Exploiting apoptosis for therapeutic tolerance induction

Abstract

Immune tolerance remains the most promising yet elusive strategy for treating immune-mediated diseases. An experimental strategy showing promise in phase 1 clinical studies is the delivery of Ag cross-linked to apoptotic leukocytes using ethylene carbodiimide. This approach originated from demonstration of the profound tolerance-inducing ability of i.v. administered Ag-coupled splenocytes (Ag-SP) in mice, which has been demonstrated to treat T cell-mediated disorders including autoimmunity, allergy, and transplant rejection. Recent studies have defined the intricate interplay between the innate and adaptive immune systems in Ag-SP tolerance induction. Innate mechanisms include scavenger receptor-mediated uptake of Ag-SP by host APCs, Ag representation, and the required upregulation of PD-L1 expression and IL-10 production by splenic marginal zone macrophages leading to Ag-specific T cell regulation via the combined effects of cell-intrinsic anergy and regulatory T cell induction. In this paper, we discuss the history, advantages, current mechanistic understanding, and clinical potential of tolerance induction using apoptotic Ag-coupled apoptotic leukocytes.

Fig 1. Proposed Mechanisms of Ag-SP Tolerance

A. Innate Immune Responses Required for Ag-SP Tolerance Induction The splenic marginal zone is the primary interface between the splenic non-lymphoid compartment and the lymphoid. It is comprised of B cells and macrophages important for capturing exogenous antigens and debris, which may be processed for subsequent presentation to T cells in T cell zones. For efficient tolerance, Ag-SP must be delivered (1) via intravenous administration. Once within the marginal sinus the Ag-SP rapidly degrade via apoptotic pathways (2), with debris and cells recognized and rapidly taken up via scavenger receptors on marginal zone macrophages. Dendritic cells may take up antigen directly from the marginal zone sinus, or via membrane transfer (3). The uptake of Ag-SP triggers the production and secretion of soluble mediators including IL-10 and TGF-β (4), which have multifarious functions including the regulation of co-stimulatory molecules, such as PD-L1, on APCs (5). B. Mechanisms of Ag-SP-Induced T Cell Regulation. Ag-SP tolerance is the result of a number of independent, but overlapping regulatory mechanisms. The upregulation of negative co-stimulatory molecules on APC, including CTLA-4 and PD-L1, can trigger effector cell anergy and apoptosis (6). In the context of naive T cells, T cell receptor stimulation (Signal 1), without positive co-stimulation results in T cell anergy (7). In addition, IL-10/TGF-β secreted in response to Ag-SP infusion supports the differentiation of naïve T cells into Tr1 and/or iT_REGS(8). While the precise temporal contribution of each regulatory mechanism requires further examination, it seems that tolerance is the result of early anergy, with T_REGS playing a major role in long-term tolerance maintenance.