Clinical Reviews in Allergy & Immunology

, Volume 55, Issue 2, pp 172–189 | Cite as

Enhancing the Safety and Efficacy of Food Allergy Immunotherapy: a Review of Adjunctive Therapies

  • Yamini V. VirkudEmail author
  • Julie Wang
  • Wayne G. Shreffler


Food allergy is a potentially life-threatening condition with no approved curative therapy. A number of food allergen immunotherapies are being investigated in phase II/III trials; however, these are limited in their ability to restore immune tolerance to food allergens and often result in high rates of allergic side effects, sometimes involving anaphylaxis, that may curtail their impact. A variety of adjunctive therapies have been developed in order to enhance the efficacy and/or improve the safety of food allergen immunotherapy through either shifting the immune response from a Th2 polarized response to a Th1 and regulatory T cell dominated response or by blocking downstream effects of the allergic inflammatory response by targeting IgE or mast cell mediators. Upstream therapies that shift towards a Th1/Treg response include toll-like receptor (TLR) 4 agonists (e.g., MPL and GLA), TLR9 agonists (CpG oligonucleotides), nanoparticles encapsulating peanut allergen (with and without adjuvants, such as CpG or rapamycin), Chinese herbal medicine (food allergy herbal formula (FAHF-2)), probiotics, and interferon-gamma. In contrast, anti-IgE therapies such as omalizumab, anti-histamines like ketotifen, and leukotriene receptor antagonists all target the downstream allergic response. Anti-IgE-based therapies appear to be furthest along with probiotics, Chinese herbal medicines, and TLR-4 agonists currently in early phase clinical trials. Meanwhile, nanoparticles represent an innovative delivery vehicle for immunotherapy that could improve both efficacy and decrease allergic side effects. Furthermore, other biologic therapies directed towards the allergic immune response are on the horizon. A number of factors will need to be evaluated in comparing these treatments, including ability to decrease allergic adverse events, safety of the adjunctive therapies themselves, effect on long-term sustained unresponsiveness, and cost. Further phenotyping of food allergy patients may be necessary to determine which ones respond best to each therapy. However, with so many promising adjunctive therapies, it appears likely that clinicians will have a variety of options to optimize the administration of food allergen immunotherapy. We provided a review of these methods, their influence on allergic adverse events, and utility in improving the immunomodulatory effects of food allergen immunotherapy.


Food allergy Oral immunotherapy Immunotherapy Anti-IgE Omalizumab Nanoparticles Toll-like receptor agonists 



Immunoglobulin E


Toll-like receptor


T helper




Immunostimulatory sequence


Monophosphoryl lipid A


Glucopyranosyl lipid A




Mammalian target of rapamycin


Food allergy herbal formula 2


Leukotriene receptor antagonists


Double-blind, placebo-controlled food challenge


Compliance with Ethical Standards

Conflicts of Interest

The authors declare that they have no conflict of interest.

Research Involving Human Participants and/or Animals

This review article does not contain any studies with human participants or animals performed by any of the authors.

Informed Consent

This review article does not contain any primary work involving human participants requiring informed consent.


