We’re sorry, something doesn't seem to be working properly.

Please try refreshing the page. If that doesn't work, please contact support so we can address the problem.

Skip to main content

Advertisement

SpringerLink
Log in

Re-educating immunity in respiratory allergies: the potential for hematopoietic stem cell-mediated gene therapy

  • Review
  • Published:
Journal of Molecular Medicine Aims and scope Submit manuscript

Abstract

Respiratory allergies represent a significant disease burden worldwide affecting up to 300 million people globally. Medication and avoidance of known triggers do not address the underlying pathology. Traditional immunotherapies for allergy aim to reinstate immune homeostasis but require years of treatment and have poor long-term efficacy. Novel approaches, such as gene-engineered hematopoietic stem cell transplantation, induce profound antigen-specific tolerance in autoimmunity. Recent evidence shows this approach may also have therapeutic utility for allergy. Here, we review the mechanisms of antigen-specific tolerance and the potential of stem cell-mediated gene therapy to induce tolerance in allergic respiratory diseases.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Lambrecht BN, Hammad H (2014) Allergens and the airway epithelium response: gateway to allergic sensitization. J Allergy Clin Immunol 134(3):499–507

    Article  CAS  PubMed  Google Scholar 

  2. Webb DC, McKenzie ANJ, Koskinen AML, Yang M, Mattes J, Foster PS (2000) Integrated signals between IL-13, IL-4, and IL-5 regulate airways hyperreactivity. J Immunol 165(1):108–113

    Article  CAS  PubMed  Google Scholar 

  3. Leckie MJ, Brinke A, Khan J, Diamant Z, O'Connor BJ, Walls CM, Mathur AK, Cowley HC, Chung KF, Djukanovic R et al (2000) Effects of an interleukin-5 blocking monoclonal antibody on eosinophils, airway hyper-responsiveness, and the late asthmatic response. Lancet 356(9248):2144–2148

    Article  CAS  PubMed  Google Scholar 

  4. Wenzel S, Wilbraham D, Fuller R, Getz EB, Longphre M (2007) Effect of an interleukin-4 variant on late phase asthmatic response to allergen challenge in asthmatic patients: results of two phase 2a studies. Lancet 370(9596):1422–1431

    Article  CAS  PubMed  Google Scholar 

  5. Nicholson GC et al. (2011) The effects of an anti-IL-13 mAb on cytokine levels and nasal symptoms following nasal allergen challenge. J Allergy Clin Immunol 128 (4):800–807.e809

  6. Licona-Limon P et al (2013) TH2, allergy and group 2 innate lymphoid cells. Nat Immunol 14(6):536–542

    Article  CAS  PubMed  Google Scholar 

  7. Stone KD, Prussin C, Metcalfe DD (2010) IgE, mast cells, basophils, and eosinophils. J Allergy Clin Immunol 125(2 Suppl 2):S73–S80

    Article  PubMed  PubMed Central  Google Scholar 

  8. Gould HJ, Sutton BJ (2008) IgE in allergy and asthma today. Nat Rev Immunol 8(3):205–217

    Article  CAS  PubMed  Google Scholar 

  9. Wynn TA (2015) Type 2 cytokines: mechanisms and therapeutic strategies. Nat Rev Immunol 15(5):271–282

    Article  CAS  PubMed  Google Scholar 

  10. Talay O, Yan D, Brightbill HD, Straney EEM, Zhou M, Ladi E, Lee WP, Egen JG, Austin CD, Xu M et al (2012) IgE(+) memory B cells and plasma cells generated through a germinal-center pathway. Nat Immunol 13(4):396–404

    Article  CAS  PubMed  Google Scholar 

  11. Hanania NA, Alpan O, Hamilos DL, Condemi JJ, Reyes-Rivera I, Zhu J, Rosen KE, Eisner MD, Wong DA, Busse W (2011) Omalizumab in severe allergic asthma inadequately controlled with standard therapy: a randomized trial. Ann Intern Med 154(9):573–582

    Article  PubMed  Google Scholar 

  12. Lin H, Boesel KM, Griffith DT, Prussin C, Foster B, Romero FA, Townley R, Casale TB (2004) Omalizumab rapidly decreases nasal allergic response and FcepsilonRI on basophils. J Allergy Clin Immunol 113(2):297–302

    Article  CAS  PubMed  Google Scholar 

  13. Prussin C, Griffith DT, Boesel KM, Lin H, Foster B, Casale TB (2003) Omalizumab treatment downregulates dendritic cell FcepsilonRI expression. J Allergy Clin Immunol 112(6):1147–1154

    Article  CAS  PubMed  Google Scholar 

  14. Legorreta AP, Christian-Herman J, O'Connor RD, Hasan MM, Evans R, Leung KM (1998) Compliance with national asthma management guidelines and specialty care: a health maintenance organization experience. Arch Intern Med 158(5):457–464

