Small bowel transplantation in the rat. Effect of pretransplant blood transfusions and cyclosporine on host survival.

We investigated the effect of pretransplant conditioning as a way to reduce the need for the aggressive immunosuppressive therapy reportedly required in small bowel (SB) allograft recipients. LEW rats were conditioned with (1) a donor-specific blood transfusion (DST) on day -8 and a concurrent 5-day course of CsA (10 mg/kg/day); (2) a nonspecific blood transfusion and CsA; (3) CsA alone. A 10-cm segment of the host native bowel was then replaced with an equivalent segment of SB obtained from ACI rats. Postoperative treatment consisted of CsA at 2.5 mg/kg/day for 30 days. Rats conditioned with a nonspecific transfusion and CsA or with CsA alone survived for 14.1 +/- 5.8 and 18.3 +/- 5.7 days, respectively. In contrast, rats conditioned with DST and CsA survived for 60.3 +/- 36.2 days (P less than 0.001 vs. both controls). Biopsies taken from long-term survivors showed a normal bowel architecture. The function of the allografts was studied in a group of animals totally deprived of their native bowel and transplanted with a 30-cm segment of ACI SB. CsA-DST-treated recipients survived an average of 90 +/- 43 days and grew at a rate comparable to isografted animals. Treated allograft recipients had maltose absorption indistinguishable from isografted controls at all times tested. In contrast, maltose absorption was severely impaired in recipients rejecting their grafts. This study demonstrates that long-term survival of SB allograft recipients can be achieved with good functional results with low doses of CsA in recipients conditioned with DST and CsA.

Pretransplant conditioning with donor-specific transfusions using heated blood and cyclosporine. Preservation of the transfusion effect in the absence of sensitization.

Previous studies from our laboratory showed that pretransplant conditioning with fresh donor-specific blood (DST) combined with cyclosporine (CsA) resulted in long-term prolongation of ACI heterotopic cardiac allografts in LEW recipients treated with subtherapeutic doses of CsA. The concomitant administration of CsA profoundly reduced but did not eliminate the DST-induced sensitization. The purpose of the present study was to investigate in the ACI-to-LEW cardiac allograft model whether heat-treatment of the blood would further reduce the sensitizing potential of DST while maintaining their benefits in our protocol. Fresh heparinized ACI blood was heated at 45 degrees C for 60 min. Then 1.5 ml was administered i.v. to LEW rats on day -8 with respect to grafting (day 0). Controls received heat-treated BUF blood. Donor heat-treated blood (HT-DST), unlike fresh blood, did not induce a humoral cytotoxic response and resulted in the prolongation of cardiac allograft survival (13.2 +/- 2.7 vs. 7.2 +/- 1.0; P less than 0.01). Treatment of HT-DST recipients with postoperative subtherapeutic doses of CsA (2.5 mg/kg/day x 30) extended graft survival (46.6 +/- 22.0 vs. 7.7 +/- 2.0 days; P less than 0.01). The combined pretransplant administration of HT-DST and CsA followed by posttransplant subtherapeutic doses of CsA led to long-term prolongation of cardiac grafts (122.0 +/- 73.0 vs. 31.7 +/- 22.0 days; P less than 0.01). These studies demonstrate that heat-treatment of allogeneic blood eliminates the humoral responses to DST and actually enhances their beneficial effects in terms of graft survival. Such effects can be dramatically increased by CsA. The possible mechanism of these phenomena are discussed.

Long-term prolongation of cardiac allografts by subtherapeutic levels of cyclosporine in rats conditioned with pretransplant blood transfusions and cyclosporine.

This study was aimed at ascertaining whether long-term graft survival was achievable with short term cyclosporine (CsA) therapy or with subtherapeutic doses of CsA in rats conditioned with blood transfusions (BT) combined with CsA. Previous studies had shown that donor-specific transfusions combined with a short course of CsA interacted synergistically, resulting in considerable prolongations of ACI and BUF grafts in LEW hosts receiving no postoperative treatment. The donor-specific depression of alloreactivity was confirmed in the present study by showing a depression of mixed-lymphocyte reaction (MLR) reactivity as well as of humoral antidonor responses in BT-CsA conditioned rats. The effects of postoperative CsA were then studied in recipients conditioned with BT-CsA or BT alone. ACI and BUF cardiac graft survival in LEW hosts conditioned with BT and treated with a five-day postoperative course of CsA (20 mg/kg/day) were indistinguishable from graft survival in untransfused hosts (ACI: 35.6 +/- 15.5 vs. 38.8 +/- 7.4; BUF: 58.4 +/- 39.8 vs. 48.0 +/- 21.7) indicating no interaction between BT and CsA under these conditions. In contrast, the effect of a post-operative five-day course of CsA (10 mg/kg/day) was extended by conditioning the recipients with donor-specific BT and CsA (ACI:41.7 +/- 7.0 vs. 27.4 +/- 11.6; P less than 0.05). More remarkably, a thirty-day course of subtherapeutic doses of CsA (2.5 mg/kg/day) resulted in long-term prolongation (greater than 100 days) of ACI grafts in a large proportion of hosts conditioned with donor-specific BT and CsA, while the majority of controls conditioned with nonspecific BT and CsA or CsA alone rejected their grafts within three weeks (P less than 0.01). The possible mechanisms of this phenomenon are discussed.