15AU81, A Prostacyclin Analog, Enhances Donor-Specific Hepatocytes to Prolong the Survival of Rat Heart but Not Small Bowel Allografts

Abstract

Prostacyclin analogs have previously been shown to have not only cytoprotective but also independent immunosuppressive effects. The effect of one such analog, 15AU81, to enhance the immunosuppressive effects of liver was investigated. We have previously demonstrated that cyclosporine (CsA) in conjunction with rapamycin (RAPA) potentiates class I+, class II– donor-specific hepatocytes to prolong rat cardiac and small bowel allograft survival. Brown Norway (BN; RT1a) hepatocytes alone (5 × 107/kg, administered intrasplenically) failed to prolong the survival of BN heart allografts in Wistar Furth (WFu; RT1#) recipients, beyond that of untreated controls (MST = 7.2 ± 0.8 days). Survival of BN hearts was increased to 11.4 ± 1.7 days in WFu recipients treated with BN hepatocytes and 50 μg/kg/day 15AU81 administered by continuous SC infusion for 14 days using osmotic pumps (p < 0.05). The further addition of RAPA 0.0075 mg/kg/day and CsA 0.375 mg/kg/day delivered for 14 days by continuous IV infusion (CIVI) using osmotic pumps (a combination that alone prolonged BN heart allografts in WFu hosts to 18.4 ± 1.3 days and in conjunction with BN hepatocytes prolonged survival to 27.2 ± 1.9 days) prolonged allograft survival to 35.2 ± 5.2 days. In contrast, the survival of small bowel allografts was not enhanced by 15AU81 administration. Survival of BN small bowel transplants in LEW recipients treated with hepatocytes alone (MST = 11.6 ± 1.5 days) or hepatocytes plus 15AU81 (MST = 10.0 ± 1.0 days) was similar to controls (MST = 10.2 ± 1.9 days). Treatment with hepatocytes and RAPA/CsA increased survival to 21.2 ± 1.5 days. The further addition of 15AU81 failed to augment this (MST = 17.0 ± 1.9 days). In vitro WFu lymphocyte proliferative responses from animals pretreated with BN hepatocytes, 15AU81, or both treatments, for 2 weeks prior to harvesting, exhibited a reduction of at least 50%, compared to untreated controls upon allostimulation with irradiated BN or ACI spleen cells. These findings demonstrate that 15AU81 interacts favorably with hepatocytes either alone or in conjunction with RAPA and CsA to enhance their immunosuppressive effects on rat heart allograft survival. The failure to enhance small bowel allograft survival may be explained by the inability at this low dosage of 15AU81 to influence the intense graft versus host reaction elicited by small bowel transplants.