Immunological Tolerance: Therapeutic Induction

Stephen M Anderton, University of Edinburgh, Edinburgh, United Kingdom

Published online: September 2009

DOI: 10.1002/9780470015902.a0001285.pub2

When the natural mechanisms of immune tolerance breakdown, 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 rodent models of autoimmune disease, allergy and graft rejection.
  • Administration of antigen in tolerogenic form (without adjuvant) also provides protection from disease models.
  • Transfer of antigen-specific regulatory T cells can also protect against disease, and can be curative in some models.
  • Translation of cellular therapies (using DC or regulatory T cells) or tolerogenic antigen will require a fuller understanding of the critical autoantigens/epitopes that drive autoimmune pathology.

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

Figure 1. Checkpoints for therapeutic intervention. Immune cell depletion (e.g. CAMPATH-1H for leukocytes, 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-, 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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 References
    Anderton SM (2001) Peptide-based immunotherapy of autoimmunity: a path of puzzles, paradoxes and possibilities. Immunology 104: 367–376.
    Anderton SM, Manickasingham SP, Burkhart C et al. (1998) Fine specificity of the myelin-reactive T cell repertoire: implications for TCR antagonism in autoimmunity. Journal of Immunology 161: 3357–3364.
    Anderton SM and Wraith DC (2002) Selection and fine-tuning of the autoimmune T-cell repertoire. Nature Reviews. Immunology 2: 487–498.
    Bar-Or A, Vollmer T, Antel J et al. (2007) Induction of antigen-specific tolerance in multiple sclerosis after immunization with DNA encoding myelin basic protein in a randomized, placebo-controlled phase 1/2 trial. Archives of Neurology 64: 1407–1415.
    Barrat FJ, Cua DJ, Boonstra A et al. (2002) In vitro generation of interleukin 10-producing regulatory CD4(+) T cells is induced by immunosuppressive drugs and inhibited by T helper type 1 (Th1)- and Th2-inducing cytokines. Journal of Experimental Medicine 195: 603–616.
    Battaglia M, Stabilini A and Roncarolo MG (2005) Rapamycin selectively expands CD4+CD25+FoxP3+ regulatory T cells. Blood 105: 4743–4748.
    Bielekova B, Goodwin B, Richert N et al. (2000) Encephalitogenic potential of the myelin basic protein peptide (amino acids 83–99) in multiple sclerosis: results of a phase II clinical trial with an altered peptide ligand. Nature Medicine 6: 1167–1175.
    Bluestone JA, St Clair EW and Turka LA (2006) CTLA4Ig: bridging the basic immunology with clinical application. Immunity 24: 233–238.
    Bresnihan B (2002) Anakinra as a new therapeutic option in rheumatoid arthritis: clinical results and perspectives. Clinical and Experimental Rheumatology 20: S32–S34.
    Chatenoud L (2003) CD3-specific antibody-induced active tolerance: from bench to bedside. Nature Reviews. Immunology 3: 123–132.
    Chatenoud L, Thervet E, Primo J et al. (1994) Anti-CD3 antibody induces long-term remission of overt autoimmunity in nonobese diabetic mice. Proceedings of the National Academy of Sciences of the USA 91: 123–127.
    Coles AJ, Compston DA, Selmaj KW et al. (2008) Alemtuzumab vs. interferon beta-1a in early multiple sclerosis. New England Journal of Medicine 359: 1786–1801.
    Coombes JL, Siddiqui KR, Arancibia-Carcamo CV et al. (2007) A functionally specialized population of mucosal CD103+ DCs induces Foxp3+ regulatory T cells via a TGF-beta and retinoic acid-dependent mechanism. Journal of Experimental Medicine 204: 1757–1764.
