**8.2. Proteasome inhibitors**

Proteasome nonselective inhibitors prevent the antibody-mediated AR of the graft. However, adverse effects outweigh the benefits by limiting their application in clinical practice. Up till now, the inhibition of immunoproteasomes is effective in experimental models in the context of autoimmune diseases being used for several weeks of treatment, without significant side effects. The ONX 0914, a selective proteasome inhibitor (B5i) of the LMP7 subunit, prevents chronic rejection in allogenic kidneys transplanted in rodents. The selective inhibition of immunoproteasomes by ONX 0914 and bortezomib reduces the number of plasma cells and B lymphocytes, and suppresses the formation of donor-specific antibodies in transplanted organs.

In renal grafts, T lymphocyte, B lymphocyte, and macrophage infiltration is reduced, as well as the complement deposit, interferon-γ, interleukin-17, and IgG [99].

Several series of cases have shown the efficacy of bortezomib in reversing the severe antibody-mediated rejection, establishing the maintenance therapy in posttransplant patients, and has even been used as a desensitization treatment in recipients with a positive cross test considered highly sensitized with satisfactory results; formulating guidelines to establish strategies for adjusting immunosuppression in long-term RT recipients. However, there are contradictory results. The BORTEJECT study [100] used bortezomib as a treatment for late antibody-mediated AR in 44 patients, with a follow- up of 3 years, with immunosuppression based on imTOR or CNI, with MMF 1–2 g/day and PDN, without finding a significant difference in the incidence of AR and renal function compared with placebo. Therefore, studies that evaluate the use of the drug in the induction and maintenance of immunosuppression are necessary to allow the minimization or optimization of the therapy used in selected cases (**Table 1**).

#### **8.3. Belatacept**

Belatacept (CTLA-4 Ig fusion protein) is a new drug with a mechanism of action that allows CNI-free maintained immunosuppression. Clinical studies show a higher incidence of T cellmediated AR in the first 6 months after transplantation, but show better long-term renal graft function. Likewise, the use of belatacept shows a lower incidence of DSA formation and less graft damage compared to the use of CsA. The most relevant adverse reactions include: herpes virus infections, tuberculosis, and a higher frequency of posttransplant lymphoproliferative disorders.

Belatacept has not yet been compared to a TAC/MMF-based regimen, considered the immunosuppression maintenance standard in RT.

The current immunosuppressive treatment, far from being perfect, has contributed to the overall improvement of the renal graft and patient survival, which contributes to overcoming the barrier for the development of new therapeutic agents. Consequently, most of the new drugs have failed in the course of transplantation, including janus kinase inhibitors (tofacitinib), sphingosine-1-phosphate receptor modulator (FTY720, fingolimod), protein kinase C inhibitor (sotrastaurin, AEB), inhibitors of adhesion anti-LFA-1 molecules (efalizumab), anti-ICAM-1, and the first generation of anti-CD40-ligand. Most of the current treatments, still in research and focused on the immunology of the transplant, are biological or cell-based treatments. The blocking of co-stimulation with the purpose to prevent T cell activation remains a point of interest. The ASKP1240, an anti-CD40 monoclonal antibody, has recently been tested in immunosuppression minimization regimens based on CNI dose reduction or suspension, compared to a control group based on standard dose TAC, finding higher AR and infection rates in the group treated with anti-CD40, so the future of this drug remains uncertain. More recently, CFZ533, a fully humanized monoclonal antibody has shown efficacy in primates, and clinical research is being initiated in humans (**Table 1**) [101].