  1. 1.
    Sicherer SH, Muñoz-Furlong A, Godbold JH, Sampson HA (2010) US prevalence of self-reported peanut, tree nut, and sesame allergy: 11-year follow-up. J Allergy Clin Immunol 125(6):1322–1326PubMedCrossRefGoogle Scholar
  2. 2.
    Gupta RS, Springston EE, Warrier MR, Smith B, Kumar R, Pongracic J, Holl JL (2011) The prevalence, severity, and distribution of childhood food allergy in the United States. Pediatrics 128(1):e9–e17PubMedCrossRefGoogle Scholar
  3. 3.
    Keet CA, Savage JH, Seopaul S, Peng RD, Wood RA, Matsui EC (2014) Temporal trends and racial/ethnic disparity in self-reported pediatric food allergy in the United States. Ann Allergy Asthma Immunol 112(3):222–229 e3PubMedCentralPubMedCrossRefGoogle Scholar
  4. 4.
    Sampson HA, Aceves S, Bock SA, James J, Jones S, Lang D, Nadeau K, Nowak-Wegrzyn A, Oppenheimer J, Perry TT, Randolph C, Sicherer SH, Simon RA, Vickery BP, Wood R, Sampson HA, Randolph C, Bernstein D, Blessing-Moore J, Khan D, Lang D, Nicklas R, Oppenheimer J, Portnoy J, Randolph C, Schuller D, Spector S, Tilles SA, Wallace D, Sampson HA, Aceves S, Bock SA, James J, Jones S, Lang D, Nadeau K, Nowak-Wegrzyn A, Oppenheimer J, Perry TT, Randolph C, Sicherer SH, Simon RA, Vickery BP, Wood R (2014) Food allergy: a practice parameter update-2014. J Allergy Clin Immunol 134(5):1016–1025 e43PubMedCrossRefGoogle Scholar
  5. 5.
    Boyce JA, Assa'ad A, Burks AW, Jones SM, Sampson HA, Wood RA, Plaut M, Cooper SF, Fenton MJ, Arshad SH, Bahna SL, Beck LA, Byrd-Bredbenner C, Camargo CA Jr, Eichenfield L, Furuta GT, Hanifin JM, Jones C, Kraft M, Levy BD, Lieberman P, Luccioli S, McCall K, Schneider LC, Simon RA, Simons FE, Teach SJ, Yawn BP, Schwaninger JM, NIAID-Sponsored Expert Panel (2010) Guidelines for the diagnosis and Management of Food Allergy in the United States: summary of the NIAID-sponsored expert panel report. J Allergy Clin Immunol 126(6):1105–1118PubMedCentralPubMedCrossRefGoogle Scholar
  6. 6.
    Sampson HA (2013) Peanut oral immunotherapy: is it ready for clinical practice? J Allergy Clin Immunol Pract 1(1):15–21PubMedCrossRefGoogle Scholar
  7. 7.
    Varshney P, Jones SM, Scurlock AM, Perry TT, Kemper A, Steele P, Hiegel A, Kamilaris J, Carlisle S, Yue X, Kulis M, Pons L, Vickery B, Burks AW (2011) A randomized controlled study of peanut oral immunotherapy: clinical desensitization and modulation of the allergic response. J Allergy Clin Immunol 127(3):654–660PubMedCentralPubMedCrossRefGoogle Scholar
  8. 8.
    Hofmann AM et al (2009) Safety of a peanut oral immunotherapy protocol in children with peanut allergy. J Allergy Clin Immunol 124(2):286–291 291 e1–6PubMedCentralPubMedCrossRefGoogle Scholar
  9. 9.
    Virkud YV, Burks AW, Steele PH, Edwards LJ, Berglund JP, Jones SM, Scurlock AM, Perry TT, Pesek RD, Vickery BP (2017) Novel baseline predictors of adverse events during oral immunotherapy in children with peanut allergy. J Allergy Clin Immunol 139(3):882–888 e5PubMedCrossRefGoogle Scholar
  10. 10.
    Varshney P, Steele PH, Vickery BP, Bird JA, Thyagarajan A, Scurlock AM, Perry TT, Jones SM, Burks AW (2009) Adverse reactions during peanut oral immunotherapy home dosing. J Allergy Clin Immunol 124(6):1351–1352PubMedCentralPubMedCrossRefGoogle Scholar
  11. 11.
    Wasserman RL, Factor JM, Baker JW, Mansfield LE, Katz Y, Hague AR, Paul MM, Sugerman RW, Lee JO, Lester MR, Mendelson LM, Nacshon L, Levy MB, Goldberg MR, Elizur A (2014) Oral immunotherapy for peanut allergy: multipractice experience with epinephrine-treated reactions. J Allergy Clin Immunol Pract 2(1):91–96PubMedCrossRefGoogle Scholar
  12. 12.
    Kim EH, Bird JA, Kulis M, Laubach S, Pons L, Shreffler W, Steele P, Kamilaris J, Vickery B, Burks AW (2011) Sublingual immunotherapy for peanut allergy: clinical and immunologic evidence of desensitization. J Allergy Clin Immunol 127(3):640–646 e1PubMedCentralPubMedCrossRefGoogle Scholar
  13. 13.
