INTRAGRAFT DELIVERY OF 16, 16-DIMETHYL PGE2 INDUCES DONOR-SPECIFIC TOLERANCE IN RAT CARDIAC ALLOGRAFT RECIPIENTS

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Abstract
The stable prostaglandin E2 analogue, 16, 16-dimethyl PGE2 (di-M-PGE2) was continuously infused by osmotic pump directly into rat heterotopic cardiac allografts. Intragraft delivery of 20 μg/kg/day di-M-PGE2 for 2 weeks completely prevented graft rejection for more than 150 days (n = 10), while untreated Buffalo recipients rejected Lewis cardiac allografts within 8 days after transplantation (mean survival time = 7.4±0.5 days, n = 5). When given for only 1 week, 20 μg/kg/ day had a partial effect, since 60% of recipients accepted grafts long-term and 40% experienced rejection by day 14 (n = 5). In contrast, systemic intravenous administration of 20 μg/kg/day di-M-PGE2 for 2 weeks could not prolong graft survival (MST=7.0±0.0 days, n = 3), and the higher dose of 200 μg/kg/day resulted in death by day 2 (n = 5). Long-term BUF recipients of LEW cardiac allografts accepted LEW donor strain skin grafts for more than 35 days while rejecting third-party Wistar Furth skin grafts in a normal fashion (MST=7.3±0.5 days, n = 3), indicating the induction of donor-specific tolerance. Long-surviving LEW cardiac allografts re-transplanted into naive BUF recipients were rejected within 7 days (MST=6.7±0.5 days, n = 3), indicating no change in graft immunogenicity. Therefore, a 14-day infusion of di-M-PGE2 directly into a strongly MHC-mismatched cardiac allograft uniformly has resulted in long-term engraftment and the development of recipient donor-specific tolerance.

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