    Article  CAS  PubMed  Google Scholar 

  15. Danke NA, Koelle DM, Yee C, Beheray S, Kwok WW (2004) Autoreactive T cells in healthy individuals. J Immunol 172(10):5967–5972

    Article  CAS  PubMed  Google Scholar 

  16. Duty JA, Szodoray P, Zheng NY, Koelsch KA, Zhang Q, Swiatkowski M, Mathias M, Garman L, Helms C, Nakken B et al (2009) Functional anergy in a subpopulation of naive B cells from healthy humans that express autoreactive immunoglobulin receptors. J Exp Med 206(1):139–151

    Article  PubMed  PubMed Central  Google Scholar 

  17. Wilson NS, El-Sukkari D, Belz GT, Smith CM, Steptoe RJ, Heath WR, Shortman K, Villadangos JA (2003) Most lymphoid organ dendritic cell types are phenotypically and functionally immature. Blood 102(6):2187–2194

    Article  CAS  PubMed  Google Scholar 

  18. Hawiger D, Inaba K, Dorsett Y, Guo M, Mahnke K, Rivera M, Ravetch JV, Steinman RM, Nussenzweig MC (2001) Dendritic cells induce peripheral T cell unresponsiveness under steady state conditions in vivo. J Exp Med 194(6):769–779

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Probst HC, McCoy K, Okazaki T, Honjo T, van den Broek M (2005) Resting dendritic cells induce peripheral CD8+ T cell tolerance through PD-1 and CTLA-4. Nat Immunol 6(3):280–286

    Article  CAS  PubMed  Google Scholar 

  20. Steptoe RJ, Ritchie JM, Wilson NS, Villadangos JA, Lew AM, Harrison LC (2007) Cognate CD4+ help elicited by resting dendritic cells does not impair the induction of peripheral tolerance in CD8+ T cells. J Immunol 178(4):2094–2103

    Article  CAS  PubMed  Google Scholar 

  21. Davey GM, Kurts C, Miller JFAP, Bouillet P, Strasser A, Brooks AG, Carbone FR, Heath WR (2002) Peripheral deletion of autoreactive CD8 T cells by cross presentation of self-antigen occurs by a Bcl-2-inhibitable pathway mediated by Bim. J Exp Med 196(7):947–955

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Werner-Klein M, Dresch C, Marconi P, Brocker T (2007) Transcriptional targeting of B cells for induction of peripheral CD8 T cell tolerance. J Immunol 178(12):7738–7746

    Article  CAS  PubMed  Google Scholar 

  23. Bilate AM, Lafaille JJ (2012) Induced CD4+Foxp3+ regulatory T cells in immune tolerance. Annu Rev Immunol 30(1):733–758

    Article  CAS  PubMed  Google Scholar 

  24. Chen Y, Kuchroo V, Inobe J, Hafler D, Weiner H (1994) Regulatory T cell clones induced by oral tolerance: suppression of autoimmune encephalomyelitis. Science 265(5176):1237–1240

    Article  CAS  PubMed  Google Scholar 

  25. Fillatreau S, Sweenie CH, McGeachy MJ, Gray D, Anderton SM (2002) B cells regulate autoimmunity by provision of IL-10. Nat Immunol 3(10):944–950

    Article  CAS  PubMed  Google Scholar 

  26. Ling EM, Smith T, Nguyen XD, Pridgeon C, Dallman M, Arbery J, Carr VA, Robinson DS (2004) Relation of CD4+CD25+ regulatory T-cell suppression of allergen-driven T-cell activation to atopic status and expression of allergic disease. Lancet 363(9409):608–615

    Article  CAS  PubMed  Google Scholar 

  27. Akdis M, Verhagen J, Taylor A, Karamloo F, Karagiannidis C, Crameri R, Thunberg S, Deniz G, Valenta R, Fiebig H et al (2004) Immune responses in healthy and allergic individuals are characterized by a fine balance between allergen-specific T regulatory 1 and T helper 2 cells. J Exp Med 199(11):1567–1575

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Gauld SB, Benschop RJ, Merrell KT, Cambier JC (2005) Maintenance of B cell anergy requires constant antigen receptor occupancy and signaling. Nat Immunol 6(11):1160–1167

    Article  CAS  PubMed  Google Scholar 

  29. Goodnow CC, Brink R, Adams E (1991) Breakdown of self-tolerance in anergic B lymphocytes. Nature 352(6335):532–536

    Article  CAS  PubMed  Google Scholar 

  30. O'Neill SK, Getahun A, Gauld SB, Merrell KT, Tamir I, Smith MJ, Dal Porto JM, Li QZ, Cambier JC (2011) Monophosphorylation of CD79a and CD79b ITAM motifs initiates a SHIP-1 phosphatase-mediated inhibitory signaling cascade required for B cell anergy. Immunity 35(5):746–756

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Getahun A, Beavers NA, Larson SR, Shlomchik MJ, Cambier JC (2016) Continuous inhibitory signaling by both SHP-1 and SHIP-1 pathways is required to maintain unresponsiveness of anergic B cells. J Exp Med 213(5):751–769

