REGiMMUNE Corporation announced that the American Journal of Transplantation (AJT) has published its paper that describes a novel approach to long-term tolerance in organ transplantation with continuous administration of immune suppressants. “A Novel Approach Inducing Transplant Tolerance by Activated Invariant Natural Killer T Cells with Costimulatory Blockade” was published in the AJT March 2014 Issue 3, Volume 14, pages 554-567, and was first made available online as an early view.
Robust, lifelong, donor-specific tolerance can be reliably achieved by induction of mixed chimerism in various animal models of bone transplantation. To date, the clinical application of these protocols has been impeded by the potential toxicity of the required host conditioning regimens. The REGiMMUNE paper describes the potential of a novel approach using a ligand (alpha-GalCer(aGC) for iNKT cells and suboptimal dosage of antibody for that blocks CD40:CD40L signaling as a powerful method to generate mixed chimerism. The data suggest a new insight – that the immune direction of iNKT cells is controlled through a type of APC presenting a-GalCer and costimulation signals, and that it is possible to enhance the innate ability of immune tolerance by appropriate activation of iNKT cells.
REGiMMUNE chief executive officer Haru Morita commented, “We hope that by using our regimen described in the AJT paper, transplant tolerance without continuous administration of immune suppressants might be achieved for solid organ transplantation.”
Mechanistic studies of this combination treatment revealed a synergistic expansion of tolerogenic dendritic cells (plasmacytoid dendritic cells) that results in the downstream increase of regulatory T cells. When CD8 T cells of mixed-chimera mice were functionally examined, they were found to be hypo-responsive to allogenic re-stimulation to either donor or host antigens. With mixed chimerism established, mice were able to successful accept cardiac transplants with long-term and durable tolerance. This combination therapy of aGC liposome with CD40/40L blockades offers great promise and another approach to induce solid organ transplant tolerance that may be long lasting.