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

Abstract

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.

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

Fig. 1
Fig. 2

Abbreviations

IgE:

Immunoglobulin E

TLR:

Toll-like receptor

Th:

T helper

CpG:

Cytosine-phosphate-guanine

ISS:

Immunostimulatory sequence

MPL:

Monophosphoryl lipid A

GLA:

Glucopyranosyl lipid A

OVA:

Ovalbumin

mTOR:

Mammalian target of rapamycin

FAHF-2:

Food allergy herbal formula 2

LTRA:

Leukotriene receptor antagonists

DBPCFC:

Double-blind, placebo-controlled food challenge

References

  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):1322–1326

    CAS  PubMed  Article  Google 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–e17

    PubMed  Article  Google 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 e3

    PubMed Central  PubMed  Article  Google 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 e43

    PubMed  Article  Google 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):1105–1118

    PubMed Central  PubMed  Article  Google Scholar 

  6. 6.

    Sampson HA (2013) Peanut oral immunotherapy: is it ready for clinical practice? J Allergy Clin Immunol Pract 1(1):15–21

    PubMed  Article  Google 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):654–660

    CAS  PubMed Central  PubMed  Article  Google 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 e1–6

    CAS  PubMed Central  PubMed  Article  Google 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 e5

    PubMed  Article  Google 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):1351–1352

    PubMed Central  PubMed  Article  Google 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):91–96

    PubMed  Article  Google 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 e1

    CAS  PubMed Central  PubMed  Article  Google 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 e1–5

    CAS  PubMed  Article  Google 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 e6

    CAS  PubMed  Article  Google 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 e9

    CAS  PubMed  Article  Google Scholar 

  16. 16.

    Gernez Y, Nowak-Wegrzyn A (2017) Immunotherapy for food allergy: are we there yet? J Allergy Clin Immunol Pract 5(2):250–272

    PubMed  Article  Google Scholar 

  17. 17.

    Cook QS, Burks AW (2018) Peptide and recombinant allergen vaccines for food allergy. Clin Rev Allergy Immunol

  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):803–808

    CAS  PubMed Central  PubMed  Article  Google 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 585-6

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  20. 20.

    Virkud YV, Vickery BP (2012) Advances in immunotherapy for food allergy. Discov Med 14(76):159–165

    PubMed Central  PubMed  Google 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 9:401

    Article  Google Scholar 

  22. 22.

    Van Gramberg JL et al (2013) Use of animal models to investigate major allergens associated with food allergy. J Allergy (Cairo) 2013:635695

    Google 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):1438–1445

    CAS  PubMed  Google 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):1147–1154

    CAS  PubMed  Article  Google 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):986–993

    CAS  PubMed  Article  Google 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 e1

    CAS  PubMed  Article  Google 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):1622–1624

    PubMed Central  PubMed  Article  Google 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):1368–1374

    CAS  PubMed Central  PubMed  Article  Google 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):717–719

    PubMed  Article  Google 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):544–546

    CAS  PubMed  Article  Google 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):498–501

    PubMed  Article  Google Scholar 

  32. 32.

    Peanut oral immunotherapy and anti-immunoglobulin E (IgE) for peanut allergy - full text view - ClinicalTrials.gov. Available from: https://clinicaltrials.gov/ct2/show/NCT00932282

  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):624–629

    PubMed  Article  Google 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 e1–11

    CAS  PubMed  Article  Google 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 e8

    CAS  PubMed  Article  Google 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):7

    PubMed Central  PubMed  Article  CAS  Google 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):267–276

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  38. 38.

    Begin P, Nadeau KC (2015) Changes in peanut-specific T-cell clonotype with oral immunotherapy. J Allergy Clin Immunol 135(6):1636–1638

    CAS  PubMed  Article  Google 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.e8

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  40. 40.

    Aryan Z, Rezaei N (2015) Toll-like receptors as targets for allergen immunotherapy. Curr Opin Allergy Clin Immunol 15(6):568–574

    CAS  PubMed Central  PubMed  Article  Google 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):7229–7237

    CAS  PubMed  Article  Google 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):199–204

    PubMed  Article  Google Scholar 

  43. 43.

    Gangloff SC, Guenounou M (2004) Toll-like receptors and immune response in allergic disease. Clin Rev Allergy Immunol 26(2):115–125

    CAS  PubMed  Article  Google 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):6978–6987

    CAS  PubMed Central  PubMed  Article  Google 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):631–637

    CAS  PubMed  Article  Google 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):10–20

    CAS  PubMed  Article  Google Scholar 

  47. 47.

    Wang J, Sampson HA (2012) Treatments for food allergy: how close are we? Immunol Res 54(1–3):83–94

    PubMed Central  PubMed  Article  CAS  Google 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:S233

    Google 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):906–915

    CAS  PubMed  Article  Google 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):235–241

    CAS  PubMed  Article  Google 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):498–505

    CAS  PubMed  Article  Google Scholar 

  52. 52.

