PUVA augments cyclosporine A-mediated rat cardiac allograft survival

PUVA, the administration of the photosensitizer 8-methoxypsoralen (8-MOP) followed by exposure of the skin to longwave ultraviolet radiation (UVA, 320-400 nm), is employed clinically for the treatment of skin diseases. PUVA is immunosuppressive and we have shown previously that it can significantly prolong skin allograft survival. This enhanced survival is associated with reduced spleen cell cytotoxic activity against donor cell targets with preserved ability of treated animals to be immunized to third-party alloantigens 5 days after exposure to a course of PUVA. To examine whether PUVA may potentiate the effect of cyclosporine A (CYA) in inhibiting cardiac allograft rejection, we employed a rat cardiac transplant model. Lewis rats (RT1¹) received cardiac allografts at a heterotopic site from Lewis Brown Norwegian (RT1 ^{1 n}) hybrid donors. Seventy animals were equally divided into 10 groups. Starting on the day of surgery, three groups received a suboptimal doses of CYA (1.5, 4.5, or 9.0 mg/kg im), three groups received the same doses of CYA and 1.0 mg/kg of 8-MOP injected ip followed by 6.35 J/cm² of UVA radiation to their shaved dorsums (PUVA), one group received PUVA alone, one group received UVA radiation alone, one group received 8-MOP alone, and the final group received no treatment. Therapy was carried out daily for 7 days and survival of the allograft was assessed by daily palpation of the transplanted heart. Both PUVA and CYA alone significantly prolonged survival compared to no treatment (15.8 ± 1.4 SEM days for PUVA, 14.4 ± 0.9 for 1.5 mg/kg CYA, 14.7 ± 1.2 for 4.5 mg/kg CYA, and 18.7 ± 1.3 for 9.0 mg/kg vs 7.0 ± 0.8 for the untreated control group). The combinations of PUVA and CYA significantly prolonged survival compared to either treatment alone [23.0 ± 1.6 for PUVA and 1.5 mg/kg CYA, 22.0 ± 1.7 for PUVA and 4.5 mg/kg CYA, 3 out of the 7 animals that received PUVA and 9.0 mg/kg CYA exhibited apparent permanent acceptance (>200 days); the other 4 rejected at 19, 30, 36, and 40 days]. Administration of 8-MOP alone or UVA radiation alone failed to prolong allograft survival compared to no treatment. These data show that PUVA can improve CYA-mediated cardiac allograft survival and suggest that this modality might be a useful adjunctive therapy for organ transplantation.