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Review
. 2018 Mar 21;29(3):719-732.
doi: 10.1021/acs.bioconjchem.7b00632. Epub 2017 Dec 6.

Bioconjugate Strategies for the Induction of Antigen-Specific Tolerance in Autoimmune Diseases

Chunsong Yu  1 , Jingchao Xi  1 , Meng Li  1 , Myunggi An  1 , Haipeng Liu  1   2   3
Affiliations
Review

Bioconjugate Strategies for the Induction of Antigen-Specific Tolerance in Autoimmune Diseases

Chunsong Yu et al. Bioconjug Chem. .

Abstract

Antigen-specific immunotherapy (ASI) holds great promise for the treatment of autoimmune diseases. In mice, administration of major histocompatibility complex (MHC) binding synthetic peptides which modulate T cell receptor (TCR) signaling under subimmunogenic conditions induces selective tolerance without suppressing the global immune responses. However, clinical translation has yielded limited success. It has become apparent that the TCR signaling pathway via synthetic peptide antigen alone is inadequate to induce an effective tolerogenic immunity in autoimmune diseases. Bioconjugate strategies combining additional immunomodulatory functions with TCR signaling can amplify the antigen-specific immune tolerance and possibly lead to the development of new treatments in autoimmune diseases. In this review, we provide a summary of recent advances in the development of bioconjugates to achieve antigen-specific immune tolerance in vivo, with the discussion focused on the underlying design principles and challenges that must be overcome to target these therapies to patients suffering from autoimmune diseases.

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Figures

Figure 1.
Figure 1.
Bioconjugate-based strategies for the induction of antigen-specific tolerance in autoimmune diseases. Bioconjugates have been engineered to target autoantigens and tolerogenic molecules to dendritic cells (DCs) (1); to facilitate antigen-processing via endocytic receptors (2); to inhibit costimulation (3); to link to apoptotic cells for tolerogenic presentation (4); and to deliver toxin to autoantigen-specific T cells (5). These strategies lead to peripheral tolerance as results of anergy and deletion of cognate T cells, or induction of Tregs.
Figure 2.
Figure 2.
Induction of adaptive immune responses. DCs and B cells acquire antigens and in the presence of inflammatory cues (costimulatory signals), activate T- and B-cells. Activated CD4+ T cells differentiate into T helper cell subtypes and CD8+ T cells differentiate into cytotoxic T effector cells. In parallel, activated B cells differentiate into antibody-producing plasma cells.
Figure 3.
Figure 3.
Central and peripheral tolerance mechanisms in T cells and B cells. Central tolerance occurs in the primary lymphoid organs where high-affinity self-reactive T cells and B cells are deleted in the thymus and bone marrow (negative selection), respectively. Peripheral tolerance occurs as mature self-reactive T cells and B cells escape central tolerance and enter the periphery, where they are inactivated (anergy), deleted (activation induced cell death, ACID), or suppressed.
Figure 4.
Figure 4.
Antigen delivered via DEC-205 enhances antigen presentation. (A) Anti-DEC-205, but not anti-MMR (Macrophage Mannose Receptor), is internalized by receptor-mediated endocytosis, and traffics to late endosomalcompartments where high concentrations of MHC II molecules are present. (B and C) Antigen delivered via anti-DEC-205 greatly enhances its presentation to T cells. Reproduced with permission from ref 57.
Figure 5.
Figure 5.
Tolerogenic NPs for antigen-specific immunotherapy. Schematic representation of antigen (MOG35–55) and AhR ligand (ITE) conjugated gold NPs (A) and NPs coated with peptides bound to MHC class II (B). Reproduced with permission from ref 102 (A).
Figure 6.
Figure 6.
Proposed mechanism of action of bifunctional peptide inhibitor (BPI). BPI prevents the formation of immunological synapse by binding to MHC-II and ICAM-1 on the surface of APC, which leads to inhibition of T cell activation. (A) Around the central zone, LFA-1/ICAM-1 and TCR/MHC-antigen complexes are first formed at the early stage of T cell activation; (B) both pairs are translocated to form complete immunological synapse. (C) In the presence of BPI, BPI binds to MHC-II and ICAM-1 on the surface of APC; (D) it inhibits their migration, which leads to inhibition of the immunological synapse formation. Reproduced with permission from ref 115.
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