Suppression of allograft rejection is central to successful organ transplantation; thus, immunosuppressive agents are crucial for successful allograft function. Immunosuppressive drugs are used for induction (intense immunosuppression in the initial days after transplantation), maintenance, and reversal of established rejection. This review considers the use of immunosuppressive drugs in organ transplantation, focusing on renal transplantation.

https://www.nejm.org/doi/pdf/10.1056/NEJMra033540

Immunosuppressive Drugs for Kidney Transplantation

Antibody engineering via genetic engineering of the mouse: XenoMouse strains are a vehicle for the facile generation of therapeutic human monoclonal antibodies.

Background. Mycophenolate Mofetil (MMF) has been shown to significantly decrease the number of acute rejection episodes in renal transplant recipients during the 1st year. A beneficial effect of MMF on long-term graft survival has been more difficult to demonstrate. This beneficial effect has not been detected, despite the impact of acute rejection on the development of chronic allograft nephropathy and experimental evidence that MMF may have a salutary effect on chronic allograft nephropathy independent of that of rejection. Methods. Data on 66,774 renal transplant recipients from the U.S. renal transplant scientific registry were analyzed. Patients who received a solitary renal transplant between October 1, 1988 and June 30, 1997 were studied. The Cox proportional hazard regression was used to estimate relevant risk factors. Kaplan-Meier analysis was performed for censored graft survival. Results. MMF decreased the relative risk for development of chronic allograft failure (CAF) by 27% (risk ratio [RR] 0.73, P<0.001). This effect was independent of its outcome on acute rejection. Censored graft survival using MMF versus azathioprine was significantly improved by Kaplan-Meier analysis at 4 years (85.6% v. 81.9%). The effect of an acute rejection episode on the risk of developing CAF seems to be increasing over time (RR51.9, 1988 ‐91; RR52.9, 1992‐94; RR53.7, 1995‐ 97). Conclusion. MMF therapy decreases the risk of developing CAF. This improvement is only partly caused by the decrease in the incidence of acute rejection observed with MMF; but, is also caused by an effect independent of acute rejection.

Mycophenolate mofetil reduces late renal allograft loss independent of acute rejection.

Human acute myeloid leukemia (AML) originates from rare leukemia stem cells (LSCs). Because these chemotherapy-resistant LSCs are thought to underlie disease relapse, effective therapeutic strategies specifically targeting these cells may be beneficial. Here, we report identification of a primary human LSC gene signature and functional characterization of human LSC-specific molecules in vivo in a mouse xenotransplantation model. In 32 of 61 (53%) patients with AML, either CD32 or CD25 or both were highly expressed in LSCs. CD32- or CD25-positive LSCs could initiate AML and were cell cycle–quiescent and chemotherapy-resistant in vivo. Normal human hematopoietic stem cells depleted of CD32- and CD25-positive cells maintained long-term multilineage hematopoietic reconstitution capacity in vivo, indicating the potential safety of treatments targeting these molecules. In addition to CD32 and CD25, quiescent LSCs within the bone marrow niche also expressed the transcription factor WT1 and the kinase HCK. These molecules are also promising targets for LSC-specific therapy.

Identification of Therapeutic Targets for Quiescent, Chemotherapy-Resistant Human Leukemia Stem Cells

Effective immunosuppression is an essential pre-requisite for successful organ transplantation and improvements in outcome after transplantation have to a large extent been dependent on developments in immunosuppressive therapy. Here we provide an overview of the different immunosuppressive agents currently used in solid organ transplantation. A historical perspective on the development of immunosuppression for organ transplantation is followed by a review of the individual agents, with a focus on their mechanism of action and efficacy. Steroids, anti-proliferative agents (azathioprine and mycophenolate), calcineurin inhibitors (cyclosporine and tacrolimus) and TOR inhibitors (sirolimus and everolimus) are discussed along with both polyclonal and monoclonal antibody preparations. Many of the key clinical trials that underpin current clinical usage of these agents are described and side-effects of the different agents are highlighted. Finally, a number of newer agents still in various stages of clinical development are briefly considered.

Immunosuppressive agents in solid organ transplantation: Mechanisms of action and therapeutic efficacy.

Background Acute rejection is still a major problem in renal transplantation and is one of the most important causes of chronic graft dysfunction and late graft loss. Selective immunosuppression with a humanized antibody against the alpha-chain of the interleukin (IL)-2 receptor (CD25) was evaluated to demonstrate the efficacy of this type of immunoprophylaxis in combination with dual immunosuppression. Methods We studied the effect of daclizumab, a humanized monoclonal antibody against the alpha-chain of the IL-2 receptor, in a randomized double-blind, prospective phase III clinical trial in 275 patients receiving a first cadaveric renal allograft. Among them 111 (83%) in the placebo arm and 116 (82%) in the daclizumab arm received the full regimen of five doses (1.0 mg/kg) every other week. Baseline immunosuppression consisted of cyclosporine and corticosteroids. Results At 6 months, 39 (28%) of the patients in the daclizumab group had biopsy-proven rejections, as compared with 63 (47%) in the placebo group (P=0.001). The need for additional antilymphocyte therapy, antithymocyte globulin, antilymphocyte globulin (ATG, ALG, OKT3) was also lower in the daclizumab group (8% vs. 16%, P=0.02), and they required significantly lower mean (+/- SD) cumulative doses of prednisone (3750+/-1981 mg vs. 4438+/-2667 mg in the placebo group, P=0.01). Graft function was significantly better (P=0.02) in the daclizumab group (graft function rate: 58 vs. 51 ml/min, mean) as was patient survival (P=0.01, 99% vs. 94%). No specific adverse events were observed in daclizumab-treated patients. Patients receiving daclizumab experienced fewer cytomegalovirus infections (18% vs. 25%), and none died from severe infectious complications, compared to four patients in the placebo arm. No patient in the daclizumab group had a lymphoproliferative disorder or any other form of immunosuppression-related tumor during the first year after transplant. Conclusions Administration of daclizumab in addition to dual immunosuppression therapy significantly reduced biopsy-proven acute rejection after renal transplantation, improved patient survival, and did not add to the toxicity of the immunosuppressive regimen.

I R Hardie

Papers

Reduction of acute renal allograft rejection by daclizumab. Daclizumab Double Therapy Study Group.