S. Korom et al., INHIBITION OF CD26 DIPEPTIDYL PEPTIDASE-IV ACTIVITY IN-VIVO PROLONGS CARDIAC ALLOGRAFT SURVIVAL IN RAT RECIPIENTS/, Transplantation, 63(10), 1997, pp. 1495-1500
The CD26 antigen, one of the major costimulatory molecules in T cell a
ctivation, was shown to possess dipeptidyl peptidase IV (DPP IV) activ
ity, Previously, we demonstrated that immunosuppressed kidney transpla
nt patients exhibit lower DPP IV serum activity as compared with healt
hy individuals, In the present study, we analyzed the role of CD26/DPP
IV in the immune cascade triggered by organ transplantation and leadi
ng to acute rejection of cardiac allografts in rat recipients, Transpl
antation of hearts from (Lewis x Brown Norway)F-1 donors into Lewis ho
sts resulted in an early (24 hr) increase in cellular CD26 expression,
followed by a rise in DPP IV serum activity, which peaked at day 6, i
,e,, before the time of actual graft loss, Specific targeting of DPP I
V activity with a novel, low-molecular-weight inhibitor of the dipheny
l-phosphonate group (prodipine) abrogated acute rejection and prolonge
d cardiac allograft survival to 14.0+/-0.9 days (P<0,0001), Prodipine
treatment prevented the early peak of cellular CD26 expression and tho
roughly suppressed systemic DPP IV activity, The inhibition of DPP IV
was associated with severely impaired host cytotoxic T lymphocyte resp
onses in vitro, These results demonstrate the role of CD26/DPP TV in a
lloantigen-mediated immune regulation in vivo and provide the first di
rect evidence that CD26/DPP IV plays an important role in the mechanis
m of allograft rejection, The model of targeting CD26/DPP IV may revea
l essential interactions on the level of co-stimulatory alternate T ce
ll activation pathways, allowing a more subtle approach for more selec
tive immunosuppression in transplant recipients.