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Rathmell JC, Townsend SE, Xu JC, Flavell RA, Goodnow CC (1996) Expansion or elimination of B cells in vivo: dual roles for CD40- and Fas (CD95)-ligands modulated by the B cell antigen receptor. Cell 87(2):319–329

    Article  CAS  PubMed  Google Scholar 

  33. Cyster JG, Hartley SB, Goodnow CC (1994) Competition for follicular niches excludes self-reactive cells from the recirculating B-cell repertoire. Nature 371(6496):389–395

    Article  CAS  PubMed  Google Scholar 

  34. Cooke MP, Heath AW, Shokat KM, Zeng Y, Finkelman FD, Linsley PS, Howard M, Goodnow CC (1994) Immunoglobulin signal transduction guides the specificity of B cell-T cell interactions and is blocked in tolerant self-reactive B cells. J Exp Med 179(2):425–438

    Article  CAS  PubMed  Google Scholar 

  35. Cyster JG, Goodnow CC (1995) Antigen-induced exclusion from follicles and anergy are separate and complementary processes that influence peripheral B cell fate. Immunity 3(6):691–701

    Article  CAS  PubMed  Google Scholar 

  36. Taylor JJ, Martinez RJ, Titcombe PJ, Barsness LO, Thomas SR, Zhang N, Katzman SD, Jenkins MK, Mueller DL (2012) Deletion and anergy of polyclonal B cells specific for ubiquitous membrane-bound self-antigen. J Exp Med 209(11):2065–2077

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Hartley SB, Crosbie J, Brink R, Kantor AB, Basten A, Goodnow CC (1991) Elimination from peripheral lymphoid tissues of self-reactive B lymphocytes recognizing membrane-bound antigens. Nature 353(6346):765–769

    Article  CAS  PubMed  Google Scholar 

  38. Maaske A, Devos FC, Niezold T, Lapuente D, Tannapfel A, Vanoirbeek JA, Überla K, Peters M, Tenbusch M (2016) Mucosal expression of DEC-205 targeted allergen alleviates an asthmatic phenotype in mice. J Control Release 237:14–22

    Article  CAS  PubMed  Google Scholar 

  39. Lim HW, Hillsamer P, Kim CH (2004) Regulatory T cells can migrate to follicles upon T cell activation and suppress GC-Th cells and GC-Th cell-driven B cell responses. J Clin Invest 114(11):1640–1649

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Sage PT et al. (2016) Suppression by TFR cells leads to durable and selective inhibition of B cell effector function. Nat Immunol

  41. Linterman MA, Pierson W, Lee SK, Kallies A, Kawamoto S, Rayner TF, Srivastava M, Divekar DP, Beaton L, Hogan JJ et al (2011) Foxp3+ follicular regulatory T cells control the germinal center response. Nat Med 17(8):975–982

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Sage PT, Sharpe AH (2016) T follicular regulatory cells. Immunol Rev 271(1):246–259

    Article  CAS  PubMed  Google Scholar 

  43. Lim HW, Hillsamer P, Banham AH, Kim CH (2005) Cutting edge: direct suppression of B cells by CD4+ CD25+ regulatory T cells. J Immunol 175(7):4180–4183

    Article  CAS  PubMed  Google Scholar 

  44. Gotot J, Gottschalk C, Leopold S, Knolle PA, Yagita H, Kurts C, Ludwig-Portugall I (2012) Regulatory T cells use programmed death 1 ligands to directly suppress autoreactive B cells in vivo. Proc Natl Acad Sci U S A 109(26):10468–10473

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Akdis CA, Akdis M (2011) Mechanisms of allergen-specific immunotherapy. J Allergy Clin Immunol 127(1):18–27; quiz 28-19

    Article  CAS  PubMed  Google Scholar 

  46. Hylander T, Latif L, Petersson-Westin U, Cardell LO (2013) Intralymphatic allergen-specific immunotherapy: an effective and safe alternative treatment route for pollen-induced allergic rhinitis. J Allergy Clin Immunol 131(2):412–420

    Article  CAS  PubMed  Google Scholar 

  47. Akdis CA, Blesken T, Akdis M, Wüthrich B, Blaser K (1998) Role of interleukin 10 in specific immunotherapy. J Clin Invest 102(1):98–106

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Secrist H, Chelen CJ, Wen Y, Marshall JD, Umetsu DT (1993) Allergen immunotherapy decreases interleukin 4 production in CD4+ T cells from allergic individuals. J Exp Med 178(6):2123–2130

    Article  CAS  PubMed  Google Scholar 

  49. Faith A, Akdis CA, Akdis M, Simon HU, Blaser K (1997) Defective TCR stimulation in anergized type 2 T helper cells correlates with abrogated p56(lck) and ZAP-70 tyrosine kinase activities. J Immunol 159(1):53–60

