Future Immunosuppression in Organ Transplantation: Treating the Innate Immune System of the Deceased Donor—Start Tomorrow

Abstract

This article, based in part on an invited talk at the Annual International Conference of Saudi Society of Nephrology & Transplantation in 2012, reviews current notions of the emerging field of innate alloimmunity by highlighting novel thoughts regarding future immunosuppressive therapy in organ transplantation. In light of new insights into the mechanisms of innate immunity on one hand and the essential role of regulatory T cells in controlling alloimmune responses on the other hand, potential clinical tools to generate tolerogenic dendritic cells are explored. These cells have been shown to promote induction of regulatory T cells that possess the potential to prevent acute and chronic allograft rejection. Experimental findings from both research areas are discussed in support of the notion that presentation of alloantigens under sub­immunogenic noninflammatory conditions, achieved by vigorous inhibition of oxidative injury-induced allograft inflammation (known to occur in both the deceased donor and the recipient during allograft reperfusion), may lead to the induction of tolerogenic dendritic cells-mediated regulatory T cells, thereby offering a realistic opportunity to induce allotolerance in transplant recipients. However, before planning clinical trials in recipients, the start of such a novel therapeutic strategy to prevent allograft rejection could consist of designing and performing a quadruple drug treatment of deceased (brain-dead) donors aimed at generating donor-derived tolerogenic dendritic cells. The combination use of (1) an antioxidant, (2) a complement-inhibiting agent, (3) an IL-1β inhibitor, and (4) a polyclonal antilymphocytic preparation is recommended as the preferred choice of such a donor treatment. If proven successful in organ donors, similar therapeutic modalities should subsequently be considered to apply to the recipient during allograft reperfusion under strict study conditions.