Inhibition of Cd26/Dipeptidyl Peptidase Iv Activity in Vivo Prolongs Cardiac Allograft Survival in Rat Recipients1,2

Abstract

The CD26 antigen, one of the major costimulatory molecules in T cell activation, was shown to possess dipeptidyl peptidase IV (DPP IV) activity. Previously, we demonstrated that immunosuppressed kidney transplant patients exhibit lower DPP IV serum activity as compared with healthy individuals. In the present study, we analyzed the role of CD26/DPP IV in the immune cascade triggered by organ transplantation and leading to acute rejection of cardiac allografts in rat recipients. Transplantation of hearts from (Lewis x Brown Norway)F1 donors into Lewis hosts 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 IV activity with a novel, low-molecular-weight inhibitor of the diphenyl-phosphonate group (prodipine) abrogated acute rejection and prolonged cardiac allograft survival to 14.0+/-0.9 days (P<0.0001). Prodipine treatment prevented the early peak of cellular CD26 expression and thoroughly suppressed systemic DPP IV activity. The inhibition of DPP IV was associated with severely impaired host cytotoxic T lymphocyte responses in vitro. These results demonstrate the role of CD26/DPP IV in alloantigen-mediated immune regulation in vivo and provide the first direct evidence that CD26/DPP IV plays an important role in the mechanism of allograft rejection. The model of targeting CD26/DPP IV may reveal essential interactions on the level of costimulatory alternate T cell activation pathways, allowing a more subtle approach for more selective immunosuppression in transplant recipients.

Targeting Dipeptidyl Peptidase IV (CD26) Suppresses Autoimmune Encephalomyelitis and Up-Regulates TGF-β1 Secretion In Vivo

“…3). Our conclusion is further supported by a recent study in a rat transplantation model (47). Treatment with the irreversible DP IV inhibitor prodipine prevented the increase in serum DP IV normally seen during the first days after cardiac allotransplantation.…”

“…Treatment with the irreversible DP IV inhibitor prodipine prevented the increase in serum DP IV normally seen during the first days after cardiac allotransplantation. Both allograft rejection and the concomitant increase of DP IV activity in transplant tissue were delayed (47). In another study, arthritis signs in rats could be suppressed by several biochemically distinct DP IV inhibitors, including I49, indicating that the effect was very likely to be due to the specific inhibitory effect on DP IV (48).…”

Truncation of Macrophage-derived Chemokine by CD26/ Dipeptidyl-Peptidase IV beyond Its Predicted Cleavage Site Affects Chemotactic Activity and CC Chemokine Receptor 4 Interaction

“…The involvement of the enzymatic activity in the immunoregulatory function of CD26/ DPP IV is demonstrated under several circumstances. These include the in vitro normalization of impaired responses to recall antigens by the addition of soluble CD26/DPP IV (6,7) and the in vivo suppression of immune activation upon alloantigen challenge by specific CD26/DPP IV inhibitors (8). Recently, CD26/DPP IV has been shown to process the NH 2 terminus of a number of chemokines including RANTES, granulocyte chemotactic protein-2 (GCP-2), and SDF-1, generating naturally occurring truncated molecules with a significantly altered biological activity (9 -12).…”

TGF-β1-Mediated Control of Central Nervous System Inflammation and Autoimmunity through the Inhibitory Receptor CD26

“…The CD26 molecule functions as the cell membrane-associated exopeptidase dipeptidyl peptidase (DP) 4 IV (EC 3.4.14.5), an enzyme capable of cleaving N-terminal dipeptides from polypeptides with either proline or alanine residues at the penultimate position (1)(2)(3). Many recent reports have demonstrated that CD26/DP IV serves as an important regulator of immune responses by affecting T cell activation, proliferation, and cytokine production (1)(2)(3)(4)(5)(6)(7)(8). Subsequently, multiple roles were predicted for CD26/DP IV in leukocyte homing and inflammation.…”