    CAS  PubMed  Google Scholar 

  50. van de Veen W, Stanic B, Yaman G, Wawrzyniak M, Söllner S, Akdis DG, Rückert B, Akdis CA, Akdis M (2013) IgG4 production is confined to human IL-10-producing regulatory B cells that suppress antigen-specific immune responses. J Allergy Clin Immunol 131(4):1204–1212

    Article  PubMed  CAS  Google Scholar 

  51. Monti P, Scirpoli M, Maffi P, Ghidoli N, De Taddeo F, Bertuzzi F, Piemonti L, Falcone M, Secchi A, Bonifacio E (2008) Islet transplantation in patients with autoimmune diabetes induces homeostatic cytokines that expand autoreactive memory T cells. J Clin Invest 118(5):1806–1814

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Vendrame F, Pileggi A, Laughlin E, Allende G, Martin-Pagola A, Molano RD, Diamantopoulos S, Standifer N, Geubtner K, Falk BA et al (2010) Recurrence of type 1 diabetes after simultaneous pancreas-kidney transplantation, despite immunosuppression, associated with autoantibodies and pathogenic autoreactive CD4 T-cells. Diabetes 59(4):947–957

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Curtsinger JM, Lins DC, Mescher MF (1998) CD8+ memory T cells (CD44high, Ly-6C+) are more sensitive than naive cells to (CD44low, Ly-6C-) to TCR/CD8 signaling in response to antigen. J Immunol 160(7):3236–3243

    CAS  PubMed  Google Scholar 

  54. Croft M, Bradley LM, Swain SL (1994) Naive versus memory CD4 T cell response to antigen. Memory cells are less dependent on accessory cell costimulation and can respond to many antigen-presenting cell types including resting B cells. J Immunol 152(6):2675–2685

    CAS  PubMed  Google Scholar 

  55. Grayson JM, Zajac AJ, Altman JD, Ahmed R (2000) Increased expression of Bcl-2 in antigen-specific memory CD8+ T cells. J Immunol 164(8):3950–3954

    Article  CAS  PubMed  Google Scholar 

  56. Casorati G, Locatelli F, Pagani S, Garavaglia C, Montini E, Lisini D, Turin I, Rossi F, Dellabona P, Maccario R et al (2005) Bone marrow-resident memory T cells survive pretransplant chemotherapy and contribute to early immune reconstitution of patients with acute myeloid leukemia given mafosfamide-purged autologous bone marrow transplantation. Exp Hematol 33(2):212–218

    Article  CAS  PubMed  Google Scholar 

  57. Valujskikh A (2008) Targeting T-cell memory: where do we stand? Curr Opin Organ Transplant 13(4):344–349

    Article  PubMed  Google Scholar 

  58. Adams AB, Durham MM, Kean L, Shirasugi N, Ha J, Williams MA, Rees PA, Cheung MC, Mittelstaedt S, Bingaman AW et al (2001) Costimulation blockade, busulfan, and bone marrow promote titratable macrochimerism, induce transplantation tolerance, and correct genetic hemoglobinopathies with minimal myelosuppression. J Immunol 167(2):1103–1111

    Article  CAS  PubMed  Google Scholar 

  59. Valujskikh A, Pantenburg B, Heeger PS (2002) Primed allospecific T cells prevent the effects of costimulatory blockade on prolonged allograft survival in mice. Am J Transplant 2(6):501–509

    Article  CAS  PubMed  Google Scholar 

  60. Yang J, Brook MO, Carvalho-Gaspar M, Zhang J, Ramon HE, Sayegh MH, Wood KJ, Turka LA, Jones ND (2007) Allograft rejection mediated by memory T cells is resistant to regulation. Proc Natl Acad Sci U S A 104(50):19954–19959

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Afzali B, Mitchell PJ, Scottà C, Canavan J, Edozie FC, Fazekasova H, Lord GM, John S, Barber LD, Hernandez-Fuentes MP et al (2011) Relative resistance of human CD4(+) memory T cells to suppression by CD4(+) CD25(+) regulatory T cells. Am J Transplant 11(8):1734–1742

    Article  CAS  PubMed  Google Scholar 

  62. Bernasconi NL, Onai N, Lanzavecchia A (2003) A role for Toll-like receptors in acquired immunity: up-regulation of TLR9 by BCR triggering in naive B cells and constitutive expression in memory B cells. Blood 101(11):4500–4504

    Article  CAS  PubMed  Google Scholar 

  63. Bernasconi NL, Traggiai E, Lanzavecchia A (2002) Maintenance of serological memory by polyclonal activation of human memory B cells. Science 298(5601):2199–2202

    Article  CAS  PubMed  Google Scholar 

  64. Tangye SG, Avery DT, Deenick EK, Hodgkin PD (2003) Intrinsic differences in the proliferation of naive and memory human B cells as a mechanism for enhanced secondary immune responses. J Immunol 170(2):686–694

    Article  CAS  PubMed  Google Scholar 

  65. Bovia F, Nabili-Tehrani AC, Werner-Favre C, Barnet M, Kindler V, Zubler RH (1998) Quiescent memory B cells in human peripheral blood co-express bcl-2 and bcl-x(L) anti-apoptotic proteins at high levels. Eur J Immunol 28(12):4418–4423

