Immunological Tolerance: Therapeutic Induction

Abstract

When the natural mechanisms of immune tolerance break down, autoimmune or allergic disease can result. There is considerable experimental evidence that the ultimate response to antigen, full immunity or tolerance, is dependent on the activation status of the antigen‐presenting dendritic cells, with those in steady state inducing tolerance. Current therapeutic options either deplete immune cell populations, interfere with immune cell trafficking to the tissues or inhibit inflammatory cytokine function or lymphocyte signalling. Although these treatments can be effective for certain diseases, they carry with them significant adverse effects and it is unlikely that they induce true, long‐lived immune tolerance. Cellular therapies using either tolerogenic dendritic cells or regulatory T cells may be able to achieve this. Alternatively, administration of antigen in tolerogenic form can provide the most specific therapy, with the least risk of adversely affecting normal immune function against infection or neoplasia.

Key Concepts:

  • Peripheral tolerance mechanisms consist of lymphocyte apoptosis, anergy and regulation.

  • Current therapeutic options for the clinic can be effective, but in general are nonspecific and may not provide long‐term tolerance.

  • Dendritic cell (DC) activation status determines the type of immune response. Activated DC provokes immunity whereas steady‐state DC promotes tolerance.

  • ‘Tolerogenic’ DC can be administered to give protection from autoimmune disease, allergy and graft rejection as shown in animal models, and are being tested for clinical application.

  • Administration of antigen in tolerogenic form (without adjuvant) also provides protection from disease in animal models; however, clinical translation is proving challenging.

  • Transfer of antigen‐specific regulatory T cells (Treg) can also protect against disease, and can be curative in some models.

  • Translation of cellular therapies (using DC or Treg) or tolerogenic antigen will require a fuller understanding of the critical autoantigens/epitopes that drive autoimmune pathology.

Keywords: immune tolerance; immunotherapy; autoimmunity; allergy; transplantation

Figure 1.

Checkpoints for therapeutic intervention. Immune cell depletion (e.g. CAMPATH‐1H for leucocytes, rituximab for B cells) can have profound effects, as can preventing the recruitment of immune cells to the tissues (natalizumab or Fingolimod/FTY720). Various therapies are available to suppress actions of inflammatory cytokines (TNF‐α, IL‐1, IL‐6 and others). Altering T cell signalling may promote tolerance (e.g. CTLA4Ig/abatacept). Antigen presentation to naive T cells (Tn) by steady‐state DC tends to induce tolerance rather than full differentiation to effector T cells (Teff). This tolerance may be due to T cells apoptosis, anergy, or a shift in the balance from Teff towards Treg. Various pharmacological agents may also result in such a shift, for example, rapamycin, retinoic acid or vitamin D. Cellular therapy for tolerance induction may be achievable with tolerogenic DC or in‐vitro expanded/induced Treg. Administration of tolerogenic antigen (without adjuvant) is a robust approach in many rodent models and clinical trials continue in some human autoimmune and allergic conditions.

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Mair, Iris, Reynolds, Ben C, and Anderton, Stephen M(Sep 2013) Immunological Tolerance: Therapeutic Induction. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0001285.pub3]