    Dolgin E (2016) Setbacks rattle allergy vaccine frontrunners, but hopes remain. Nat Biotechnol 34(9):901–902

    CAS  PubMed  Article  Google 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):336–344

    CAS  PubMed  Article  Google 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 e1–2

    PubMed  Article  Google 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–e189

    PubMed  Article  Google 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):AB266

    Article  Google 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):AB129

    Article  Google 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):5760–5765

    CAS  PubMed  Article  Google Scholar 

  59. 59.

    De Souza Reboucas J et al (2012) Nanoparticulate adjuvants and delivery systems for allergen immunotherapy. J Biomed Biotechnol 2012:474605

    PubMed Central  PubMed  Article  CAS  Google 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):241–249

    PubMed  Article  CAS  Google 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):387–391

    CAS  PubMed  Article  Google Scholar 

  62. 62.

    Gomez S et al (2007) Gantrez AN nanoparticles as an adjuvant for oral immunotherapy with allergens. Vaccine 25(29):5263–5271

    CAS  PubMed  Article  Google Scholar 

  63. 63.

    De SRJ et al (2014) Immunogenicity of peanut proteins containing poly(anhydride) nanoparticles. Clin Vaccine Immunol 21(8):1106–1112

    Article  CAS  Google 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):656–664

    PubMed  Article  CAS  Google 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 e4

    CAS  PubMed  Article  Google 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):3049–3061

    CAS  PubMed Central  PubMed  Article  Google 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–E165

    CAS  PubMed  Article  Google 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):1259–1270

    CAS  PubMed  Article  Google Scholar 

  69. 69.

    Mennini M, Dahdah L, Artesani MC, Fiocchi A, Martelli A (2017) Probiotics in asthma and allergy prevention. Front Pediatr 5:165

    PubMed Central  PubMed  Article  Google 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):e2562

    Article  Google 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):1739–1745

    CAS  PubMed  Google 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):794–806

    CAS  PubMed  Article  Google 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):485–498

    CAS  PubMed Central  PubMed  Article  Google 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):337–341

    CAS  PubMed  Article  Google 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):13145–13150

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  76. 76.

    Van Overtvelt L et al (2010) Lactic acid bacteria as adjuvants for sublingual allergy vaccines. Vaccine 28(17):2986–2992

    PubMed  Article  CAS  Google 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 e8

    CAS  PubMed  Article  Google 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):6058–6062

    CAS  PubMed Central  PubMed  Google 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):131–136

    CAS  PubMed  Article  PubMed Central  Google 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):1804–1808

    CAS  PubMed  Article  Google 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):468–475

    CAS  PubMed  Article  Google 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 1:97–105

    Article  Google 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):367–374

    CAS  PubMed  Article  Google Scholar 

  84. 84.

    Tang MLK et al. (2017) Probiotics and oral immunotherapy for peanut allergy – Authors' reply. Lancet Child Adolesc Health 1(3):e1–e2

    Article  Google 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):171–178

    PubMed  Article  Google Scholar 

  86. 86.

    Bensky D, Gamble A (1993) Chinese Herbal Medicine: Materia Medica. Eastland Press, Seattle

    Google Scholar 

  87. 87.

    He FH, Wu WP (2004) Clinical application of Wu-Mei-wan. Zhong Gui Yi Yao Xue Ba 19:748–750

    Google 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):153–156

    CAS  PubMed  Article  Google Scholar 

  89. 89.

    Huang KC (1999) The pharmacology of Chinese herbs, 2nd edn. CRC Press, Boca Raton

    Google 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):846–855

    CAS  PubMed  Article  Google 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):443–451

    CAS  PubMed  Article  Google 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.e3

    CAS  PubMed Central  PubMed  Article  Google 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.e1

    CAS  PubMed  Article  Google 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):75–84

    CAS  PubMed Central  PubMed  Article  Google 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.e2

    PubMed Central  PubMed  Article  Google 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.e1

    PubMed Central  PubMed  Article  Google 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):582–591

    CAS  PubMed  Article  Google 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):1038–1049

    CAS  PubMed Central  PubMed  Article  Google 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):203–207

    CAS  PubMed  Article  Google 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):667–675

    CAS  Article  Google 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):46–52

    CAS  PubMed  Article  Google 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):626–630

    CAS  PubMed  Article  Google 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):310–314

    CAS  PubMed  Article  Google 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):36

    PubMed Central  PubMed  Article  CAS  Google Scholar 

  105. 105.

    Tantisira KG, Drazen JM (2009) Genetics and pharmacogenetics of the leukotriene pathway. J Allergy Clin Immunol 124(3):422–427

    CAS  PubMed Central  PubMed  Article  Google 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.e2

    CAS  PubMed  Article  Google 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):181–185

    CAS  PubMed Central  PubMed  Article  Google 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):335–358

    PubMed Central  PubMed  Article  Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to Yamini V. Virkud.

Ethics declarations

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.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Virkud, Y.V., Wang, J. & Shreffler, W.G. Enhancing the Safety and Efficacy of Food Allergy Immunotherapy: a Review of Adjunctive Therapies. Clinic Rev Allerg Immunol 55, 172–189 (2018). https://doi.org/10.1007/s12016-018-8694-z

Download citation

Keywords

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