    Article  CAS  PubMed  Google Scholar 

  66. Arpin C, Banchereau J, Liu YJ (1997) Memory B cells are biased towards terminal differentiation: a strategy that may prevent repertoire freezing. J Exp Med 186(6):931–940

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Hebeis BJ, Klenovsek K, Rohwer P, Ritter U, Schneider A, Mach M, Winkler TH (2004) Activation of virus-specific memory B cells in the absence of T cell help. J Exp Med 199(4):593–602

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Linhart B, Bigenzahn S, Hartl A, Lupinek C, Thalhamer J, Valenta R, Wekerle T (2007) Costimulation blockade inhibits allergic sensitization but does not affect established allergy in a murine model of grass pollen allergy. J Immunol 178(6):3924–3931

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Marth K, Wollmann E, Gallerano D, Ndlovu P, Makupe I, Valenta R, Sibanda E (2014) Persistence of IgE-associated allergy and allergen-specific IgE despite CD4+ T cell loss in AIDS. PLoS One 9(6):e97893. https://doi.org/10.1371/journal.pone.0097893

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  70. Lucae S, Schmid-Grendelmeier P, Wüthrich B, Kraft D, Valenta R, Linhart B (2016) IgE responses to exogenous and endogenous allergens in atopic dermatitis patients under long-term systemic cyclosporine A treatment. Allergy 71(1):115–118

    Article  CAS  PubMed  Google Scholar 

  71. Manz RA, Thiel A, Radbruch A (1997) Lifetime of plasma cells in the bone marrow. Nature 388(6638):133–134

    Article  CAS  PubMed  Google Scholar 

  72. Slifka MK, Antia R, Whitmire JK, Ahmed R (1998) Humoral immunity due to long-lived plasma cells. Immunity 8(3):363–372

    Article  CAS  PubMed  Google Scholar 

  73. Miller JJ, Cole LJ (1967) The radiation resistance of long-lived lymphocytes and plasma cells in mouse and rat lymph nodes. J Immunol 98(5):982–990

    CAS  PubMed  Google Scholar 

  74. Hoyer BF, Moser K, Hauser AE, Peddinghaus A, Voigt C, Eilat D, Radbruch A, Hiepe F, Manz RA (2004) Short-lived plasmablasts and long-lived plasma cells contribute to chronic humoral autoimmunity in NZB/W mice. J Exp Med 199(11):1577–1584

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Ellyard JI, Avery DT, Phan TG, Hare NJ, Hodgkin PD, Tangye SG (2004) Antigen-selected, immunoglobulin-secreting cells persist in human spleen and bone marrow. Blood 103(10):3805–3812

    Article  CAS  PubMed  Google Scholar 

  76. Edwards JC et al (2004) Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis. N Engl J Med 350(25):2572–2581

    Article  CAS  PubMed  Google Scholar 

  77. Kreiner E et al. (2017) Shared genetic variants suggest common pathways in allergy and autoimmune diseases. J Allergy Clin Immunol

  78. Paternoster L, Standl M, Waage J, Baurecht H, Hotze M, Strachan DP, Curtin JA, Bønnelykke K, Tian C, Takahashi A et al (2015) Multi-ancestry genome-wide association study of 21,000 cases and 95,000 controls identifies new risk loci for atopic dermatitis. Nat Genet 47(12):1449–1456

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  79. Sabatos-Peyton CA, Verhagen J, Wraith DC (2010) Antigen-specific immunotherapy of autoimmune and allergic diseases. Curr Opin Immunol 22(5):609–615

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Malhotra D, Linehan JL, Dileepan T, Lee YJ, Purtha WE, Lu JV, Nelson RW, Fife BT, Orr HT, Anderson MS et al (2016) Tolerance is established in polyclonal CD4(+) T cells by distinct mechanisms, according to self-peptide expression patterns. Nat Immunol 17(2):187–195

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Doan T, McNally A, Thomas R, Steptoe RJ (2009) Steady-state dendritic cells continuously inactivate T cells that escape thymic negative selection. Immunol Cell Biol 87(8):615–622

    Article  PubMed  Google Scholar 

  82. Kenna TJ, Thomas R, Steptoe RJ (2008) Steady-state dendritic cells expressing cognate antigen terminate memory CD8+ T-cell responses. Blood 111(4):2091–2100

    Article  CAS  PubMed  Google Scholar 

  83. Nasreen M, Waldie TM, Dixon CM, Steptoe RJ (2010) Steady-state antigen-expressing dendritic cells terminate CD4+ memory T-cell responses. Eur J Immunol 40(7):2016–2025

    Article  CAS  PubMed  Google Scholar 

  84. Kenna TJ, Waldie T, McNally A, Thomson M, Yagita H, Thomas R, Steptoe RJ (2010) Targeting antigen to diverse APCs inactivates memory CD8+ T cells without eliciting tissue-destructive effector function. J Immunol 184(2):598–606

