[1]Hepatopancreatobiliary Surgery, Third Hospital of Jilin University, Changchun, Jilin, China.
Extracorporeal photopheresis (ECP), a procedure that exposes isolated WBC to photoactivatable 8-methoxypsoralen and ultraviolet A radiation, is used clinically to treat patients with cutaneous T-cell lymphoma and transplant rejection. We aimed to test effect of infusion of ECP treated donor splenocyte (ECP-DSp) in inducing donorspecific immune tolerance after allogenic liver transplantation. Livers from ACI rats were orthotopically transplanted into allogeneic Lewis recipients with no treatment (untreated), treated with ECP-DSp, a single infusion of ECP-DSp (100 x 10(6) ) 7 days prior to receiving liver transplant, or low dose TAC (TAC , 1mg/kg, S.C. day 0-21). To test whether donor-specific tolerance was achieved by ECP-DSp treatment, full thickness skin grafts from ACI donors and third-party BN rats were transplanted onto back of recipients with ECP treatment at 100 post-operative days (POD). All untreated recipients died from acute rejection within 15 days, whereas TAC prolonged allograft survival with median survival time (MST) of 60 days. In marked contrast, all allografts with ECP-DSp survived beyond POD100 (MST=100), significantly superior to untreated (p<0.001) or TAC treated allografts (p<0.01). Compared to the untreated allografts, liver function measured at day 7 and 14 was significantly improved in ECP group, as manifested by lower AST (p<0.001) and ALT (p<0.05), and higher albumin levels (p<0.05). Interestingly, ECP-DSp mediated liver graft protection was coincided with increased numbers of CD4(+)CD25(+)FoxP3(+) T regulatory cells (Tregs) in the blood of ECP treated recipients as compared with the untreated (p<0.05) and TAC treated recipients (p<0.05) at POD 7 and 14. Furthermore, ECPDSp treated allografts (after POD100) accepted donor-type (ACI) skin grafts but not third-party skin grafts, suggesting that ECP could successfully induce donor-specific tolerance. In conclusion, a single pre-transplant infusion of ECP-DSp facilitated long-term liver allograft survival and led to donor specific tolerance, demonstrating a novel role of ECP, an existing immunotherapy, in induction of transplant tolerance. Promoting generation of Tregs may contribute to the mechanism of action for protection of liver allograft from rejection by ECP-DSp infusion.
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