    Davidson TS, DiPaolo RJ, Andersson J et al. (2007) Cutting Edge: IL-2 is essential for TGF-beta-mediated induction of Foxp3+ T regulatory cells. Journal of Immunology 178: 4022–4026.
    Earle KE, Tang Q, Zhou X et al. (2005) In vitro expanded human CD4+CD25+ regulatory T cells suppress effector T cell proliferation. Clinical Immunology 115: 3–9.
    Edwards JC and Cambridge G (2006) B-cell targeting in rheumatoid arthritis and other autoimmune diseases. Nature Reviews. Immunology 6: 394–403.
    Edwards JC, Szczepanski L, Szechinski J et al. (2004) Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis. New England Journal of Medicine 350: 2572–2581.
    Elliott MJ, Maini RN, Feldmann M et al. (1993) Treatment of rheumatoid arthritis with chimeric monoclonal antibodies to tumor necrosis factor alpha. Arthritis and Rheumatism 36: 1681–1690.
    Emery P, Keystone E, Tony HP et al. (2008) IL-6 receptor inhibition with tocilizumab improves treatment outcomes in patients with rheumatoid arthritis refractory to anti-tumour necrosis factor biologicals: results from a 24-week multicentre randomised placebo-controlled trial. Annals of Rheumatic Diseases 67: 1516–1523.
    Engelhardt B and Ransohoff RM (2005) The ins and outs of T-lymphocyte trafficking to the CNS: anatomical sites and molecular mechanisms. Trends in Immunology 26: 485–495.
    Fife BT and Bluestone JA (2008) Control of peripheral T-cell tolerance and autoimmunity via the CTLA-4 and PD-1 pathways. Immunological Reviews 224: 166–182.
    Fillatreau S, Gray D and Anderton SM (2008) Not always the bad guys: B cells as regulators of autoimmune pathology. Nature Reviews. Immunology 8: 391–397.
    Groux H, O'Garra A, Bigler M et al. (1997) A CD4+ T-cell subset inhibits antigen-specific T-cell responses and prevents colitis. Nature 389: 737–742.
    von Herrath MG, Coon B, Wolfe T et al. (2002) Nonmitogenic CD3 antibody reverses virally induced (rat insulin promoter-lymphocytic choriomeningitis virus) autoimmune diabetes without impeding viral clearance. Journal of Immunology 168: 933–941.
    Kappos L, Antel J, Comi G et al. (2006) Oral fingolimod (FTY720) for relapsing multiple sclerosis. New England Journal of Medicine 355: 1124–1140.
    Kappos L, Comi G, Panitch H et al. (2000) Induction of a non-encephalitogenic type 2T helper-cell autoimmune response in multiple sclerosis after administration of an altered peptide ligand in a placebo-controlled, randomized phase II trial. The altered peptide ligand in relapsing MS study group. Nature Medicine 6: 1176–1182.
    Keymeulen B, Vandemeulebroucke E, Ziegler AG et al. (2005) Insulin needs after CD3-antibody therapy in new-onset type 1 diabetes. New England Journal of Medicine 352: 2598–2608.
    Kohm AP, Williams JS, Bickford AL et al. (2005) Treatment with nonmitogenic anti-CD3 monoclonal antibody induces CD4+ T cell unresponsiveness and functional reversal of established experimental autoimmune encephalomyelitis. Journal of Immunology 174: 4525–4534.
    Larche M and Wraith DC (2005) Peptide-based therapeutic vaccines for allergic and autoimmune diseases. Nature Medicine 11: S69–S76.
    Leech MD, Chung CY, Culshaw A et al. (2007) Peptide-based immunotherapy of experimental autoimmune encephalomyelitis without anaphylaxis. European Journal of Immunology 37: 3576–3581.
    Linker RA, Kieseier BC and Gold R (2008) Identification and development of new therapeutics for multiple sclerosis. Trends in Pharmacological Sciences 29: 558–565.
    Lundquist L (2007) Abatacept: a novel therapy approved for the treatment of patients with rheumatoid arthritis. Advances in Therapy 24: 333–345.
    Marrack P and Kappler J (2004) Control of T cell viability. Annual Review of Immunology 22: 765–787.
