Dipeptidyl peptidase IV on activated T cells as a target molecule for therapy of rheumatoid arthritis.
The extracellular domain of the T cell co-stimulatory molecule CD26 possesses dipeptidyl peptidase IV (DP IV) enzyme activity. Activated T cells are known to increase expression of cell surface DP IV and some specific inhibitors of this enzyme have been reported to suppress T cell function. Previously we have identified a DP IV inhibitor, designated TMC-2, found in culture supernatant of Aspergillus oryzae. Administration of TMC-2 to rats with adjuvant arthritis caused marked suppression of paw swelling. To elucidate the mechanism of TMC-2 antiarthritic activity, we have studied its effects on T cell function. Here we show that TMC-2 inhibited DP IV activity of CD26 immunoprecipitated from T cell lysates, and also inhibited proliferative responses of T cells to specific antigen or anti-CD3 antibody. Suppression of IL-2 production was demonstrated at both the mRNA and protein levels. TMC-2 did not alter the PTPase activity of pure CD45, but when this molecule was co-precipitated from T cell lysates together with associated CD26, its PTPase was virtually completely abolished by TMC-2. These results suggest that modulation of CD45 PTPase activity might be responsible for functional suppression of T cells by TMC-2. Because the effects of TMC-2 on T cells were reversible and it was not toxic at the concentrations used, TMC-2 may be a candidate novel therapeutic agent for rheumatoid arthritis.
Williams
Y N
YN
Graduate School of Allied Health Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
Baba
H
H
Hayashi
S
S
Ikai
H
H
Sugita
T
T
Tanaka
S
S
Miyasaka
N
N
Kubota
T
T
D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000276:immunology; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D003864:Depression, Chemical; D018819:Dipeptidyl Peptidase 4 / Q000097:blood; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D006801:Humans; D007211:Indoles / Q000627:therapeutic use*; D007376:Interleukin-2 / Q000276:immunology; D007546:Isoquinolines / Q000627:therapeutic use*; D017493:Leukocyte Common Antigens / Q000097:blood; D008213:Lymphocyte Activation; D013601:T-Lymphocytes / Q000201:enzymology* / Q000276:immunology
D004791:Enzyme Inhibitors; D007211:Indoles; D007376:Interleukin-2; D007546:Isoquinolines; C108548:TMC 2A; D017493:Leukocyte Common Antigens; D018819:Dipeptidyl Peptidase 4