Inhibition of T-cell activation is the most efficient way to prevent transplant rejection.
Protein kinase C (PKC) is an important signaling enzyme in the activation and regulation
of T lymphocytes. AEB-071 (AEB) is a low-molecular-weight compound that blocks early
T-cell activation via selective inhibition of PKC, a mechanism that differs from that
of the calcineurin inhibitors. The present study sought to compare the effects of
AEB versus tacrolimus (Tac) to prevent acute rejection in rats that had undergone
heterotopic heart transplantation. We investigated the Brown Norway-Lewis rat strain
combination for cardiac graft survival over 30 days after transplantation using varying
doses of oral AEB and Tac monotherapy. Grafts were monitored by daily palpation; cessation
of palpable ventricular contraction was considered to be rejection. Apart from necropsy,
we performed histologic examinations of cardiac graft at 7 days after transplantation.
In untreated recipients, allograft mean survival times (MST) was 6.83+/-0.41 days.
AEB at 15, 30, or 60 mg/kg versus Tac at 1.2 mg/kg significantly prolonged graft survival
to a MST of 12.33+/-1.21, 16.67+/-1.21, and 19.33+/-3.83, versus 17.00+/-6.90 days,
respectively. Histologic assessment at 7 days after transplantation showed that high-dose
AEB significantly decreased the histologic rejection score, indicative of decreased
inflammatory cell infiltration into the graft. These results suggested that the administration
of AEB (medium or high-dose), a PKC inhibitor, mitigated acute rejection and displayed
significantly longer MST, similar to high-dose Tac after heterotopic heart transplantation
in the rat.