Tempering allorecognition to induce transplant tolerance with chemically modified apoptotic donor cells

Abstract

The development of organ transplantation as a therapy for end-stage organ failure is among the most significant achievements of 20th century medicine, but chronic rejection remains a barrier to achieving long-term success. Current therapeutic regimens consist of immunosuppressive drugs that are efficient at delaying rejection but are associated with significant risks such as opportunistic infections, toxicity, and malignancy. Thus, the induction of specific immune tolerance to transplant antigens is the coveted aim of researchers. The use of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (ECDI)-treated, autoantigen-coupled syngeneic leukocytes has been developed as a specific immunotherapy in preclinical models of autoimmunity and is currently in a phase II clinical trial for the treatment of multiple sclerosis. In this review, we discuss the use of allogeneic ECDI-treated apoptotic donor leukocytes (allo-ECDI-SP) as a strategy for inducing antigen-specific tolerance in allogeneic transplantation. Allo-ECDI-SP therapy induces long-term systemic immune tolerance to transplant antigens by subverting alloimmune recognition and exploiting apoptotic cell uptake pathways to recapitulate innate mechanisms of peripheral tolerance. Lastly, we discuss potential indications and challenges for transitioning allo-ECDI-SP therapy into clinical practice.

Keywords: Basic (laboratory) research/science; T cell biology; cell death: apoptosis; dendritic cell; immunobiology; islet transplantation; tolerance; translational research/science.

Figure 1. Proposed mechanisms of Allo-ECDI-SP tolerance

Innate immune responses are required for allo-ECDI-SP tolerance induction. The splenic marginal zone is the primary interface between the splenic non-lymphoid compartment and the lymphoid compartment. It is composed of B cells and macrophages important for capturing exogenous Ags and debris, which may be processed for subsequent presentation to T cells in T cell zones. For efficient tolerance, allo-ECDI-SP must be delivered (1) via i.v. administration. Once within the marginal sinus, the ECDI-SP rapidly degrade via apoptotic pathways (2), with debris and cells recognized and rapidly taken up via scavenger receptors on MZMs and DCs either directly from the marginal zone sinus or via membrane transfer. The uptake of allo-ECDI-SP triggers the production and secretion of soluble mediators including IL-10 and TGF-β, which have multifarious functions including the regulation of costimulatory molecules, such as PD-L1, on APCs (3). The immunoregulatory milieu provided by the MZM response to the apoptotic allo-ECDI-SP conditions DCs to present antigen to T cells in the context of low CD80/CD86 expression and increased PD-L1 expression, thereby favoring costimulation through the inhibitory receptors such as CTLA-4 and PD-1 (4). T cells of the indirect allorecognition pathway recognizing cognate peptide/MHC ligands on host APCs undergo deletion in this context (4), while T cells directly engaging peptide/MHC ligands on allo-ECDI-SP become anergic (5). Regulatory T cells of the Foxp3⁺ lineage expand in the presence of TGF-β to inhibit further priming in the secondary lymphoid organs and effector responses in the transplanted tissue (6).