Triggering endogenous immunosuppressive mechanisms by combined targeting of Dipeptidyl peptidase IV (DPIV/CD26) and Aminopeptidase N (APN/ CD13)--a novel approach for the treatment of inflammatory bowel disease.
The ectopeptidases Dipeptidylpeptidase IV and Alanyl-Aminopeptidase N, strongly expressed by both, activated and regulatory T cells were shown to co-operate in T cell regulation. Based on the findings that DPIV and APN inhibitors induce the TGF-beta1 and IL-10 production and a suppression of T helper cell proliferation in parallel, and that particularly APN inhibitors amplify the suppressing activity of regulatory T cells, both peptidases represent a promising target complex for treatment of diseases associated with an imbalanced T cell response, such as inflammatory bowel diseases (IBD). The aim of the present study was to analyze the therapeutic potential of DPIV and APN inhibitors in vivo in a mouse model of colitis. Balb/c mice received 3% (w/v) dextran sulphate sodium with the drinking water for 7 days. After onset of colitis symptoms, inhibitor treatment started at day 3. Disease activity index (DAI) was assessed daily, supplemented by histological and immunological analysis. While the DPIV inhibitor Lys-[Z(NO])(2)]-pyrrolidide or the APN-inhibitor Actinonin alone had marked but no significant therapeutic effects, the simultaneous administration of both inhibitors reduced colitis activity in comparison to placebo treated mice, significantly (DAI 4.8 vs. 7.7, p<0.005). A newly developed compound IP12.C6 with inhibitory capacity toward both enzymes significantly attenuated the clinical manifestation of colitis (DAI 3.2 vs. 7.6, p<0.0001). TGF-beta mRNA was found to be up-regulated in colon tissue of inhibitor-treated animals. In summary our results strongly suggest that combined DPIV and APN inhibition by synthetic inhibitors represents a novel and efficient approach for the pharmacological therapy of IBD by triggering endogenous immunosuppressive mechanisms.
Bank
Ute
U
IMTM GmbH, Leipziger Str. 44, 39120 Magdeburg, Germany. bank@imtm.de <bank@imtm.de>
Heimburg
Anke
A
Helmuth
Martin
M
Stefin
Sofia
S
Lendeckel
Uwe
U
Reinhold
Dirk
D
Faust
Jürgen
J
Fuchs
Petra
P
Sens
Bianca
B
Neubert
Klaus
K
Täger
Michael
M
Ansorge
Siegfried
S
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D018826:CD13 Antigens / Q000037:antagonists & inhibitors*; D003092:Colitis / Q000097:blood / Q000139:chemically induced / Q000188:drug therapy; D003106:Colon / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016207:Cytokines / Q000097:blood; D016264:Dextran Sulfate / Q000494:pharmacology; D054873:Dipeptidyl-Peptidase IV Inhibitors; D004359:Drug Therapy, Combination; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects; D006877:Hydroxamic Acids / Q000627:therapeutic use; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D015212:Inflammatory Bowel Diseases / Q000139:chemically induced / Q000188:drug therapy*; D008239:Lysine / Q000031:analogs & derivatives / Q000627:therapeutic use; D051379:Mice; D008807:Mice, Inbred BALB C; D011480:Protease Inhibitors / Q000627:therapeutic use*; D011759:Pyrrolidines / Q000627:therapeutic use; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016212:Transforming Growth Factor beta / Q000235:genetics
D016207:Cytokines; D054873:Dipeptidyl-Peptidase IV Inhibitors; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D006877:Hydroxamic Acids; D007166:Immunosuppressive Agents; D011480:Protease Inhibitors; D011759:Pyrrolidines; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; C110164:lysyl-(Z(nitro))pyrrolidide; D016264:Dextran Sulfate; D018826:CD13 Antigens; D008239:Lysine; C010531:actinonin