    Keet CA et al (2012) The safety and efficacy of sublingual and oral immunotherapy for milk allergy. J Allergy Clin Immunol 129(2):448–455 455 e1–5PubMedCrossRefGoogle Scholar
  14. 14.
    Narisety SD, Frischmeyer-Guerrerio PA, Keet CA, Gorelik M, Schroeder J, Hamilton RG, Wood RA (2015) A randomized, double-blind, placebo-controlled pilot study of sublingual versus oral immunotherapy for the treatment of peanut allergy. J Allergy Clin Immunol 135(5):1275–1282 e6PubMedCrossRefGoogle Scholar
  15. 15.
    Jones SM, Sicherer SH, Burks AW, Leung DY, Lindblad RW, Dawson P, Henning AK, Berin MC, Chiang D, Vickery BP, Pesek RD, Cho CB, Davidson WF, Plaut M, Sampson HA, Wood RA, Consortium of Food Allergy Research (2017) Epicutaneous immunotherapy for the treatment of peanut allergy in children and young adults. J Allergy Clin Immunol 139(4):1242–1252 e9PubMedCrossRefGoogle Scholar
  16. 16.
    Gernez Y, Nowak-Wegrzyn A (2017) Immunotherapy for food allergy: are we there yet? J Allergy Clin Immunol Pract 5(2):250–272PubMedCrossRefGoogle Scholar
  17. 17.
    Cook QS, Burks AW (2018) Peptide and recombinant allergen vaccines for food allergy. Clin Rev Allergy ImmunolGoogle Scholar
  18. 18.
    Wood RA, Sicherer SH, Burks AW, Grishin A, Henning AK, Lindblad R, Stablein D, Sampson HA (2013) A phase 1 study of heat/phenol-killed, E. coli-encapsulated, recombinant modified peanut proteins Ara h 1, Ara h 2, and Ara h 3 (EMP-123) for the treatment of peanut allergy. Allergy 68(6):803–808PubMedCentralPubMedCrossRefGoogle Scholar
  19. 19.
    Vickery BP, Scurlock AM, Jones SM, Burks AW (2011) Mechanisms of immune tolerance relevant to food allergy. J Allergy Clin Immunol 127(3):576–584 quiz 585-6PubMedCentralPubMedCrossRefGoogle Scholar
  20. 20.
    Virkud YV, Vickery BP (2012) Advances in immunotherapy for food allergy. Discov Med 14(76):159–165PubMedCentralPubMedGoogle Scholar
  21. 21.
    Wambre E et al (2017) A phenotypically and functionally distinct human TH2 cell subpopulation is associated with allergic disorders. Sci Transl Med 9:401CrossRefGoogle Scholar
  22. 22.
    Van Gramberg JL et al (2013) Use of animal models to investigate major allergens associated with food allergy. J Allergy (Cairo) 2013:635695Google Scholar
  23. 23.
    MacGlashan DW Jr et al (1997) Down-regulation of fc(epsilon)RI expression on human basophils during in vivo treatment of atopic patients with anti-IgE antibody. J Immunol 158(3):1438–1445PubMedGoogle Scholar
  24. 24.
    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):1147–1154PubMedCrossRefGoogle Scholar
  25. 25.
    Leung DY, Sampson HA, Yunginger JW, Burks AW Jr, Schneider LC, Wortel CH, Davis FM, Hyun JD, Shanahan WR Jr, Avon Longitudinal Study of Parents and Children Study Team (2003) Effect of anti-IgE therapy in patients with peanut allergy. N Engl J Med 348(11):986–993PubMedCrossRefGoogle Scholar
  26. 26.
    Sampson HA, Leung DYM, Burks AW, Lack G, Bahna SL, Jones SM, Wong DA (2011) A phase II, randomized, doubleblind, parallelgroup, placebocontrolled oral food challenge trial of Xolair (omalizumab) in peanut allergy. J Allergy Clin Immunol 127(5):1309–1310 e1PubMedCrossRefGoogle Scholar
  27. 27.
    Nadeau KC, Schneider LC, Hoyte L, Borras I, Umetsu DT (2011) Rapid oral desensitization in combination with omalizumab therapy in patients with cow's milk allergy. J Allergy Clin Immunol 127(6):1622–1624PubMedCentralPubMedCrossRefGoogle Scholar
  28. 28.
    Schneider LC, Rachid R, LeBovidge J, Blood E, Mittal M, Umetsu DT (2013) A pilot study of omalizumab to facilitate rapid oral desensitization in high-risk peanut-allergic patients. J Allergy Clin Immunol 132(6):1368–1374PubMedCentralPubMedCrossRefGoogle Scholar
  29. 29.
    Lafuente I, Mazon A, Nieto M, Uixera S, Pina R, Nieto A (2014) Possible recurrence of symptoms after discontinuation of omalizumab in anti-IgE-assisted desensitization to egg. Pediatr Allergy Immunol 25(7):717–719PubMedCrossRefGoogle Scholar
  30. 30.
