REVIEWS Advances in immunosuppression for renal transplantation Antoine Durrbach, Helene Francois, Severine Beaudreuil, Antoine Jacquet and Bernard Charpentier Abstract | The development of immunosuppressants with minimal adverse and nephrotoxic effects is important to improve outcomes, such as acute and chronic antibody-mediated rejection, after organ transplantation. In addition, the application of expanded criteria for donors and transplantation in immunized patients necessitates the development of new therapies. Drug development over the past 10 years has generally been disappointing, but several new promising compounds have been or are being developed to prevent acute and chronic transplant rejection. In this Review, we report on several compounds that have been developed to remove allogenic T cells and/or to inhibit T-cell activation. We also discuss compounds that interfere with antibody-mediated rejection. Durrbach, A. et al. Nat. Rev. Nephrol. 6, 160–167 (2010); published online 2 February 2010; doi:10.1038/nrneph.2009.233 Introduction Renal transplantation has specific features that make or as a result of previous transplantation, has increased it different from transplantation procedures for other over the past decade. In addition, ABO­incompatible organs. For example, outcomes can be affected by grafts are becoming more frequently used. Together, these common states, such as donor and/or recipient age, high factors have led to a rise in the number of ‘immuno logically blood pressure, diabetes mellitus, metabolic disturbances at­risk’ kidney transplantations. Few immunosuppressants (such as high LDL cholesterol) and abnormalities in fluid targeted to B cells have, however, been available to control and electrolyte balance. The kidney is also very sensitive the antibody­mediated response. to injury by ischemia and reperfusion and by the use of New immunosuppressants are needed. These should nephrotoxic drugs. ideally be free from any nephrotoxic effects, be strong In the 1970s, immunosuppressants were not nephro­ enough to act on T­cell and B­cell pathways, interfere toxic (for example, azathioprine, steroids, anti lymphocyte with the immunological components of chronic graft globulins). The 1980s saw the introduction of a new nephropathy, and prevent or treat antibody­mediated generation of cyclic molecules that had anticalcineurin rejection. Many molecules have been newly selected for activity (for example, ciclosporin and macrolide anti­ drug development on the basis of their ability to affect biotics with strong inhibitory properties against T­cell activated T­cell pathways, but over the past 10 years, most activation, such as tacro limus). These drugs, which were of these have failed in clinical development. Agents that included in additive, multidrug, immuno suppressive can address the changing challenges of organ transplanta­ regimens, reduced acute allograft rejection rates and tion will, however, almost certainly become available. In markedly increased overall graft survival. Use of these this Review, we discuss the different drugs that have been drugs, however, notably increases the risk of chronic dys­ developed to remove allogenic T cells and other new com­ function, with immunological (chronic allograft rejec­ pounds that inhibit T­cell activation. We also report on tion) and nonimmuno logical (nephrotoxic effects from results obtained for agents that interfere with antibody­ calcineurin inhibitors) compo nents, which can lead to mediated rejection. The different agents are summarized irreversible graft failure and a return to dialysis. in Table 1 and the pathways are described in Figure 1. Nephrology and Transplantation Other phenomena also impact on the success rates of Department, Hopital renal transplantation. For example, organs from deceased Strategies to target T cells Bicetre, UMR U542 donors with extended criteria (that is, age >65 years, renal The use of agents to deplete T cells is only proposed for INSERM/University Paris-Sud XI, 78 Rue du grafts with reduced glomerular filtration rates, donors with the induction phase of transplantation. Although some Général Leclerc, Paris, risk factors for cardiovascular disease) are increasingly studies have highlighted benefits with such treatments, for France (A. Durrbach, H. Francois, transplanted, which has resulted in an increased risk of example prolonging survival of transplanted organs, their S. Beaudreuil, recipients developing chronic renal dysfunction. Moreover, long­term use is not recommended. Immunodepletion of A. Jacquet, B. Charpentier) the number of recipients who are immunized before trans­ alloreactive T cells during sequential immunosuppression plantation, such as through pregnancy, blood transfusions may be beneficial