**8.4. Belimumab**

The therapeutic effect of alemtuzumab is not different from the immunological induction with thymoglobulin in the areas of AR incidence, delayed graft function, CMV infection,

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

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

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 lymphoprolifera-

Belatacept has not yet been compared to a TAC/MMF-based regimen, considered the immu-

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

development of NODAT, and use of granulocyte colony stimulant [98].

364 Organ Donation and Transplantation - Current Status and Future Challenges

as the complement deposit, interferon-γ, interleukin-17, and IgG [99].

**8.2. Proteasome inhibitors**

selected cases (**Table 1**).

**8.3. Belatacept**

tive disorders.

nosuppression maintenance standard in RT.

Belimumab (human monoclonal antibody that inhibits B cell activating factor), approved for treatment in systemic lupus erythematosus (SLE), is in use in early-stage clinical studies for the prevention of antibody-mediated RA, as well as in patients sensitized with low titers of anti-donor-specific antibodies.

Cellular therapies represent an innovative therapeutic objective for the maintenance of longterm renal graft, and thus avoidance of adverse reactions related to the maintenance of immunosuppression. The premise of cell therapy is the induction of donor-specific nonresponse in the context of operational tolerance or mixed chimerism (**Table 1**) [100].

A single center study evaluated the autologous use of mesenchymal progenitor cells instead of the antibody-based induction with schemes based on low and high doses of CNI, comparing induction with basiliximab and standard maintenance with MMF-CNI. The induction of autologous mesenchymal progenitor cells resulted in a lower AR rate, a decrease in opportunistic infections, and better renal graft function 1 year after transplantation, concluding with conventional immunosuppressive maintenance [102].

Another study was carried out in hematopoietic progenitor cells transplant with HLA concordant kidney donors in adjunct with total lymphoid radiation and thymoglobulin, which resulted in persistent mixed chimerism with stable renal graft function and removal of all immunosuppressants in 50% of the patients (**Table 1**) [103].

The most recently used strategies include the use of a product based on hematopoietic stem cells "facilitating cells" co-administered with nonmyeloablative reconditioning in living donor kidney graft recipients, reaching, in five out of eight patients, a satisfactory donorchimerism with successful immunosuppression maintenance withdrawal without evidence of AR or graft-versus-host disease [104].

The results of the previous studies, although very encouraging, should be validated in larger multi-centric controlled and randomized studies, from the safety-efficacy and cost–benefit points of view, compared with conventional immunosuppression therapy.