    Martorell-Calatayud C, Michavila-Gómez A, Martorell-Aragonés A, Molini-Menchón N, Cerdá-Mir JC, Félix-Toledo R, de las Marinas-Álvarez MD (2016) Anti-IgE-assisted desensitization to egg and cow's milk in patients refractory to conventional oral immunotherapy. Pediatr Allergy Immunol 27(5):544–546PubMedCrossRefGoogle Scholar
  31. 31.
    Burk CM, Dellon ES, Steele PH, Virkud YV, Kulis M, Burks AW, Vickery BP (2017) Eosinophilic esophagitis during peanut oral immunotherapy with omalizumab. J Allergy Clin Immunol Pract 5(2):498–501PubMedCrossRefGoogle Scholar
  32. 32.
    Peanut oral immunotherapy and anti-immunoglobulin E (IgE) for peanut allergy - full text view - Available from:
  33. 33.
    Lucendo AJ, Arias A, Tenias JM (2014) Relation between eosinophilic esophagitis and oral immunotherapy for food allergy: a systematic review with meta-analysis. Ann Allergy Asthma Immunol 113(6):624–629PubMedCrossRefGoogle Scholar
  34. 34.
    Wood RA et al (2016) A randomized, double-blind, placebo-controlled study of omalizumab combined with oral immunotherapy for the treatment of cow's milk allergy. J Allergy Clin Immunol 137(4):1103–1110 e1–11PubMedCrossRefGoogle Scholar
  35. 35.
    MacGinnitie AJ, Rachid R, Gragg H, Little SV, Lakin P, Cianferoni A, Heimall J, Makhija M, Robison R, Chinthrajah RS, Lee J, Lebovidge J, Dominguez T, Rooney C, Lewis MO, Koss J, Burke-Roberts E, Chin K, Logvinenko T, Pongracic JA, Umetsu DT, Spergel J, Nadeau KC, Schneider LC (2017) Omalizumab facilitates rapid oral desensitization for peanut allergy. J Allergy Clin Immunol 139(3):873–881 e8PubMedCrossRefGoogle Scholar
  36. 36.
    Begin P et al (2014) Phase 1 results of safety and tolerability in a rush oral immunotherapy protocol to multiple foods using Omalizumab. Allergy Asthma Clin Immunol 10(1):7PubMedCentralPubMedCrossRefGoogle Scholar
  37. 37.
    Bedoret D, Singh AK, Shaw V, Hoyte EG, Hamilton R, DeKruyff RH, Schneider LC, Nadeau KC, Umetsu DT (2012) Changes in antigen-specific T-cell number and function during oral desensitization in cow's milk allergy enabled with omalizumab. Mucosal Immunol 5(3):267–276PubMedCentralPubMedCrossRefGoogle Scholar
  38. 38.
    Begin P, Nadeau KC (2015) Changes in peanut-specific T-cell clonotype with oral immunotherapy. J Allergy Clin Immunol 135(6):1636–1638PubMedCrossRefGoogle Scholar
  39. 39.
    Frischmeyer-Guerrerio PA, Masilamani M, Gu W, Brittain E, Wood R, Kim J, Nadeau K, Jarvinen KM, Grishin A, Lindblad R, Sampson HA (2017) Mechanistic correlates of clinical responses to omalizumab in the setting of oral immunotherapy for milk allergy. J Allergy Clin Immunol 140:1043–1053.e8PubMedCentralPubMedCrossRefGoogle Scholar
  40. 40.
    Aryan Z, Rezaei N (2015) Toll-like receptors as targets for allergen immunotherapy. Curr Opin Allergy Clin Immunol 15(6):568–574PubMedCentralPubMedCrossRefGoogle Scholar
  41. 41.
    Tsai YG, Yang KD, Niu DM, Chien JW, Lin CY (2010) TLR2 agonists enhance CD8+Foxp3+ regulatory T cells and suppress Th2 immune responses during allergen immunotherapy. J Immunol 184(12):7229–7237PubMedCrossRefGoogle Scholar
  42. 42.
    Dabbagh K, Lewis DB (2003) Toll-like receptors and T-helper-1/T-helper-2 responses. Curr Opin Infect Dis 16(3):199–204PubMedCrossRefGoogle Scholar
  43. 43.
    Gangloff SC, Guenounou M (2004) Toll-like receptors and immune response in allergic disease. Clin Rev Allergy Immunol 26(2):115–125PubMedCrossRefGoogle Scholar
  44. 44.
    Bashir ME et al (2004) Toll-like receptor 4 signaling by intestinal microbes influences susceptibility to food allergy. J Immunol 172(11):6978–6987PubMedCentralPubMedCrossRefGoogle Scholar
  45. 45.
    Zhu FG, Kandimalla ER, Yu D, Agrawal S (2007) Oral administration of a synthetic agonist of toll-like receptor 9 potently modulates peanut-induced allergy in mice. J Allergy Clin Immunol 120(3):631–637PubMedCrossRefGoogle Scholar
  46. 46.
    Adel-Patient K, Ah-Leung S, Bernard H, Durieux-Alexandrenne C, Créminon C, Wal JM (2007) Oral sensitization to peanut is highly enhanced by application of peanut extracts to intact skin, but is prevented when CpG and cholera toxin are added. Int Arch Allergy Immunol 143(1):10–20PubMedCrossRefGoogle Scholar
