Tolerance to Cardiac Grafts Following Intra-Graft Infusion of 16,16 Dimethyl PGE₂

Abstract

Although prostaglandins of the E series (PGE) have been reported to down-regulate immune responses as indicated by inhibition of T cell proliferation,¹ interference with the effector activity of cytotoxic T cells,² reduction of IL-2 production,^3,4 suppression of lymphocyte migration⁵ and decreased Ia expression by macrophages,⁶ attempts to demonstrate a beneficial effect of PGE on solid-organ allograft survival have been limited. Quagliata et al.⁷ increased mouse skin graft survival by 8 days when systemically administered PGE₁ was combined with procarbazine, while PGE₁ alone had no effect. Subcutaneous PGE₁ given twice daily (1 mg/kg) also increased hamster to rat cardiac xenograft survival from 74 to 94 hours.⁸ The limited effectiveness of PGE is partly due to its very short half life in vivo.⁹ PGE is usually rapidly metabolized locally at injection site and almost totally inactivated during a single passage through the lung.⁹ In contrast, the more stable synthetic PGE₂ analogues have half lives of several hours.¹⁰ Kort et al.¹¹ found that although oral (15S)–15 methyl PGE₁ alone did not increase rat heart allograft survival, when combined with prednisolone or azathioprine, survival was increased from 8 to 25.5 and 16.5 days respectively. Using 16, 16 dimethyl prostaglandin E₂ methyl ester (di-M-PGE₂), Anderson et al.¹² reported prolongation of mean skin graft survival from 13.8 to 16.7 days in mice given di-M-PGE₂ intraperitoneally.