Delayed graft function (DGF), defined as persistent renal failure that requires dialysis within the first week after kidney transplantation, occurs commonly after cadaveric renal transplantation (CRT). This has important implications for long-term outcome because the 1-year allograft survival rate is significantly reduced when DGF occurs. The mechanisms contributing to the development of DGF are not well established. However, several lines of evidence indicate that excess renin system activity, in both the cadaver kidney donor and recipient, contributes importantly to the pathogenesis of DGF. If this hypothesis can be verified in clinical studies, then pharmacologic agents that interrupt the renin-angiotensin system (eg, type 1 angiotensin II receptor blockade, angiotensin converting enzyme inhibition, and beta-adrenergic blockade) in the donor and recipient might significantly improve the outcome of cadaveric renal transplants.

Adoptive cellular immunotherapy, infusions of interleukin 2 (IL-2) in conjunction with in vitro-activated killer cells, has brought new hope to patients with cancer. The broad application of this strategy, however, is constrained by the need for repeated leukapheresis and by the labor-intensive process of in vitro activation of cells. Also, current protocols generally use nonphysiological and toxic concentrations of IL-2. Identification of an in vivo stimulant that renders T cells responsive to physiologic concentrations of IL-2 represents a potential improvement over existing approaches. We have determined whether in vivo administration of monoclonal antibodies (mAbs) directed at the T-cell surface protein CD3 induces T-cell responsiveness to IL-2, stimulates cytolytic molecular programs of natural killer cells and cytotoxic T cells, and induces tumor regression. These hypotheses were explored in a murine hepatic MCA-102 fibrosarcoma model. We report that in vivo administration of anti-CD3 mAbs plus IL-2 results in intrahepatic expression of mRNA-encoding perforin, cytotoxic T-cell-specific serine esterase, and tumor necrosis factor alpha. Anti-CD3 mAbs alone or IL-2 alone failed to induce or induced minimal expression of these molecular mediators of cytotoxicity. The anti-CD3 mAbs plus IL-2 regimen also resulted in a significantly smaller number of hepatic metastases and a significantly longer survival time of tumor-bearing mice, compared to treatment with anti-CD3 mAbs alone or IL-2 alone. Our findings suggest that a regimen of anti-CD3 mAbs plus IL-2 is a more effective antitumor regimen compared with anti-CD3 mAbs alone or IL-2 alone and advance an alternative immunotherapy strategy of potential value for the treatment of cancer in humans.

The addition of novel immunosuppressive agents and transfusion regimens to the therapy of human kidney transplantation has significantly improved the outcome of transplants that are performed today. At its inception, kidney transplantation quickly gained a foothold as an effective treatment modality for end-stage kidney disease because of the availability of living related donors and the drug azathioprine. That the procedure has established itself as acceptable, thus allowing for the development of the interventions to be discussed here, was largely due to our gradual understanding of how to use azathioprine safely, coupled with the fact that a viable alternative for prolonging life was not then available. When chronic hemodialysis emerged as a safe, effective, and readily available therapeutic regimen, the use of less noxious drugs and procedures in transplant recipients was virtually mandated. The interventions that subsequently gained a place in transplantation then were those that had relatively little down-side risk for the patient using azathioprine and corticosteroids as the reference standard. This procedural approach largely reduced the number of experimental immunosuppressive regimens initially deemed worthy of sustained clinical investigation. Often, however, the risk-benefit ratio approach proved to be difficult to assess. Indeed, the finding of associated side effects with dramatically effective drugs such as cyclosporin have presented new problems and decisions for the investigator to cope with.