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Antigen-specific immunotherapies in rheumatic diseases

Nature Reviews Rheumatology volume 13, pages 525–537 (2017)Cite this article

Subjects

Key Points

  • The main goal of antigen-specific immunotherapies (ASIs) in autoimmune diseases is to reprogramme or remove autoreactive cells and to induce immune tolerance to self-antigens

  • Depleting autoreactive T cells, B cells and plasma cells could be a future therapeutic strategy for rheumatic diseases and could lead to temporary improvement in disease

  • Awakening antigen-specific tolerance by inducing regulatory T (Treg) cells using antigen-specific tolerogenic peptides alone or coupled to cells or nanoparticles can reprogramme autoreactive cells, resulting in long-term tolerance

  • T cells can be engineered to specifically target and delete self-reactive B cells or to redirect the specificity of Treg cells towards self-antigens

  • The use of antigen-boosted tolerogenic dendritic cells and DNA-based vaccines are promising ASIs.

Abstract

The main goal of antigen-specific immunotherapy (ASI) in autoimmune and rheumatic diseases is to reprogramme or remove autoreactive cells and/or induce immune tolerance to self-antigens. Current therapies in these diseases either treat symptoms or slow down disease progression but are not yet curative or preventative — disease-specific treatments are urgently needed. In contrast to the nonspecific treatments in current use that induce generalized immune suppression, which is associated with several adverse effects including increased risk of infections, ASIs target a restricted subset of B cells or T cells, and thus do not compromise systemic immunity and host defence. This Review provides a summary of novel approaches for identifying autoepitopes and detecting and targeting autoreactive cells that might help in the development of ASIs. Promising approaches include the use of tolerizing peptides coupled to MHC constructs and/or nanocompounds, tolerizing dendritic cells and antigen-specific vaccines. Following studies in animal models of rheumatoid arthritis and systemic lupus erythematosus, several of these strategies have now entered clinical trials. However, to use these approaches in humans, several important limitations must first be addressed, such as; selecting the proper immunodominant autoantigen; identifying the optimal timing, dosing and route of administration; finding biomarkers for monitoring the therapy; and optimizing methodology.

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Figure 1: Induction of immune tolerance.
Figure 2: Strategies for detecting or eliminating autoreactive B cells and/or autoantibodies.
Figure 3: Strategies for neutralizing or re-programming autoreactive T cells.
Figure 4: Strategies for utilizing dendritic cells to target autoreactive T cells.

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Acknowledgements

The work of the authors was supported by the Hungarian National Science Fund (NKFI OTKA NK 104846) (G.S.) and by the European Union and the State of Hungary co-financed by the European Social Fund in the framework of TAMOP-4.2.4.A/2-11/1-2012-0001 'National Excellence Program' (Z.S.).

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Authors and Affiliations

  1. Department of Immunology, Eötvös Loránd University (ELTE), Pázmány Péter Sétány 1/C, Budapest, 1117, Hungary

    Judit Pozsgay & Gabriella Sármay

  2. Division of Rheumatology, Department of Medicine, University of Debrecen Faculty of Medicine, Nagyerdei Körút 98, Debrecen, 4032, Hungary

    Zoltán Szekanecz

Authors
  1. Judit Pozsgay
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  2. Zoltán Szekanecz
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  3. Gabriella Sármay
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Contributions

All authors wrote the manuscript. Z.S. and J.P. researched the data for the article. Z.S. and G.S. undertook review and/or editing of the manuscript before submission and provided substantial contributions to discussions of its content.

Corresponding author

Correspondence to Zoltán Szekanecz.

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The authors declare no competing financial interests.

PowerPoint slides

Glossary

Tetramer

An oligomer comprised of four monomers; in the case of MHC–peptide tetramers, four copies of biotinylated MHC–peptide molecules are bound to streptavidin.

Nanoparticles

Microscopic particles sized 1–100 nm.

Mimetope

A protein or peptide that resembles the conformation or structure of an antigen, resulting in cross-reactivity.

Heteropolymer

A compound formed from multiple subunits that are not all the same.

Autoepitope

A part of the self-protein that is recognized by autoantibodies or autoreactive B cells or T cells.

Anergy

Lymphocyte unresponsiveness.

Epitope spreading

Diversification of epitope specificity, whereby during an autoimmune response additional new epitopes of the same antigen are recognized.

Shared epitope

A common sequence of amino acids at residues 70–74 of HLA-DRB1, found in alleles associated with rheumatoid arthritis.

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Pozsgay, J., Szekanecz, Z. & Sármay, G. Antigen-specific immunotherapies in rheumatic diseases. Nat Rev Rheumatol 13, 525–537 (2017). https://doi.org/10.1038/nrrheum.2017.107

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  • DOI: https://doi.org/10.1038/nrrheum.2017.107

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