Costimulation Blockade in Kidney Transplant Recipients

Abstract

Costimulation between T cells and antigen-presenting cells is essential for the regulation of an effective alloimmune response and is not targeted with the conventional immunosuppressive therapy after kidney transplantation. Costimulation blockade therapy with biologicals allows precise targeting of the immune response but without non-immune adverse events. Multiple costimulation blockade approaches have been developed that inhibit the alloimmune response in kidney transplant recipients with varying degrees of success. Belatacept, an immunosuppressive drug that selectively targets the CD28-CD80/CD86 pathway, is the only costimulation blockade therapy that is currently approved for kidney transplant recipients. In the last decade, belatacept therapy has been shown to be a promising therapy in subgroups of kidney transplant recipients; however, the widespread use of belatacept has been tempered by an increased risk of acute kidney transplant rejection. The purpose of this review is to provide an overview of the costimulation blockade therapies that are currently in use or being developed for kidney transplant indications.

Fig. 1

Costimulation between T cells and antigen-presenting cells. Schematic overview of signal 1, 2 and 3 of T-cell activation. During signal 2, costimulatory molecules on T cells and antigen-presenting cells interact to activate or inhibit T cells after alloantigen recognition. Two important groups of costimulatory molecules are presented: the immunoglobulin superfamily and the TNF/TNFR superfamily. The costimulatory molecules discussed in this review are green and the costimulatory molecules that are not discussed are yellow. Several biologicals are developed that interfere with the costimulatory molecules on T cells and antigen-presenting cells. CTLA 4 cytotoxic T lymphocyte protein 4, HLA human leucocyte antigen, ICOS inducible T-cell costimulator, PD programmed death, SLAM signaling lymphocytic activation molecule, TCR T-cell receptor, TIM T cell/transmembrane, immunoglobulin, and mucin, TNF tumor necrosis factor, TNFR tumor necrosis factor receptor

Fig. 2

Timeline of the development of costimulation blockade. The costimulation blockade drugs that are currently used or tested in kidney transplant recipients are shown in black, whereas the costimulation blockade drugs that are no longer being used or have not developed for kidney transplantation are shown in grey. EMA European Medicines Agency, FDA United States Food and Drug Administration, FR104 pegylated monoclonal antibody fragment antagonist of CD28, TGN1412 CD28 humanized antibody

Fig. 3

Future directions for belatacept treatment in kidney transplant recipients. A more tailored approach in the selection, treatment strategy, and postconversion monitoring might be a way to expand the use of belatacept in kidney transplant recipients. AR acute kidney transplant rejection, CNI calcineurin inhibitors, DGF delayed graft function, DM diabetes mellitus, DSA donor-specific anti-HLA antibodies, EBV Epstein–Barr virus, HLA human leucocyte antigen, MPA mycophenolic acid, mTOR mammalian target of rapamycin, PD-1 programmed death-1, PRA panel reactive antigens, TAC tacrolimus, Th17 T helper 17, TMA thrombotic microangiopathy, Treg regulatory T cells