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Finding the right immunosuppressive approach for the individual transplant patient is of utmost importance. In truth, a ‘one size fits all’ does not exist, and as patients differ, so should therapeutic suppression of the immune system be individualized. For over three decades, biologics have been a central component of transplant immunosuppression. Our growing knowledge of immunological processes combined with biotechnological advances is leading to promising new therapeutic concepts and possibilities including novel biologics. Use of biologics may be appropriate at various phases of kidney transplantation, from desensitization and induction to maintenance therapy and management of acute rejection. Their mechanisms of action include depleting or modulating immune cells, eliminating preformed antibodies, and inhibiting the complement system. Herein, we summarize the current approaches to applying ‘established’ biologics to prevent and treat allograft rejection in kidney transplantation. We also provide insights into new developments and possible future directions.A number of candidate biologics were found to be efficacious in more recent preclinical and early phase clinical trials. Their properties are outlined and their potential for future utilization discussed.The extraordinary capabilities of biologics are undisputed and our technological progress offers unprecedented opportunities to devise new agents and refine old ones. However, the rationale for their use in kidney allograft recipients must be rigorously examined in every case and, given the significant risk of early and late-onset adverse effects, the risk-to-benefit ratio carefully balanced. We also need to expand and use our knowledge of the underlying physiology of allograft rejection to adjust the characteristics of therapeutic biologics and thus harness their full potential for the benefit of our patients.