for graft outcome by avoiding initial Correspondence to: acute rejection. Noncontrolled use of T­cell­depleting B. Charpentier bernard.charpentier@ Competing interests agents is associated with several complica tions, such bct.aphp.fr The authors declare no competing interests. as infections and tumor development. For instance, 160 | MARCH 2010 | VOLUME 6 www.nature.com/nrneph © 2010 Macmillan Publishers Limited. All rights reserved nrneph_233_MAR10.indd 160 8/2/10 15:29:12 REVIEWS increasing numbers of tumors are reported in registries.1 Key points The development of tumors is a multifactorial event: ■ Allogenic organ transplantation is limited by drug-associated toxicity and the long­term exposure to immunosuppressants, the dura­ occurrence of antibody-mediated or chronic rejection tion of the trans plantation, patient’s age, the number of ■ Improved understanding of the molecular mechanisms of rejection has led to transplantations and genetic predisposition or epigenetic the development of agents that regulate T-cell function, complement activation factors can all influence the occurrence of tumors. The and/or the survival of plasma and B cells in immunized or naive patients use of depleting agents can, however, lower this risk and ■ These new agents may control acute, antibody-mediated rejection and chronic improve management. rejection to increase long-term renal transplantation outcomes ■ The safety of these new agents remains to be evaluated to ensure that they do Clonal deletion with alefacept not increase the risk of infections or tumor formation in transplanted patients Depletion of allogenic T cells by inducing apoptosis of activated T cells (clonal deletion) has emerged as a useful immunomodulatory strategy. Alefacept is a fusion protein Table 1 | Immunological effects of promising new immunosuppressants that binds to the immunological synapse­associated Inhibitory Target Molecule type Method of Main function protein CD2. CD2 is expressed on T cells and normally molecule administration interacts with lymphocyte­function­associated antigen­3 Alefacept CD2 Fusion protein Intravenous Deletion of activated (LFA­3) on antigen­presenting cells to participate in the T cells formation and stabilization of the immune synapse. Belatacept CD80 Fusion protein Intravenous Inhibition of the second LFA­3–CD2 signaling has important roles in the activa­ and signal of activation tion of memory–effector T cells, increased proliferative CD86 responses, and cytotoxic T­cell effector functions.2,3 By Sotrastaurin PKC Small molecule Oral Inhibition of PKC contrast, the use of paired antibodies or monoclonal anti­ CP-690,550 JAK-3 Small molecule Oral JAK-3 inhibitor bodies (mAbs) against CD2 prevents interaction with LFA Eculizumab C5 Antibody Intravenous Inhibition of complement and induces caspase­dependent and caspase­independent activation 4–9 apoptosis of alloreactive T cells. Use of monoclonal Bortezomib NFκB Small molecule Intravenous Depletion of plasmocytes 9 antibodies in mice prevents and treats acute rejection. and inhibition of NFκB Similarly, a human fusion protein, comprising the first Abbreviations: JAK, Janus kinase 3; NFκB, nuclear factor κB; PKC, protein kinase C. extracellular domain of LFA­3 fused to two constant domains of human IgG1, has been designed to prevent interaction between LFA­3 and CD2, and thus to interfere LFA­3–Ig. The modest decrease in lymphocyte count is with the activation of T cells.10–12 In addition, the IgG1 attributable to the selective depletion of memory T­cell domain can activate the complement cascade and inter­ levels without altering the number of naive T cells. acts with CD16 (Fc γ receptor type III) on natural killer Alefacept has also been used to treat chronic exten­ cells to induce granzyme­mediated apoptosis of memory sive graft­versus­host disease (cGVHD) in humans.16,17 T cells and/or, preferentially, alloreactive T cells.11 Among 12 patients with steroid­resistant cGVHD, Alefacept was initially developed to treat psoriasis, a eight (75%) responded to alefacept therapy. Six of the lymphocyte­dependent disease. In animal models this 12 patients were still alive more than 30 months after drug prevents psoriasis­like lesions. A randomized, therapy; the others died from progression of cGVHD. double­blind, placebo­controlled, multicenter, phase III Alefacept has also been shown to control cGVHD that study demonstrated that, compared with placebo, occurs after liver transplantation.17 These findings indi­ intravenous alefacept improved cutaneous lesions.13 cate that alefacept could be useful in the control of allo­ Intramuscular administration of this agent was also genic lymphocytes in transplantation and could be used associ ated with a dose­dependent reduction in memory