Induction and Maintenance Immunosuppressants in Sensitized Renal Allograft Recipients

Abstract

Induction and maintenance immunosuppression for sensitized allograft recipients having immune memory cells should be different from those for standard/low-immunologic risk patients, as memory cells elicit immunologic recall responses that can result in early and often severe antibody-mediated rejection. The peri-transplant period, when donor-specific T and B memory cells rapidly expand in response to antigen (allograft) challenge, appears to be a unique window of chance to reduce the size of donor-specific clones more selectively by cell-depleting induction agents. Induction with antithymocyte globulin has been shown to reduce the incidence of antibody-mediated rejection in sensitized kidney transplant recipients. It predominantly depletes T cells but it also has immune modulatory effects on other cell lineages such as dendritic cells, and interferes with the generation of plasmablasts by blocking T cell help. Plasmablasts rapidly proliferate during the early posttransplant period by immunologic recall response in sensitized patients. Because these cells retain CD20 on the cell surface and are susceptible to rituximab-induced cytolysis, induction with rituximab can be a valuable tool for depletion of donor-specific plasma cell precursors in sensitized patients. Bortezomib is a nonspecific inhibitor of proteasome and can induce apoptosis of actively dividing and immunoglobulin-producing cells, such as plasmablasts. It has been suggested that long-lived plasmacytes are resistant to bortezomib-induced cytolysis, while young plasmablasts are more susceptible. Thus, bortezomib may also have a role as an induction agent in sensitized patients. One, or a combination of two or more, of these drugs can be used for induction in sensitized renal allograft recipients. Currently available literature indicates that the tacrolimus-based triple regimen including mycophenolate and prednisolone is the most appropriate maintenance immunosuppression for sensitized patients, and that the overall potency of immunosuppression including the tacrolimus drug-level should be appropriately maintained, as both the incidence of immunologic rejection and patient loss secondary to over-immunosuppression is higher in these patients.