Dual inhibition of dipeptidyl peptidase IV and aminopeptidase N suppresses inflammatory immune responses.
The ectopeptidases dipeptidyl peptidase IV (DP IV, CD26) and aminopeptidase N (APN, CD13) are known to regulate T cell activation. Since selective inhibitors of DP IV and APN suppress DNA synthesis and cytokine production of stimulated T cells in a TGF-beta1-dependent manner, we tested whether combined application of DP IV and APN inhibitors enhances this immunomodulatory effect. The results show that simultaneous application of DP IV and APN inhibitors significantly suppressed DNA synthesis in mitogen- or anti-CD3-stimulated human T cells in vitro when compared to the use of a single DP IV or APN inhibitor. Moreover, the combined action of DP IV and APN inhibitors markedly increased TGF-beta1 production associated with the observed immunosuppressive effects. In vivo, targeting both DP IV and APN led to a potent treatment of experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis (MS). This review summarizes the evidence for the role of both enzymes in T cell activation in vitro and in vivo and provides a rationale for using combined and dual peptidase inhibitors to treat autoimmune diseases like MS.
Reinhold
Dirk
D
Institute of Immunology, Otto-von-Guericke-University Magdeburg, Leipziger Str. 44, 39120 Magdeburg, Germany. dirk.reinhold@medizin.uni-magdeburg.de
Biton
Aliza
A
Goihl
Alexander
A
Pieper
Stefanie
S
Lendeckel
Uwe
U
Faust
Jürgen
J
Neubert
Klaus
K
Bank
Ute
U
Täger
Michael
M
Ansorge
Siegfried
S
Brocke
Stefan
S
D000818:Animals; D018826:CD13 Antigens / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism*; D018819:Dipeptidyl Peptidase 4 / Q000276:immunology / Q000378:metabolism*; D054873:Dipeptidyl-Peptidase IV Inhibitors; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000201:enzymology / Q000276:immunology; D011480:Protease Inhibitors / Q000494:pharmacology / Q000627:therapeutic use
D054873:Dipeptidyl-Peptidase IV Inhibitors; D011480:Protease Inhibitors; D018826:CD13 Antigens; D018819:Dipeptidyl Peptidase 4