  47. 47.
    Wang J, Sampson HA (2012) Treatments for food allergy: how close are we? Immunol Res 54(1–3):83–94PubMedCentralPubMedCrossRefGoogle Scholar
  48. 48.
    Srivastava K et al (2001) Investigation of the use of Iss-linked Ara h2 for the treatment of peanut-induced allergy. J Allergy Clin Immunol 107:S233Google Scholar
  49. 49.
    Kulis M, Gorentla B, Burks AW, Zhong XP (2013) Type B CpG oligodeoxynucleotides induce Th1 responses to peanut antigens: modulation of sensitization and utility in a truncated immunotherapy regimen in mice. Mol Nutr Food Res 57(5):906–915PubMedCrossRefGoogle Scholar
  50. 50.
    Tulic MK, Fiset PO, Christodoulopoulos P, Vaillancourt P, Desrosiers M, Lavigne F, Eiden J, Hamid Q (2004) Amb a 1-immunostimulatory oligodeoxynucleotide conjugate immunotherapy decreases the nasal inflammatory response. J Allergy Clin Immunol 113(2):235–241PubMedCrossRefGoogle Scholar
  51. 51.
    Drachenberg KJ, Wheeler AW, Stuebner P, Horak F (2001) A well-tolerated grass pollen-specific allergy vaccine containing a novel adjuvant, monophosphoryl lipid a, reduces allergic symptoms after only four preseasonal injections. Allergy 56(6):498–505PubMedCrossRefGoogle Scholar
  52. 52.
    Dolgin E (2016) Setbacks rattle allergy vaccine frontrunners, but hopes remain. Nat Biotechnol 34(9):901–902PubMedCrossRefGoogle Scholar
  53. 53.
    Pfaar O, Barth C, Jaschke C, Hörmann K, Klimek L (2011) Sublingual allergen-specific immunotherapy adjuvanted with monophosphoryl lipid a: a phase I/IIa study. Int Arch Allergy Immunol 154(4):336–344PubMedCrossRefGoogle Scholar
  54. 54.
    Patel P et al (2014) Efficacy of a short course of specific immunotherapy in patients with allergic rhinoconjunctivitis to ragweed pollen. J Allergy Clin Immunol 133(1):121–129 e1–2PubMedCrossRefGoogle Scholar
  55. 55.
    Rosewich M et al (2010) Ultra-short course immunotherapy in children and adolescents during a 3-yrs post-marketing surveillance study. Pediatr Allergy Immunol 21(1 Pt 2):e185–e189PubMedCrossRefGoogle Scholar
  56. 56.
    Lu H et al TLR4 Agonist GLA Modifies Th1/Th2 Cytokine Profiles in PBMC from Patients with Pollen Allergy. J Allergy Clin Immunol 137(2):AB266CrossRefGoogle Scholar
  57. 57.
    Soos TJ et al Glucopyranosyl Lipid a (GLA) a Toll-like Receptor 4 (TLR4) Agonist for Use As an Adjuvant in Combination with Peanut Allergen Immunotherapy. J Allergy Clin Immunol 137(2):AB129CrossRefGoogle Scholar
  58. 58.
    Treanor JJ, Essink B, Hull S, Reed S, Izikson R, Patriarca P, Goldenthal KL, Kohberger R, Dunkle LM (2013) Evaluation of safety and immunogenicity of recombinant influenza hemagglutinin (H5/Indonesia/05/2005) formulated with and without a stable oil-in-water emulsion containing glucopyranosyl-lipid a (SE+GLA) adjuvant. Vaccine 31(48):5760–5765PubMedCrossRefGoogle Scholar
  59. 59.
    De Souza Reboucas J et al (2012) Nanoparticulate adjuvants and delivery systems for allergen immunotherapy. J Biomed Biotechnol 2012:474605PubMedCentralPubMedCrossRefGoogle Scholar
  60. 60.
    Reboucas Jde S et al (2012) Development of poly(anhydride) nanoparticles loaded with peanut proteins: the influence of preparation method on the immunogenic properties. Eur J Pharm Biopharm 82(2):241–249PubMedCrossRefGoogle Scholar
  61. 61.
    Roy K, Mao HQ, Huang SK, Leong KW (1999) Oral gene delivery with chitosan--DNA nanoparticles generates immunologic protection in a murine model of peanut allergy. Nat Med 5(4):387–391PubMedCrossRefGoogle Scholar
  62. 62.
    Gomez S et al (2007) Gantrez AN nanoparticles as an adjuvant for oral immunotherapy with allergens. Vaccine 25(29):5263–5271PubMedCrossRefGoogle Scholar
  63. 63.
    De SRJ et al (2014) Immunogenicity of peanut proteins containing poly(anhydride) nanoparticles. Clin Vaccine Immunol 21(8):1106–1112CrossRefGoogle Scholar
  64. 64.
