REJECTION OF SPONTANEOUSLY ACCEPTED RAT LIVER ALLOGRAFTS WITH RECIPIENT INTERLEUKIN-2 TREATMENT OR DONOR IRRADIATION1,2

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Abstract
While MHC incompatible DA (RTla) to Lewis (RT11, LEW) rat liver allografts are acutely rejected, the reciprocal LEW to DA liver grafts are spontaneously accepted. The mechanism of this acceptance remains unclear. We evaluated the effect of donor treatment with total body irradiation (TBI) or gadolinium chloride (GdCl3), and recipient treatment with exogenous IL-2 after transplantation on the survival of the spontaneously accepted liver grafts. Male LEW and DA rats were used as donors and recipients for orthotopic liver allo- or iso-graft transplants. The LEW liver donor was treated by TBI (10 gray) 7 days before transplantation, or LEW donor Kupffer cell phagocytosis was blocked with GdCl3 (7 mg/kg) on days -2 and -1 pretransplant. In an attempt to reverse LEW liver graft acceptance, 180,000 units human IL-2 (hIL-2) were administered daily IP to the DA liver recipients from days 1 to 7 after liver grafting. While untreated LEW recipients rejected DA liver grafts within 13 days, DA recipients accepted LEW livers indefinitely (>302 days). In contrast, irradiation of the LEW liver donor prevented the spontaneous acceptance by DA recipients, and resulted in acute rejection of the liver grafts in 9-20 days. However, spontaneous graft tolerance was restored by parking the irradiated LEW donor liver in naive LEW rats for 48 hr before retransplantation to DA recipients (>50 days). When LEW donors were treated with GdCl3, which is known to block Kupffer cell phagocytosis and antigen processing, the spontaneous acceptance of the LEW liver grafts by DA recipients was unaffected. However, when exogenous rhIL-2 was given daily, LEW liver allografts were rejected by the DA recipients. The resulting liver failure correlated with a progressive increase in serum bilirubin and the development of a predominantly lymphocytic portal tract infiltration, bile duct epithelial damage, and portal vein endothelitis, which is consistent with acute allograft rejection. LEW and DA recipients of liver isografts developed no toxicity and survived indefinitely (>100 days) when treated with the same dose of IL-2. These results indicate that spontaneous rat liver allograft acceptance is associated with the presence of radiosensitive cells in the donor liver that may interact with recipient T cells to inhibit (Th1) production of IL-2.