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Posttransplant lymphoproliferative disorder (PTLD) is a life-threatening complication of transplantation, which comprises a morphologically and clinically heterogeneous spectrum of B-lymphocyte diseases. Risk factors include primary or reactivated Epstein-Barr virus (EBV) infection, and the type and duration of immunosuppression. Interleukin-10 (IL-10) is a pleiotropic cytokine, produced primarily by T-helper 2 (Th2) lymphocytes in the later stages of T-cell activation, suggested to play a role in EBV-associated PTLD. We recently reported preliminary findings on IL-10 in relation to the development of PTLD in three kidney transplanted patients. The study now includes nine patients that could be followed before and/or after the occurrence of lymphoma.Nine patients with lymphomas (eight PTLDs and one Hodgkin's disease) were diagnosed among 268 consecutive renal transplantations (1990-1997). All were treated with cyclosporine with an initial 10-day course of antilymphocyte globulin, supplemented from 1995 with mycophenolate mofetil. Serum antibodies against EBV were detected using recombinant antigens. A double sandwich enzyme-linked immunosorbent assay using rabbit antibodies to purified human recombinant IL-10 was employed; the assay is specific for human natural and viral IL-10.Three patients experienced primary EBV infection, five reactivated EBV infections, and one did not change EBV status. Three patients had a fulminant course and died with EBV-associated PTLD confirmed post mortem. The other six are alive and are apparently cured. Treatment was immediate discontinuation of immunosuppression (in all PTLDs) and long-term high-dose aciclovir in all but one. Two patients have maintained excellent graft function for 3 and 2 years, respectively, without immunosuppression and are now in a state of operational tolerance. In three of four cases with initial lymphoma, EBV infection (primary or reactivation) preceded the increase in IL-10. In all four cases, the IL-10 increase preceded the PTLD diagnosis. In six cases, IL-10 could be followed after treatment showing either immediate zero or a decrease to zero.IL-10 seems to play a role in EBV-associated PTLD. Moreover, IL-10 may have an important role in transplant tolerance by inducing long-lasting anergy to donor- and host-specific alloantigens, perhaps caused by down-regulation of Th1 cytokines in the graft. If substantiated, this may provide new insight into the pathogenesis of PTLD introducing new strategies for prevention and therapy of PTLD, and for the induction of tolerance in transplanted patients.