    Pali-Scholl I et al (2013) Protamine nanoparticles with CpG-oligodeoxynucleotide prevent an allergen-induced Th2-response in BALB/c mice. Eur J Pharm Biopharm 85(3 Pt A):656–664PubMedCrossRefGoogle Scholar
  65. 65.
    Srivastava KD, Siefert A, Fahmy TM, Caplan MJ, Li XM, Sampson HA (2016) Investigation of peanut oral immunotherapy with CpG/peanut nanoparticles in a murine model of peanut allergy. J Allergy Clin Immunol 138(2):536–543 e4PubMedCrossRefGoogle Scholar
  66. 66.
    Goldinger SM, Dummer R, Baumgaertner P, Mihic-Probst D, Schwarz K, Hammann-Haenni A, Willers J, Geldhof C, Prior JO, Kündig TM, Michielin O, Bachmann MF, Speiser DE (2012) Nano-particle vaccination combined with TLR-7 and -9 ligands triggers memory and effector CD8(+) T-cell responses in melanoma patients. Eur J Immunol 42(11):3049–3061PubMedCentralPubMedCrossRefGoogle Scholar
  67. 67.
    Maldonado RA, LaMothe RA, Ferrari JD, Zhang AH, Rossi RJ, Kolte PN, Griset AP, O’Neil C, Altreuter DH, Browning E, Johnston L, Farokhzad OC, Langer R, Scott DW, von Andrian UH, Kishimoto TK (2015) Polymeric synthetic nanoparticles for the induction of antigen-specific immunological tolerance. Proc Natl Acad Sci U S A 112(2):E156–E165PubMedCrossRefGoogle Scholar
  68. 68.
    Yamaki K, Yoshino S (2012) Preventive and therapeutic effects of rapamycin, a mammalian target of rapamycin inhibitor, on food allergy in mice. Allergy 67(10):1259–1270PubMedCrossRefGoogle Scholar
  69. 69.
    Mennini M, Dahdah L, Artesani MC, Fiocchi A, Martelli A (2017) Probiotics in asthma and allergy prevention. Front Pediatr 5:165PubMedCentralPubMedCrossRefGoogle Scholar
  70. 70.
    Zhang GQ, Hu HJ, Liu CY, Zhang Q, Shakya S, Li ZY (2016) Probiotics for prevention of atopy and food hypersensitivity in early childhood: a PRISMA-compliant systematic review and meta-analysis of randomized controlled trials. Medicine (Baltimore) 95(8):e2562CrossRefGoogle Scholar
  71. 71.
    Sudo N et al (1997) The requirement of intestinal bacterial flora for the development of an IgE production system fully susceptible to oral tolerance induction. J Immunol 159(4):1739–1745PubMedGoogle Scholar
  72. 72.
    Geuking MB, Cahenzli J, Lawson MAE, Ng DCK, Slack E, Hapfelmeier S, McCoy KD, Macpherson AJ (2011) Intestinal bacterial colonization induces mutualistic regulatory T cell responses. Immunity 34(5):794–806PubMedCrossRefGoogle Scholar
  73. 73.
    Ivanov II, Atarashi K, Manel N, Brodie EL, Shima T, Karaoz U, Wei D, Goldfarb KC, Santee CA, Lynch SV, Tanoue T, Imaoka A, Itoh K, Takeda K, Umesaki Y, Honda K, Littman DR (2009) Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell 139(3):485–498PubMedCentralPubMedCrossRefGoogle Scholar
  74. 74.
    Atarashi K, Tanoue T, Shima T, Imaoka A, Kuwahara T, Momose Y, Cheng G, Yamasaki S, Saito T, Ohba Y, Taniguchi T, Takeda K, Hori S, Ivanov II, Umesaki Y, Itoh K, Honda K (2011) Induction of colonic regulatory T cells by indigenous Clostridium species. Science 331(6015):337–341PubMedCrossRefGoogle Scholar
  75. 75.
    Stefka AT, Feehley T, Tripathi P, Qiu J, McCoy K, Mazmanian SK, Tjota MY, Seo GY, Cao S, Theriault BR, Antonopoulos DA, Zhou L, Chang EB, Fu YX, Nagler CR (2014) Commensal bacteria protect against food allergen sensitization. Proc Natl Acad Sci U S A 111(36):13145–13150PubMedCentralPubMedCrossRefGoogle Scholar
  76. 76.
    Van Overtvelt L et al (2010) Lactic acid bacteria as adjuvants for sublingual allergy vaccines. Vaccine 28(17):2986–2992PubMedCrossRefGoogle Scholar
  77. 77.
    Tang ML et al (2015) Administration of a probiotic with peanut oral immunotherapy: a randomized trial. J Allergy Clin Immunol 135(3):737–744 e8PubMedCrossRefGoogle Scholar
  78. 78.
    Miettinen M, Matikainen S, Vuopio-Varkila J, Pirhonen J, Varkila K, Kurimoto M, Julkunen I (1998) Lactobacilli and streptococci induce interleukin-12 (IL-12), IL-18, and gamma interferon production in human peripheral blood mononuclear cells. Infect Immun 66(12):6058–6062PubMedCentralPubMedGoogle Scholar
  79. 79.
