L.R. rejection have been reported, favored by the fact that cytotoxic T lymphocyte-associated protein pathway has an inhibitory effect on the Mollugin alloimmune response; thereby its inhibition is detrimental in this regard. This has led to the development of antibodies that target CD28. The most advanced is FR104, it has shown promise in nonhuman primate models of autoimmune diseases and allotransplantation. In addition, research into blocking the CD40-CD154 pathway is underway. A phase II study testing ASK1240, that is, anti-CD40 antibody has been completed, and the results are pending. Blockade of co-stimulation is obviously the most promising way to avoid calcineurin-inhbitors in organ transplantation. The authors highlight the most recent results obtained with drugs already available such as belatacept and give interesting insights regarding drugs to come such as anti-CD28 and anti-40L monoclonal antibodies. In organ transplant recipients, the cornerstone of immunosuppression relies on calcineurin inhibitors (CNIs), that is, cyclosporine A or tacrolimus. Since the publication of the Efficacy Limiting Toxicity Elimination (ELITE)-Symphony trial,1most kidney transplant centers have used tacrolimus as their first choice of CNI. However, CNIs are nephrotoxic, particularly when CNI trough levels are high for a long period, as demonstrated by Nankivell et al.2This CNI-related nephrotoxicity has prompted physicians to explore new classes of immunosuppressants that avoid nephrotoxicity, for example, mammalian target of rapamycin inhibitors and costimulation blockers. However, the use of mammalian target of rapamycin inhibitors has been limited because they have many other side effects,3,4they are less powerful than EYA1 CNIs at preventing acute rejection,1and a CNI-free immunosuppressive regimen can facilitate the formation of de novo donor-specific alloantibodies.5 A costimulation blockade could be an alternative, with the recent development and registration of a modified cytotoxic T lymphocyte-associated protein 4 (CTLA4)-Ig, that is, belatacept (Nulojix). This was demonstrated in 2 phase III randomized controlled trials that compared recipients of either kidneys from standard donors (belatacept evaluation of nephroprotection and efficacy as first-line immunosuppression [BENEFIT]) or kidneys from donors with expanded criteria (BENEFIT-EXT) and that had received belatacept-based immunosuppression or cyclosporine Abased immunosuppression.6,7In the BENEFIT study, the results at 7-year posttransplantation showed that, compared with cyclosporine A, belatacept (i) significantly reduced death and graft loss and (ii) significantly improved long-term renal function, thereby increasing the half-lives of transplanted kidneys.8,9Prediction models have shown that as compared with Cyclosporin A, belatacept-based immunosuppression in both studies increased on Mollugin average by 2 years kidney allograft half-lives.8 However, preventing cluster of differentiation (CD)28 access to its ligand using a CD80/86 (B7-1 and B7-2, respectively) antagonist, such as belatacept, was associated in phase III studies, especially the BENEFIT study, with high rates of acute rejection even though they were of mild grade and could be easily treated. This is the reason why selective targeting of CD28 to prevent its engagement with CD80/86, but not with CTLA-4 (CD152), may prevent maturation of deleterious effectors while also preserving regulatory T (Treg) cell function. Recent data from nonhuman primates indicate this. Finally, the blockade of the CD40/CD40L pathway may also be a useful approach, although few data are available from humans. == Targeting Costimulation Pathways == Linsley et al10described, in 1990, the CD28 molecule on T lymphocytes (T cells) and its corresponding ligand on antigen-presenting cells (APCs), that is, CD80/CD86. The CTLA-4 was identified in 1987 on activated cytotoxic T lymphocytes,11but it was not until 1991 that it was shown that both CD28 and CTLA-4 share the same ligand on APCs12; however, CTLA-4 binds to its ligand with a much higher avidity than does CD28. In 1995, it was shown that CTLA-4 had a negative regulatory effect on T cell activation.13 The CD28 molecule is constitutively expressed on naive T cells and provides, besides T cell receptor-generated signal 1, a costimulation signal that is crucial for T cell proliferation via IL-2 secretion and for survival via Bcl2-Bclx. In addition, CD28 lowers the T cell activation threshold, that is, the number of interactions between the T cell receptor and the major histocompatibility complexbound presented peptides are lowered to activate T cells.14Upon T cell activation, CTLA-4 becomes rapidly expressed on T cell surfaces, delivering its inhibitory signal and Mollugin thereby decreasing.