to be three to fourfold higher than 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-stimulated TCC. These data suggest that CD26 plays a role in regulation of activation of autoreactive TCC. Further in-vivo investigations, first in experimental models, will clarify, whether the inhibition of the enzymatic activity of DP IV could be a useful tool for therapeutic interventions in MS or other autoimmune diseases.
Reinhold
D
D
Institute of Experimental Internal Medicine, Department of Internal Medicine, Otto-von-Guericke-University, Magdeburg, Germany. dirk.reinhold@medizin.uni-magdeburg.de
Hemmer
B
B
Gran
B
B
Born
I
I
Faust
J
J
Neubert
K
K
McFarland
H F
HF
Martin
R
R
Ansorge
S
S
D015704:CD4 Antigens / Q000032:analysis*; D002999:Clone Cells; D016207:Cytokines / Q000037:antagonists & inhibitors; D004247:DNA / Q000037:antagonists & inhibitors; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism*; D006801:Humans; D008239:Lysine / Q000031:analogs & derivatives / Q000494:pharmacology; D009103:Multiple Sclerosis / Q000473:pathology; D004676:Myelin Basic Protein / Q000276:immunology*; D011480:Protease Inhibitors / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology / Q000502:physiology*; D013844:Thiazoles / Q000494:pharmacology
D015704:CD4 Antigens; D016207:Cytokines; D004676:Myelin Basic Protein; D011480:Protease Inhibitors; D011759:Pyrrolidines; D013844:Thiazoles; C110164:lysyl-(Z(nitro))pyrrolidide; C093632:lysyl-(Z(nitro))thiazolidide; D004247:DNA; D018819:Dipeptidyl Peptidase 4; D008239:Lysine