Immunosuppression and immunological tolerance induction: lessons from a transplant model

Introduction

Patients who receive organ transplants need life-long immunosuppression to prevent rejection of their grafts. Induction of immunological tolerance to the transplanted organs can solve this problem. However, according to the current opinion in clinical immunosuppression, administration of cyclosporin A (CyA) prevents tolerance induction.

In our study, we attempted to find out whether immunosuppression with CyA is really so harmful for tolerance induction.

Methods

We established a high-responder (DA-Lew) kidney transplant model in rats.

DA kidneys were grafted into unilaterally nephrectomized LEW receiving no immunosuppression or low (1.5 mg/kg), medium (3.0 mg/kg) or high (15 mg/kg) CyA for 10 days.

To rule out nephrotoxic effect of CyA, the original DA grafts were replaced by secondary DA kidneys 30 days after first transplantation; secondary grafts were followed for 90 days. During the second engraftment, no immunosuppression was administered.

Results

Surprisingly, we observed a dramatic difference in secondary graft survival depending on the dose of immunosuppression. Animals that had received an initial graft with low-dose CyA survived indefinitely. Almost no alloantibodies were detectable. By contrast, increased (3.0 mg/kg ×10 days) or high-dose (15 mg/kg ×10 days) immunosuppression after first engraftment did not result in acceptance of secondary grafts. Animals in those groups developed acute rejection of secondary grafts. High levels of alloreactive antibodies were also detected.

Discussion

Immunosuppression with CyA does not prevent immunological tolerance by itself. Rather, higher doses of CyA have a detrimental effect on tolerance induction. CyA in low doses acts as tolerance inducer. Whether this sharp dose-dependent effect of CyA on tolerance induction is a general effect of immunosuppressive agents or is restricted only to CyA is still to be examined.