    Pohjavuori E, Viljanen M, Korpela R, Kuitunen M, Tiittanen M, Vaarala O, Savilahti E (2004) Lactobacillus GG effect in increasing IFN-gamma production in infants with cow's milk allergy. J Allergy Clin Immunol 114(1):131–136PubMedCrossRefPubMedCentralGoogle Scholar
  80. 80.
    Pessi T, Sutas Y, Hurme M, Isolauri E (2000) Interleukin-10 generation in atopic children following oral lactobacillus rhamnosus GG. Clin Exp Allergy 30(12):1804–1808PubMedCrossRefGoogle Scholar
  81. 81.
    Vickery BP, Scurlock AM, Kulis M, Steele PH, Kamilaris J, Berglund JP, Burk C, Hiegel A, Carlisle S, Christie L, Perry TT, Pesek RD, Sheikh S, Virkud Y, Smith PB, Shamji MH, Durham SR, Jones SM, Burks AW (2014) Sustained unresponsiveness to peanut in subjects who have completed peanut oral immunotherapy. J Allergy Clin Immunol 133(2):468–475PubMedCrossRefGoogle Scholar
  82. 82.
    Hsiao K-C et al. (2017) Long-term clinical and immunological effects of probiotic and peanut oral immunotherapy after treatment cessation: 4-year follow-up of a randomised, double-blind, placebo-controlled trial. Lancet Child Adolesc Health 1:97–105CrossRefGoogle Scholar
  83. 83.
    Skolnick HS, Conover-Walker MK, Koerner CB, Sampson HA, Burks W, Wood RA (2001) The natural history of peanut allergy. J Allergy Clin Immunol 107(2):367–374PubMedCrossRefGoogle Scholar
  84. 84.
    Tang MLK et al. (2017) Probiotics and oral immunotherapy for peanut allergy – Authors' reply. Lancet Child Adolesc Health 1(3):e1–e2CrossRefGoogle Scholar
  85. 85.
    Srivastava KD, Kattan JD, Zou ZM, Li JH, Zhang L, Wallenstein S, Goldfarb J, Sampson HA, Li XM (2005) The Chinese herbal medicine formula FAHF-2 completely blocks anaphylactic reactions in a murine model of peanut allergy. J Allergy Clin Immunol 115(1):171–178PubMedCrossRefGoogle Scholar
  86. 86.
    Bensky D, Gamble A (1993) Chinese Herbal Medicine: Materia Medica. Eastland Press, SeattleGoogle Scholar
  87. 87.
    He FH, Wu WP (2004) Clinical application of Wu-Mei-wan. Zhong Gui Yi Yao Xue Ba 19:748–750Google Scholar
  88. 88.
    Tasaka K, Akagi M, Miyoshi K, Mio M, Makino T (1988) Anti-allergic constituents in the culture medium of Ganoderma lucidum. (I). Inhibitory effect of oleic acid on histamine release. Agents Actions 23(3–4):153–156PubMedCrossRefGoogle Scholar
  89. 89.
    Huang KC (1999) The pharmacology of Chinese herbs, 2nd edn. CRC Press, Boca RatonGoogle Scholar
  90. 90.
    Qu C, Srivastava K, Ko J, Zhang TF, Sampson HA, Li XM (2007) Induction of tolerance after establishment of peanut allergy by the food allergy herbal formula-2 is associated with up-regulation of interferon-gamma. Clin Exp Allergy 37(6):846–855PubMedCrossRefGoogle Scholar
  91. 91.
    Srivastava KD, Qu C, Zhang T, Goldfarb J, Sampson HA, Li XM (2009) Food allergy herbal Formula-2 silences peanut-induced anaphylaxis for a prolonged posttreatment period via IFN-gamma-producing CD8+ T cells. J Allergy Clin Immunol 123(2):443–451PubMedCrossRefGoogle Scholar
  92. 92.
    Song Y, Qu C, Srivastava K, Yang N, Busse P, Zhao W, Li XM (2010) Food allergy herbal formula 2 protection against peanut anaphylactic reaction is via inhibition of mast cells and basophils. J Allergy Clin Immunol 126(6):1208–1217.e3PubMedCentralPubMedCrossRefGoogle Scholar
  93. 93.
    Srivastava KD, Bardina L, Sampson HA, Li XM (2012) Efficacy and immunological actions of FAHF-2 in a murine model of multiple food allergies. Ann Allergy Asthma Immunol 108(5):351–358.e1PubMedCrossRefGoogle Scholar
  94. 94.
    Wang J, Patil SP, Yang N, Ko J, Lee J, Noone S, Sampson HA, Li XM (2010) Safety, tolerability, and immunologic effects of a food allergy herbal formula in food allergic individuals: a randomized, double-blinded, placebo-controlled, dose escalation, phase 1 study. Ann Allergy Asthma Immunol 105(1):75–84PubMedCentralPubMedCrossRefGoogle Scholar
  95. 95.
