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Antigen-specific tolerance strategies for the prevention and treatment of autoimmune disease

Nature Reviews Immunology volume 7, pages 665–677 (2007)Cite this article

Key Points

  • The development of antigen-specific therapies for the treatment of autoimmune disease will allow for the tolerization of autoreactive immune cells, while maintaining the ability of the host's immune system to recognize foreign antigen.

  • Human trials are often designed to parallel experiences in animal models of the disease; however, the transition between outcomes in experimental animal models and human trials is often not straight forward.

  • There are currently four different protocols employed for inducing peptide-specific immune tolerance — soluble-peptide-induced and DNA-vaccination-induced tolerance, mucosal (oral or nasal)-induced tolerance, coupled-cell-induced tolerance, and altered peptide ligand (APL)-induced tolerance — that work by various different mechanisms.

  • Three of the protocols for the induction of antigen-specific tolerance have been tested in initial clinical trails: soluble-peptide-induced and DNA-vaccination-induced tolerance, mucosal (oral or nasal)-induced tolerance and APL-induced tolerance.

  • A Phase I and II clinical trial has been awarded provisional support by the Immune Tolerance Network pending US Food and Drug Administration (FDA) approval, to test the safety and efficacy of antigen-coupled-cell-induced tolerance in early relapsing–remitting MS.

  • The clinical efficacy of antigen- or peptide-specific immunotherapies for the treatment of pre-existing autoimmune disease is still uncertain.

Abstract

The development of safe and effective antigen-specific therapies is needed to treat patients with autoimmune diseases. These therapies must allow for the specific tolerization of self-reactive immune cells without altering host immunity to infectious insults. Experimental models and clinical trials for the treatment of autoimmune disease have identified putative mechanisms by which antigen-specific therapies induce tolerance. Although advances have been made in the development of efficient antigen-specific therapies, translating these therapies from bench to bedside has remained difficult. Here, we discuss the recent advances in our understanding of antigen-specific therapies for the treatment of autoimmune diseases.

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Figure 1: CD4+ T-cell activation and tolerogenic strategies.
Figure 2: Proposed mechanisms of peptide-induced tolerance.
Figure 3: Epitope spreading.
Figure 4: Signal transduction pathways involved in T-cell anergy.

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Acknowledgements

Work in the Miller laboratory is supported by National Institutes of Health, USA, Grants P01 NS-030871, R01 NS-026543, R01 NS-030871; R01 NS-040460, R01 NS-048411; National Multiple Sclerosis Society Grants RG-3489, RG-3546, RG-3793, RG-3965; and a grant from the Myelin Repair Foundation.

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  1. Department of Microbiology–Immunology and Interdepartmental Immunobiology Center, Northwestern University Feinberg School of Medicine, Chicago, 60611, Illinois, USA

    Stephen D. Miller, Danielle M. Turley & Joseph R. Podojil

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  1. Stephen D. Miller
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Correspondence to Stephen D. Miller.

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Immune Tolerance Network

Glossary

Adjuvant

An agent mixed with an antigen that increases the immune response to that antigen after immunization.

Altered-peptide ligands

(APLs). APLs are peptide analogues that are derived from the original antigenic peptide. They commonly have amino-acid substitutions at T-cell receptor (TCR)-contact residues. TCR engagement by these APLs usually leads to partial or incomplete T-cell activation. Antagonistic APLs can specifically antagonize and inhibit T-cell activation that is induced by the wild-type antigenic peptide.

Anergy

A state of unresponsiveness to antigen. Anergic T cells or B cells cannot respond to their cognate antigens under optimal conditions of stimulation.

Activation-induced cell death

(AICD). A form of regulated cell death, which is induced during lymphocyte activation. During a normal immune response, most antigen-specific lymphocytes undergo AICD.

Anaphylaxis

Severe and rapid allergic reaction triggered by the activation of high-affinity Fc receptors for IgE in sensitized individuals. An anaphylactic shock is the most severe type of anaphylaxis and will usually lead to an individual's death in minutes if left untreated.

Central tolerance

The lack of self-responsiveness that occurs as lymphocytes develop. It is associated with the deletion of autoreactive clones. For T cells, this occurs in the thymus.

Bystander suppression

The extension of tolerogen-induced suppression of immune responses that are directed against antigens not structurally related to the tolerogen but expressed by the same target cell or organ.

Epitope spreading

The de novo activation of autoreactive T cells by self-antigens that have been released after T-cell or B-cell-mediated bystander tissue damage.

TH3 cells

A CD4+ helper T-cell subset that is characterized phenotypically by the secretion of TGFβ.

Gadolinium-enhanced magnetic resonance imaging

An imaging technique in which gadolinium is introduced as a contrast agent, allowing short data-acquisition times, large anatomical coverage and improved image quality.

E3 ubiquitin ligase

An enzyme that is required to attach the molecular tag ubiquitin to proteins. Depending on the position and number of ubiquitin molecules that are attached, the ubiquitin tag can target proteins for degradation in the proteasomal complex, sort them to specific subcellular compartments or modify their biological activity.

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Miller, S., Turley, D. & Podojil, J. Antigen-specific tolerance strategies for the prevention and treatment of autoimmune disease. Nat Rev Immunol 7, 665–677 (2007). https://doi.org/10.1038/nri2153

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