Therapeutic induction of antigen-specific immune tolerance

Abstract

The development of therapeutic approaches for the induction of robust, long-lasting and antigen-specific immune tolerance remains an important unmet clinical need for the management of autoimmunity, allergy, organ transplantation and gene therapy. Recent breakthroughs in our understanding of immune tolerance mechanisms have opened new research avenues and therapeutic opportunities in this area. Here, we review mechanisms of immune tolerance and novel methods for its therapeutic induction.

Fig. 1 ∣. Mechanisms and features in pro-inflammatory dendritic cells compared with tolerogenic dendritic cells.

Pro-inflammatory dendritic cells (DCs) can be induced via activation by pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) and upregulate the expression of surface molecules including MHC molecules, CD80 and CD86. These surface molecules, in addition to secreted pro-inflammatory cytokines, such as IL-1β, IL-6, IL-12, IL-23, tumour necrosis factor (TNF) and type I interferons, induce the differentiation of cytotoxic and effector T cells from naive T cells. Conversely, tolerogenic DCs can be induced via several mechanisms, including exposure to cytokines such as IL-10, IL-27, IL-35, IL-37 or transforming growth factor-β (TGFβ); signalling via Toll-like receptor 2 (TLR2), TLR4 or aryl hydrocarbon receptor (AHR); or exposure to molecules such as vitamin D3, vitamin A or lactate. Tolerogenic DCs express lower levels of MHC molecules, CD80 and CD86 and secrete anti-inflammatory cytokines and molecules such as IL-10, TGFβ, IL-27, indoleamine 2,3-dioxygenase (IDO) and retinoic acid. Tolerogenic DC interactions with T cells induce the differentiation and expansion of anti-inflammatory regulatory T cells (T_reg cells) from naive T cells and the apoptosis of cytotoxic T cells through death receptor signalling interactions, such as between programmed cell death 1 (PD1) and PD1 ligand 1 (PD-L1) or PD-L2. CTLA4, cytotoxic T lymphocyte associated protein 4; TCR, T cell receptor.

Fig. 2 ∣. Approaches for the induction of antigen-specific immune tolerance.

Cell-based approaches include the ex vivo induction of tolerogenic dendritic cells (DCs), apoptotic cells or regulatory T cells engineered to express chimeric antigen receptors (CAR T_reg cells), all of which can be designed to deliver antigen with or without an immunomodulatory signal. Viral particle approaches include the delivery of DNA-encoded or RNA-encoded antigen via adenoviruses, lentiviruses or plant viruses. Synthetic particles, including metallic, polymeric, lipid-based (including liposomes or lipid nanoparticles), peptide–polymer, dendrimer or polyelectrolyte particles, can be designed to co-deliver antigens, antibodies and immunomodulators, in various combinations. Alternatively, antigens can be delivered via toxin-bound MHC molecules to induce the death of antigen-specific cells, and albumin, antibodies or nanoemulsions can deliver antigens and immunomodulators to induce antigen-specific immune tolerance. FASL, FAS ligand; PEG, polyethylene glycol.

Fig. 3 ∣. Mechanisms for the induction of antigen-specific immune tolerance.

Tolerogenic antigen-specific antigen-presenting cells (APCs) can be induced in vivo through the delivery of synthetic particles, viral particles or cell-based approaches, or induced in vitro and engineered to express disease-specific antigens and an immunomodulatory signal. Tolerogenic APCs are characterized by reduced expression of pro-inflammatory markers including CD80, CD86 and CD40 and an increased expression or production of tolerogenic molecules such as IL-10, FAS ligand (FASL), programmed cell death ligand 1 (PD-L1) and prostaglandin E₂ (PGE2). Tolerogenic APCs can in turn induce naive CD4⁺ T cells to differentiate into regulatory T (T_reg) cells or can induce effector T cell anergy and ablation. Similarly, the induction of regulatory B (B_reg) cells via synthetic particle administration or T_reg cells via in vivo delivery of particles or in vitro engineering of chimeric antigen receptor (CAR) T_reg cells results in the reduction of effector T cells by the induction of anergy or cell death. PEG, polyethylene glycol.