Tolerogenic therapies in transplantation

Abstract

Since the concept of immunologic tolerance was discovered in the 1940s, the pursuit of tolerance induction in human transplantation has led to a rapid development of pharmacologic and biologic agents. Short-term graft survival remains an all-time high, but successful withdrawal of immunosuppression to achieve operational tolerance rarely occurs outside of liver transplantation. Collaborative efforts through the NIH sponsored Immune Tolerance Network and the European Commission sponsored Reprogramming the Immune System for Establishment of Tolerance consortia have afforded researchers opportunity to evaluate the safety and efficacy of tolerogenic strategies, investigate mechanisms of tolerance, and identify molecular and genetic markers that distinguish the tolerance phenotype. In this article, we review traditional and novel approaches to inducing tolerance for organ transplantation, with an emphasis on their translation into clinical trials.

Keywords: B cell therapeutics; T cell depletion; cellular therapies; costimulation blockade; mixed chimerism; regulatory T cells; tolerance; transplantation.

FIGURE 1

Approaches to transplant tolerance induction. (Top left) Mixed chimerism is achieved by infusing donor bone marrow into myelo-conditioned recipients, to establish co-existence of donor and recipient cells in the setting of organ transplantation. The dotted arrows indicate cell types originating from the bone marrow, unrelated to mixed chimerism. (Top right) Allospecific T cell responses can be abrogated through a number of mechanisms, including irradiation, pharmacologic lymphodepletion by ATG or alemtuzumab, suppression of activation by costimulation blockade or IL-2 receptor blockade. (Bottom right) Tolerogenic cell types, including regulatory T cells, macrophages, and mesenchymal stromal cells, can inhibit effector T cells through direct ligation or inhibitory cytokine production. (Bottom left) The humoral response can be suppressed through B cell depletion, and blockade of survival factors (BAFF), plasma cells, and complement.