    Meiler F, Zumkehr J, Klunker S et al. (2008) In vivo switch to IL-10-secreting T regulatory cells in high dose allergen exposure. Journal of Experimental Medicine 205: 2887–2898.
    Monti P, Scirpoli M, Maffi P et al. (2008) Rapamycin monotherapy in patients with type 1 diabetes modifies CD4+CD25+FOXP3+ regulatory T-cells. Diabetes 57: 2341–2347.
    Morelli AE and Thomson AW (2007) Tolerogenic dendritic cells and the quest for transplant tolerance. Nature Reviews. Immunology 7: 610–621.
    Mottet C, Uhlig HH and Powrie F (2003) Cutting edge: cure of colitis by CD4+CD25+ regulatory T cells. Journal of Immunology 170: 3939–3943.
    Mucida D, Park Y, Kim G et al. (2007) Reciprocal TH17 and regulatory T cell differentiation mediated by retinoic acid. Science 317: 256–260.
    Paolillo A, Coles AJ, Molyneux PD et al. (1999) Quantitative MRI in patients with secondary progressive MS treated with monoclonal antibody Campath 1H. Neurology 53: 751–757.
    Polman CH, O'Connor PW, Havrdova E et al. (2006) A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. New England Journal of Medicine 354: 899–910.
    Roord ST, Zonneveld-Huijssoon E, Le T et al. (2006) Modulation of T cell function by combination of epitope specific and low dose anticytokine therapy controls autoimmune arthritis. PLoS ONE 1: e87.
    Sakaguchi S, Yamaguchi T, Nomura T et al. (2008) Regulatory T cells and immune tolerance. Cell 133: 775–787.
    Schwartz RH (2003) T cell anergy. Annual Reviews in Immunology 21: 305–334.
    Stephens LA, Malpass KH and Anderton SM (2009) Curing CNS autoimmune disease with myelin-reactive Foxp3+ Treg. European Journal of Immunology 39: 1108–1117.
    Tang Q, Henriksen KJ, Bi M et al. (2004) In vitro-expanded antigen-specific regulatory T cells suppress autoimmune diabetes. Journal of Experimental Medicine 199: 1455–1465.
    Tarzi M, Klunker S, Texier C et al. (2006) Induction of interleukin-10 and suppressor of cytokine signalling-3 gene expression following peptide immunotherapy. Clinical and Experimental Allergy 36: 465–474.
    Thomson AW and Robbins PD (2008) Tolerogenic dendritic cells for autoimmune disease and transplantation. Annals of Rheumatic Diseases 67(suppl. 3): iii90–iii96.
    Verhoef A, Alexander C, Kay AB et al. (2005) T cell epitope immunotherapy induces a CD4+ T cell population with regulatory activity. PLoS Medicine 2: e78.
    Yamazaki S, Dudziak D, Heidkamp GF et al. (2008) CD8+ CD205+ splenic dendritic cells are specialized to induce Foxp3+ regulatory T cells. Journal of Immunology 181: 6923–6933.
    Yang XO, Nurieva R, Martinez GJ et al. (2008) Molecular antagonism and plasticity of regulatory and inflammatory T cell programs. Immunity 29: 44–56.
 Further Reading
    Bluestone JA, Thomson AW, Shevach EM and Weiner HL (2007) What does the future hold for cell-based tolerogenic therapy? Nature Reviews. Immunology 7: 650–654.
    Dong C (2008) TH17 cells in development: an updated view of their molecular identity and genetic programming. Nature Reviews. Immunology 8: 337–348.
    Mora JR, Iwata M and von Andrian UH (2008) Vitamin effects on the immune system: vitamins A and D take centre stage. Nature Reviews. Immunology 8: 685–698.
    Roncarolo MG and Battaglia M (2007) Regulatory T-cell immunotherapy for tolerance to self antigens and alloantigens in humans. Nature Reviews. Immunology 7: 585–598.
    Steinman RM and Banchereau J (2007) Taking dendritic cells into medicine. Nature 449: 419–426.

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Article Title: Immunological Tolerance: Therapeutic Induction
 
How to Cite close
Anderton, Stephen M(Sep 2009) Immunological Tolerance: Therapeutic Induction. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0001285.pub2]