Vaccine against autoimmune disease: antigen-specific immunotherapy

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Recent interest in testing whether the success of antigen-specific immunotherapy (ASIT) for autoimmune diseases in mice can be translated to humans has highlighted the need for better tools to study and understand human autoimmunity. Clinical development of ASIT for allergy has been instructive, but limited understanding of CD4 T cell epitope/determinant hierarchies hampers the rational design and monitoring of ASIT. Definitive identification of pathogenic T cell epitopes as is now known in celiac disease and recent initiatives to optimize immune monitoring will facilitate rational design, monitoring and mechanistic understanding of ASIT for human autoimmune diseases.

Highlights

► Epitope hierarchies for pathogenic T cells enable ASIT/ESIT design and monitoring. ► Epitope-specific immunotherapy (ESIT) utilizes immunodominant peptides. ► Dose, route and regimen influence the immunological outcomes of ASIT. ► Monitoring T cell responses in fresh blood are essential for clinical development. ► Celiac disease provides a unique opportunity for the development of ESIT.

Introduction

Genes encoding major histocompatibility (MHC) class II molecules are the strongest determinants of susceptibility to type-1 diabetes (T1D), rheumatoid arthritis, multiple sclerosis and many other autoimmune diseases. Consequently, CD4 T cells specific for immunodominant epitopes (see glossary) restricted by disease-associated MHC class II elements are ideal targets for immunomodulation using antigen-specific immunotherapy (ASIT) or more specifically with naked peptides in epitope-specific immunotherapy (ESIT) [1, 2]. Extrapolating from mouse models, therapeutic vaccinations for human autoimmune disorders would elicit an immune response restoring tolerance by eliminating, modulating or blocking pathogenic immune responses. Vaccines would target disease-specific pathogenic T cells without inducing generalized immunosuppression. The selectivity of ESIT is possible by using T cell epitopes recognized by disease-causing CD4 T cells. Progress in developing this new therapeutic class has been hampered by the inability to define and monitor disease-specific pathogenic T cells. Here, we will examine why vaccines are pertinent to autoimmune disorders. The potential mechanisms underlying vaccine-induced tolerance will be reviewed including a discussion of the design of ASIT, ESIT and immune monitoring, and highlight celiac disease as an informative human ‘model’.

Section snippets

Support for vaccines to treat allergic and autoimmune disorders

Rigorous clinical trials of ASIT for allergic diseases confirm that long-term disease modification is possible for established pathological immune responses in humans [3]. Authoritative guidelines have summarized the level of evidence supporting the safety and efficacy of whole-protein allergen-based therapeutic vaccines for allergic diseases [4, 5]. More recently, a vaccine formulation including allergen-derived peptides encompassing HLA-DR restricted epitopes from cat dander protein (Fel-d1)

Mechanisms underlying vaccine-mediated immune tolerance

Although pathogenic CD4 T helper 1 (Th1), 2 (Th2) and 17 (Th17) responses may not be as clearly demarcated in humans as they are in the mouse, allergic responses are typically associated with Th2 responses with high levels of IL-4, IL-5 and IL-13 [11]. In contrast, organ-specific autoimmune disorders are generally associated with pro-inflammatory Th1 and Th17 immune responses directed against self-antigens and high levels of IFN-γ and/or IL-17 production, respectively [12]. In principle, these

Celiac disease is a disease prototype for the development of vaccines against autoimmune disorders

Celiac disease is defined by the presence of small intestinal inflammation that improves or normalizes with exclusion of dietary gluten derived from foods including wheat, barley and rye. Celiac disease is one of a cluster of diseases associated with autoantibody production and T-cell mediated organ-specific immunopathology that are strongly associated with HLA-DR3-DQ2 and DR4-DQ8 haplotypes [52, 53, 54]. In fact, celiac disease is effectively ruled out in patients lacking HLA-DQ2 or HLA-DQ8.

Design of antigen-specific immunotherapy

Although advances in adjuvants, delivery systems, and optimized administration schedules influence the efficacy of ASIT in animal models, the indivisible, final active moieties of ASIT are linear peptides of 9-10 amino acids that comprise immunodominant epitopes recognized by pathogenic human CD4 T cells. Such epitopes may be delivered in whole protein antigens, encoded by DNA or RNA, or as short linear peptides [61]. In principle, individual peptides or mixtures of small numbers of peptides

Immune monitoring of vaccine efficacy

The frequency and functional phenotype of relevant antigen-experienced T cells have the potential to provide surrogate endpoints and mechanistic insights for clinical trials of ASIT and ESIT [69]. However, if auto-antigen-specific T cells cannot be detected in blood without expansion in vitro [66, 70, 71], monitoring such rare T cell populations in clinical trials will also be challenging. In autoimmune diseases such as T1D, variable reproducibility of assays for antigen specific T cells has

Conclusions

There is now strong evidence that ASIT is safe. The challenge that remains, particularly in organ-specific autoimmune disorders, is to establish that vaccines constitute an effective treatment. A major limitation to date has been to perform ASIT in the context of diseases for which immunodominant CD4 T cell epitopes responsible for pathology are not well defined and the tools to accurately monitor the vaccine-associated immune response do not exist. Defining robust surrogate immunological

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Glossary

Antigen-specific immunotherapy (ASIT)
is a composition that is intended to modify the natural history of a disease, for example cancer, allergy or autoimmunity, through inducing, enhancing, or suppressing a specific immune response.
Epitope-specific immunotherapy (ESIT)
for autoimmune diseases is a composition including peptides (<20 amino acids minimizes the risk of allergenicity) encompassing immunodominant epitopes for disease-specific CD4 T cells that is intended to modify the natural history

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    Disclosures: RPA is a shareholder in ImmusanT, Inc. and Nexpep Pty Ltd., and is named inventor on patents relating to antigen-specific therapy and diagnostics for celiac disease. BJ is a scientific advisor to ImmusanT, Inc.

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