    Article  CAS  PubMed  Google Scholar 

  85. Reeves PLS et al. (2016) APC-targeted proinsulin expression inactivates insulin-specific memory CD8+ T cells in NOD mice. Immunol Cell Biol (In press)

  86. Haniuda K, Nojima T, Ohyama K, Kitamura D (2011) Tolerance induction of IgG+ memory B cells by T cell-independent type II antigens. J Immunol 186(10):5620–5628

    Article  CAS  PubMed  Google Scholar 

  87. Passweg J, Tyndall A (2007) Autologous stem cell transplantation in autoimmune diseases. Semin Hematol 44(4):278–285

    Article  PubMed  Google Scholar 

  88. Coleman MA, Steptoe RJ (2012) Induction of antigen-specific tolerance through hematopoietic stem cell-mediated gene therapy: the future for therapy of autoimmune disease? Autoimmun Rev 12(2):195–203

    Article  CAS  PubMed  Google Scholar 

  89. Coleman MA, Bridge JA, Lane SW, Dixon CM, Hill GR, Wells JW, Thomas R, Steptoe RJ (2013) Tolerance induction with gene-modified stem cells and immune-preserving conditioning in primed mice: restricting antigen to differentiated antigen-presenting cells permits efficacy. Blood 121(6):1049–1058

    Article  CAS  PubMed  Google Scholar 

  90. Chung JY, Figgett W, Fairfax K, Bernard C, Chan J, Toh BH, Mackay F, Alderuccio F (2014) Gene therapy delivery of myelin oligodendrocyte glycoprotein (MOG) via hematopoietic stem cell transfer induces MOG-specific B cell deletion. J Immunol 192(6):2593–2601

    Article  CAS  PubMed  Google Scholar 

  91. Bracy JL, Sachs DH, Iacomini J (1998) Inhibition of xenoreactive natural antibody production by retroviral gene therapy. Science 281(5384):1845–1847

    Article  CAS  PubMed  Google Scholar 

  92. Steptoe RJ, Ritchie JM, Harrison LC (2003) Transfer of hematopoietic stem cells encoding autoantigen prevents autoimmune diabetes. J Clin Invest 111(9):1357–1363

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Baranyi U, Linhart B, Pilat N, Gattringer M, Bagley J, Muehlbacher F, Iacomini J, Valenta R, Wekerle T (2008) Tolerization of a type I allergic immune response through transplantation of genetically modified hematopoietic stem cells. J Immunol 180(12):8168–8175

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Nasa Z, Chung JY, Chan J, Toh BH, Alderuccio F (2012) Nonmyeloablative conditioning generates autoantigen-encoding bone marrow that prevents and cures an experimental autoimmune disease. Am J Transplant 12(8):2062–2071

    Article  CAS  PubMed  Google Scholar 

  95. Lei TC, Scott DW (2005) Induction of tolerance to factor VIII inhibitors by gene therapy with immunodominant A2 and C2 domains presented by B cells as Ig fusion proteins. Blood 105(12):4865–4870

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Bhatt KH, Rudraraju R, Brooks JF, Jung JW, Galea R, Wells JW, Steptoe RJ (2017) Short-course rapamycin treatment enables engraftment of immunogenic gene-engineered bone marrow under low-dose irradiation to permit long-term immunological tolerance. Stem Cell Res Ther 8(1):57

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  97. Coleman MA, Jessup CF, Bridge JA, Overgaard NH, Penko D, Walters S, Borg DJ, Galea R, Forbes JM, Thomas R et al (2016) Antigen-encoding bone marrow terminates islet-directed memory CD8+ T-cell responses to alleviate islet transplant rejection. Diabetes 65(5):1328–1340

    Article  CAS  PubMed  Google Scholar 

  98. AL-Kouba J et al (2017) Allergen-encoding bone-marrow transfer inactivates allergic T-cell responses, alleviating airways inflammation. JCI Insight 2(11):e85742

    Article  PubMed Central  Google Scholar 

  99. Keeler GD et al. (2017) Gene therapy-induced antigen-specific Tregs inhibit neuro-inflammation and reverse disease in a mouse model of multiple sclerosis. Mol Ther

  100. Chen XT, Chan ST, Hosseini H, Layton D, Boyd R, Alderuccio F, Toh BH, Chan J (2011) Transplantation of retrovirally transduced bone marrow prevents autoimmune disease in aged mice by peripheral tolerance mechanisms. Autoimmunity 44(5):384–393

    Article  CAS  PubMed  Google Scholar 

  101. Botta D, Fuller MJ, Marquez-Lago TT, Bachus H, Bradley JE, Weinmann AS, Zajac AJ, Randall TD, Lund FE, León B et al (2017) Dynamic regulation of T follicular regulatory cell responses by interleukin 2 during influenza infection. Nat Immunol 18(11):1249–1260

