The development of local immunosuppression in organ transplantation

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Considerable interest in the experimental and clinical use of MoAbs as potential therapeutic agents in allograft rejection has been generated by the recent reports of striking prolongation. In this study we investigated the efficacy of the local administration of MoAb OX-19 which is directed to the rat CD5equivalent, through the renal artery using a rat kidney transplant model, in order to develop a potent method for modifying rejection while minimizing the systemic side effects. Untreated Lewis rats (LEW,RT-1<@D11@>D1) rejected Brown-Norway rat (BN,RT-1<@D1n@>D1) kidney at 7・8(]SY.+-。[)0・2 days (n=10). Mean survival time (MST) of recipients treated with OX-19 (75 mug/kg per day) as single bolus injections via the dorsal penile vein for 7 days was 7・0(]SY.+-。[)0・2 days (n=5, NS). LEW hosts receiving OX-19 (75 mug/kg per day) continuously for 7 days via a femoral vein by using an osmotic minipump (IV-treated group) showed a slight prolongation of graft survival (MST=8・8(]SY.+-。[)0・9 day … More s, n=5), but this was not statistically significant. On the other hand, local continuous intrarenal arterial infusion of OX-19 (75 mug/kg per day) for 7 days (RA-treated group) significantly prologed the graft survivals (MST=16・8(]SY.+-。[)1・3 days, n=8, p<0・01). Histological examination of MoAb-treated LEW hosts on day 6 post-grafting revealed that kidney grafts from RA-treated hosts showed a slight tubular necrosis, but reduced mononuclear cell infiltration, whereas kidney grafts from IV-treated hosts displayd a severe mononuclear cell infiltration around the artery with interstitial oedema. Moreover, the local intrarenal administration of OX-19, even when the dose is delayd until day 4 after renal grafting, has a therapeutic effect for on-going acute allograft rejection (MST=11・4(]SY.+-。[)0・8 days, n=8) compared with administration of OX-19 intravenously from day 4 after grafting (MST=7・6(]SY.+-。[)0・2 days, n=5, P<0・01) or with no treatment (MST=7・8(]SY.+-。[)0・2 days, P<0・01). The phenotype of graft infiltrating cells (GIC) was investigated on day 6 post-grafting. There was a significantly lower percentage of cells positive for OX-19, OX-8, OX-26 (transferrin receptor), and OX-39 (IL-2 receptor) in the RA group than in the IV group. These results indicate that local administration of OX-19 via the renal artery is a more efficacious treatment than systemic i.v.injection, and suggests that it may provide a localized immunosuppression of allografts, with reduction of morbidity in clinical transplant recipients. Less