Total lymphoid irradiation: Critical timing and combination with cyclosporin A for immunosuppression in a rat heart allograft model

Abstract

Total lymphoid irradiation (TLI), a standard radiotherapeutic technique for the treatment of Hodgkin's disease, is immunosuppressive. TLI has been used for clinical renal transplantation in conjunction with pharmacological immunosuppression. The optimal recipient treatment protocol is not known. Using ACI (RT-1 a) rat heart allograft survival in Lewis (RT-1 1) rat recipients as a measure of treatment efficacy, we have determined the importance of radiation fractionation, the optimum dose per radiation fraction, the effect of delaying transplantation after completion of TLI, the effect of pretransplant versus post-transplant TLI, and the effect of combining TLI with a pharmacological immunosuppressant, cyclosporin A (CsA). Median heart allograft survival in untreated rats, in rats given 1000 rad (single dose), and in rats given 1000 rad in five fractions pretransplant were 6, 9, and 26 days, respectively. Median allograft survival in rats given 1000 rad in <5 or >5 fractions was 10–14 days. A dose fraction of between 125 and 250 rad was optimal. Heart allografts transplanted immediately after 2600 rad TLI (13 × 200 rad) survived 57 days; survival was shortened to 20 days if transplantation was delayed 1 month. Postoperative TLI alone did not prolong allograft survival. CsA (1.25 mg/kg/day) alone, in combination with preoperative TLI (5 × 200 rad), and in combination with postoperative TLI (9 × 200 rad) resulted in median survival times of 15, 96, and 60 days. Both the sequential and concurrent combination of TLI and CsA have synergistic effects on heart allograft survival. For optimal results, TLI should be fractionated preoperatively and transplantation should be performed soon after completion of radiotherapy. Post-transplant TLI is effective only if used in combination with pharmacological immunosuppression.