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. May C, Rivella S, Callegari J, Heller G, Gaensler KM, Luzzatto L, Sadelain M (2000) Therapeutic haemoglobin synthesis in beta-thalassaemic mice expressing lentivirus-encoded human beta-globin. Nature 406(6791):82–86

    Article  CAS  PubMed  Google Scholar 

  103. Ko HJ, Chung JY, Nasa Z, Chan J, Siatskas C, Toh BH, Alderuccio F (2011) Targeting MOG expression to dendritic cells delays onset of experimental autoimmune disease. Autoimmunity 44(3):177–187

    Article  CAS  PubMed  Google Scholar 

  104. Dudziak D, Kamphorst AO, Heidkamp GF, Buchholz VR, Trumpfheller C, Yamazaki S, Cheong C, Liu K, Lee HW, Park CG et al (2007) Differential antigen processing by dendritic cell subsets in vivo. Science 315(5808):107–111

    Article  CAS  PubMed  Google Scholar 

  105. Yamazaki S, Iyoda T, Tarbell K, Olson K, Velinzon K, Inaba K, Steinman RM (2003) Direct expansion of functional CD25+ CD4+ regulatory T cells by antigen-processing dendritic cells. J Exp Med 198(2):235–247

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Corbett AJ, Caminschi I, McKenzie BS, Brady JL, Wright MD, Mottram PL, Hogarth PM, Hodder AN, Zhan Y, Tarlinton DM et al (2005) Antigen delivery via two molecules on the CD8—dendritic cell subset induces humoral immunity in the absence of conventional “danger”. Eur J Immunol 35(10):2815–2825

    Article  CAS  PubMed  Google Scholar 

  107. Mitsuhashi N, Fischer-Lougheed J, Shulkin I, Kleihauer A, Kohn DB, Weinberg KI, Starnes VA, Kearns-Jonker M (2006) Tolerance induction by lentiviral gene therapy with a nonmyeloablative regimen. Blood 107(6):2286–2293

    Article  CAS  PubMed  Google Scholar 

  108. Tay J, Levesque JP, Winkler IG (2017) Cellular players of hematopoietic stem cell mobilization in the bone marrow niche. Int J Hematol 105(2):129–140

    Article  CAS  PubMed  Google Scholar 

  109. Wang X, Rivière I (2017) Genetic engineering and manufacturing of hematopoietic stem cells. Mol Ther Methods Clin Dev 5:96–105

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Booth C, Gaspar HB, Thrasher AJ (2016) Treating immunodeficiency through HSC gene therapy. Trends Mol Med 22(4):317–327

    Article  CAS  PubMed  Google Scholar 

  111. Danos O, Mulligan RC (1988) Safe and efficient generation of recombinant retroviruses with amphotropic and ecotropic host ranges. Proc Natl Acad Sci U S A 85(17):6460–6464

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Naldini L, Blomer U, Gallay P, Ory D, Mulligan R, Gage FH, Verma IM, Trono D (1996) In vivo gene delivery and stable transduction of nondividing cells by a lentiviral vector. Science 272(5259):263–267

    Article  CAS  PubMed  Google Scholar 

  113. Shaw KL, Garabedian E, Mishra S, Barman P, Davila A, Carbonaro D, Shupien S, Silvin C, Geiger S, Nowicki B et al (2017) Clinical efficacy of gene-modified stem cells in adenosine deaminase-deficient immunodeficiency. J Clin Invest 127(5):1689–1699

    Article  PubMed  PubMed Central  Google Scholar 

  114. Ferrua F, Aiuti A (2017) Twenty-five years of gene therapy for ADA-SCID: from bubble babies to an approved drug. Hum Gene Ther 28(11):972–981

    Article  CAS  PubMed  Google Scholar 

  115. Hacein-Bey-Abina S, Pai SY, Gaspar HB, Armant M, Berry CC, Blanche S, Bleesing J, Blondeau J, de Boer H, Buckland KF et al (2014) A modified gamma-retrovirus vector for X-linked severe combined immunodeficiency. N Engl J Med 371(15):1407–1417

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  116. Hacein-Bey Abina S, Gaspar HB, Blondeau J, Caccavelli L, Charrier S, Buckland K, Picard C, Six E, Himoudi N, Gilmour K et al (2015) Outcomes following gene therapy in patients with severe Wiskott-Aldrich syndrome. JAMA 313(15):1550–1563

    Article  PubMed  CAS  Google Scholar 

  117. Aiuti A, Biasco L, Scaramuzza S, Ferrua F, Cicalese MP, Baricordi C, Dionisio F, Calabria A, Giannelli S, Castiello MC et al (2013) Lentiviral hematopoietic stem cell gene therapy in patients with Wiskott-Aldrich syndrome. Science 341(6148):1233151

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  118. Wang CX, Torbett BE (2015) Role of the mammalian target of rapamycin pathway in lentiviral vector transduction of hematopoietic stem cells. Curr Opin Hematol 22(4):302–308

