Background: We have previously demonstrated that a new triazolopyrimidine derivative, NK026680 (NK) prevents activation/maturation of dendritic cells. This study investigated whether NK together with donor-specific transfusion (DST) induces regulatory T cells (Tregs) and exerts immunomodulatory effect.

Methods: BALB/c (H-2d: donor) mouse-splenocytes (20 million cells) was infused I.V. (DST) to C57BL/6 (B6, H-2b) mice, and NK (40 mg/kg/day) was given P.O. for 14 days. B6 mice received either BALB/c or C3H (H-2k: 3rd-party) mouse cardiac allograft 7 days after DST (day 0) and graft survival time was assessed. CD4+CD25+Foxp3+ Tregs were assessed by flow-cytometry.

Results: NK+DST increased Tregs significantly in the spleen after re-stimulation with donor-antigens (Ags:splenocytes), while such Treg increases were neither noted by NK or DST treatment alone nor by re-stimulation with C3H-Ags (Fig.1A). Similarly, NK+DST accelerated accumulation of Tregs into the allograft at day 7 compared with other treatment groups (Fig.1B). Accordingly, NK+DST markedly prolonged allograft survival compared with either DST or NK alone (P<0.01, MST: 75.5, 24.5, or 25.5 days, respectively). In contrast, survival of C3H graft (MST: 22.0 days) did not prolong as long as that of BALB/c graft despite NK+DST treatment (Fig.1C). Finally, administration of depleting anti CD25 mAb (PC61) before NK+DST treatment strongly abrogated the graft survival prolonging effect of NK+DST (MST: 11.0 days) (Fig.1C).

Conclusion: Treatment of NK026680 together with DST, promotes expansion of Ag-specific regulatory T cells and induces a potent immunomodulatory effect in an Ag-specific manner.

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