    Patil SP, Wang J, Song Y, Noone S, Yang N, Wallenstein S, Sampson HA, Li XM (2011) Clinical safety of food allergy herbal Formula-2 (FAHF-2) and inhibitory effect on basophils from patients with food allergy: extended phase I study. J Allergy Clin Immunol 128(6):1259–1265.e2PubMedCentralPubMedCrossRefGoogle Scholar
  96. 96.
    Wang J, Jones SM, Pongracic JA, Song Y, Yang N, Sicherer SH, Makhija MM, Robison RG, Moshier E, Godbold J, Sampson HA, Li XM (2015) Safety, clinical, and immunologic efficacy of a Chinese herbal medicine (food allergy herbal Formula-2) for food allergy. J Allergy Clin Immunol 136(4):962–970.e1PubMedCentralPubMedCrossRefGoogle Scholar
  97. 97.
    Srivastava K, Yang N, Chen Y, Lopez-Exposito I, Song Y, Goldfarb J, Zhan J, Sampson H, Li XM (2011) Efficacy, safety and immunological actions of butanol-extracted food allergy herbal Formula-2 on peanut anaphylaxis. Clin Exp Allergy 41(4):582–591PubMedCrossRefGoogle Scholar
  98. 98.
    Srivastava KD, Song Y, Yang N, Liu C, Goldberg IE, Nowak-Węgrzyn A, Sampson HA, Li XM (2017) B-FAHF-2 plus oral immunotherapy (OIT) is safer and more effective than OIT alone in a murine model of concurrent peanut/tree nut allergy. Clin Exp Allergy 47(8):1038–1049PubMedCentralPubMedCrossRefGoogle Scholar
  99. 99.
    Suomalainen H, Soppi E, Laine S, Isolauri E (1993) Immunologic disturbances in cow's milk allergy, 2: evidence for defective interferon-gamma generation. Pediatr Allergy Immunol 4(4):203–207PubMedCrossRefGoogle Scholar
  100. 100.
    Noh G, Lee SS (2009) A pilot study of interferon-gamma-induced specific oral tolerance induction (ISOTI) for immunoglobulin E-mediated anaphylactic food allergy. J Interf Cytokine Res 29(10):667–675CrossRefGoogle Scholar
  101. 101.
    Kabra SK, Pandey RM, Singh R, Seth V (2000) Ketotifen for asthma in children aged 5 to 15 years: a randomized placebo-controlled trial. Ann Allergy Asthma Immunol 85(1):46–52PubMedCrossRefGoogle Scholar
  102. 102.
    Abelson MB, Chapin MJ, Kapik BM, Shams NB (2003) Efficacy of ketotifen fumarate 0.025% ophthalmic solution compared with placebo in the conjunctival allergen challenge model. Arch Ophthalmol 121(5):626–630PubMedCrossRefGoogle Scholar
  103. 103.
    Melamed I, Feanny SJ, Sherman PM, Roifman CM (1991) Benefit of ketotifen in patients with eosinophilic gastroenteritis. Am J Med 90(3):310–314PubMedCrossRefGoogle Scholar
  104. 104.
    Jagdis A, Berlin N, Barron C, Giruparajah M, Leader N, Maclachlan S, Sussman GL (2014) Effect of ketotifen premedication on adverse reactions during peanut oral immunotherapy. Allergy Asthma Clin Immunol 10(1):36PubMedCentralPubMedCrossRefGoogle Scholar
  105. 105.
    Tantisira KG, Drazen JM (2009) Genetics and pharmacogenetics of the leukotriene pathway. J Allergy Clin Immunol 124(3):422–427PubMedCentralPubMedCrossRefGoogle Scholar
  106. 106.
    Alexander JA, Ravi K, Enders FT, Geno DM, Kryzer LA, Mara KC, Smyrk TC, Katzka DA (2017) Montelukast does not maintain symptom remission after topical steroid therapy for eosinophilic esophagitis. Clin Gastroenterol Hepatol 15(2):214–221.e2PubMedCrossRefGoogle Scholar
  107. 107.
    Attwood SE, Lewis CJ, Bronder CS, Morris CD, Armstrong GR, Whittam J (2003) Eosinophilic oesophagitis: a novel treatment using Montelukast. Gut 52(2):181–185PubMedCentralPubMedCrossRefGoogle Scholar
  108. 108.
    Lucendo AJ, Molina-Infante J, Arias Á, von Arnim U, Bredenoord AJ, Bussmann C, Amil Dias J, Bove M, González-Cervera J, Larsson H, Miehlke S, Papadopoulou A, Rodríguez-Sánchez J, Ravelli A, Ronkainen J, Santander C, Schoepfer AM, Storr MA, Terreehorst I, Straumann A, Attwood SE (2017) Guidelines on eosinophilic esophagitis: evidence-based statements and recommendations for diagnosis and management in children and adults. United European Gastroenterol J 5(3):335–358PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Division of Allergy and Immunology, Department of PediatricsMassachusetts General HospitalBostonUSA
  2. 2.Division of Allergy and Immunology, Department of PediatricsMount Sinai HospitalNew YorkUSA

Personalised recommendations