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Farahbakhshian E, Verstegen MM, Visser TP, Kheradmandkia S, Geerts D, Arshad S, Riaz N, Grosveld F, van Til NP, Meijerink JPP (2014) Angiopoietin-like protein 3 promotes preservation of stemness during ex vivo expansion of murine hematopoietic stem cells. PLoS One 9(8):e105642. https://doi.org/10.1371/journal.pone.0105642

    Article  PubMed  PubMed Central  Google Scholar 

  120. Zonari E, Desantis G, Petrillo C, Boccalatte FE, Lidonnici MR, Kajaste-Rudnitski A, Aiuti A, Ferrari G, Naldini L, Gentner B (2017) Efficient ex vivo engineering and expansion of highly purified human hematopoietic stem and progenitor cell populations for gene therapy. Stem Cell Reports 8(4):977–990

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Pala F, Morbach H, Castiello MC, Schickel JN, Scaramuzza S, Chamberlain N, Cassani B, Glauzy S, Romberg N, Candotti F et al (2015) Lentiviral-mediated gene therapy restores B cell tolerance in Wiskott-Aldrich syndrome patients. J Clin Invest 125(10):3941–3951

    Article  PubMed  PubMed Central  Google Scholar 

  122. Chattong S, Ruangwattanasuk O, Yindeedej W, Setpakdee A, Manotham K (2017) CD34+ cells from dental pulp stem cells with a ZFN-mediated and homology-driven repair-mediated locus-specific knock-in of an artificial beta-globin gene. Gene Ther 24(7):425–432

    Article  CAS  PubMed  Google Scholar 

  123. Saydaminova K, Ye X, Wang H, Richter M, Ho M, Chen H, Xu N, Kim JS, Papapetrou E, Holmes MC et al (2015) Efficient genome editing in hematopoietic stem cells with helper-dependent Ad5/35 vectors expressing site-specific endonucleases under microRNA regulation. Mol Ther Methods Clin Dev 1:14057

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  124. Schiroli G, Ferrari S, Conway A, Jacob A, Capo V, Albano L, Plati T, Castiello MC, Sanvito F, Gennery AR et al (2017) Preclinical modeling highlights the therapeutic potential of hematopoietic stem cell gene editing for correction of SCID-X1. Sci Transl Med 9(411):eaan0820

    Article  PubMed  Google Scholar 

  125. Alzubi J, Pallant C, Mussolino C, Howe SJ, Thrasher AJ, Cathomen T (2017) Targeted genome editing restores T cell differentiation in a humanized X-SCID pluripotent stem cell disease model. Sci Rep 7(1):12475

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  126. Sugimura R, Jha DK, Han A, Soria-Valles C, da Rocha EL, Lu YF, Goettel JA, Serrao E, Rowe RG, Malleshaiah M et al (2017) Haematopoietic stem and progenitor cells from human pluripotent stem cells. Nature 545(7655):432–438

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Kushida T, Inaba M, Hisha H, Ichioka N, Esumi T, Ogawa R, Iida H, Ikehara S (2001) Intra-bone marrow injection of allogeneic bone marrow cells: a powerful new strategy for treatment of intractable autoimmune diseases in MRL/lpr mice. Blood 97(10):3292–3299

    Article  CAS  PubMed  Google Scholar 

  128. Richter M, Saydaminova K, Yumul R, Krishnan R, Liu J, Nagy EE, Singh M, Izsvak Z, Cattaneo R, Uckert W et al (2016) In vivo transduction of primitive mobilized hematopoietic stem cells after intravenous injection of integrating adenovirus vectors. Blood 128(18):2206–2217

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

RJS was supported by a University of Queensland Vice Chancellor’s Senior Research Fellowship. JMD was supported by Queensland University of Technology. JWW was supported by a Fellowship from the Perpetual Trustees. JFB was supported by an Australian Postgraduate Research Award and Children’s Hospital Foundation Top-up award (#50209 RPCPHD0072017).

Author information

Authors and Affiliations

  1. The University of Queensland, Translational Research Institute, University of Queensland Diamantina Institute, Level 6, 37 Kent Street, Woolloongabba, Queensland, 4102, Australia

    Jeremy F. Brooks, James W. Wells & Raymond J. Steptoe

  2. School of Biomedical Sciences, Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland, Australia

    Janet M. Davies

  3. Office of Research, Metro North Hospital and Health Service, Herston, Brisbane, Queensland, Australia

    Janet M. Davies

Authors
  1. Jeremy F. Brooks
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Janet M. Davies
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. James W. Wells
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Raymond J. Steptoe
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Raymond J. Steptoe.

Ethics declarations

Conflict of interest

The authors declare that they have no conflicts of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Brooks, J.F., Davies, J.M., Wells, J.W. et al. Re-educating immunity in respiratory allergies: the potential for hematopoietic stem cell-mediated gene therapy. J Mol Med 96, 21–30 (2018). https://doi.org/10.1007/s00109-017-1611-8

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00109-017-1611-8

Keywords

Search

Navigation