Novel strategies in immunotherapy for allergic diseases

Mohana Rajakulendran; Elizabeth Huiwen Tham; Jian Yi Soh; HP Van Bever

doi:10.5415/apallergy.2018.8.e14

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Rajakulendran, Tham, Soh, and Bever: Novel strategies in immunotherapy for allergic diseases

Current Review

Asia Pac Allergy 2018;8(2):e14.

Published online: 4 April 2018

DOI: https://doi.org/10.5415/apallergy.2018.8.e14

Novel strategies in immunotherapy for allergic diseases

Mohana Rajakulendran^1,^*, Elizabeth Huiwen Tham^1,², Jian Yi Soh^1,², HP Van Bever^1,²

¹Khoo Teck Puat – National University Children's Medical Institute, National University Health System, Singapore 119229

²Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119229

^*Correspondence to Mohana Rajakulendran Department of Paediatrics, National University Health System, Tower Block Level 12, 1E Kent Ridge Road., Singapore 119229. Tel: +65-6772-4112 Fax: +65-6779-7486 E-mail: mohana_rajakulendran@nuhs.edu.sg

Received 30 January 2018 Accepted 2 April 2018

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Conventional immunotherapy (IT) for optimal control of respiratory and food allergies has been fraught with concerns of efficacy, safety, and tolerability. The development of adjuvants to conventional IT has potentially increased the effectiveness and safety of allergen IT, which may translate into improved clinical outcomes and sustained unresponsiveness even after cessation of therapy. Novel strategies incorporating the successful use of adjuvants such as allergoids, immunostimulatory DNA sequences, monoclonal antibodies, carriers, recombinant proteins, and probiotics have now been described in clinical and murine studies. Future approaches may include fungal compounds, parasitic molecules, vitamin D, and traditional Chinese herbs. More robust comparative clinical trials are needed to evaluate the safety, clinical efficacy, and cost effectiveness of various adjuvants in order to determine ideal candidates in disease-specific and allergen-specific models. Other suggested approaches to further optimize outcomes of IT include early introduction of IT during an optimal window period. Alternative routes of administration of IT to optimize delivery and yet minimize potential side effects require further evaluation for safety and efficacy before they can be recommended.

Keywords: Immunotherapy, Allergy immunology, Allergoid, Immunologic stimulation, Monoclonal antibody, Probiotics

References

1. Larenas-Linnemann D, Pfaar O. Patient-reported outcomes and quality-of-life questionnaires in the assessment of rhinoconjunctivitis in childhood. Curr Opin Allergy Clin Immunol. 2014; 14:192–9.

2. Zuberbier T, Lötvall J, Simoens S, Subramanian SV, Church MK. Economic burden of inadequate management of allergic diseases in the European Union: a GA(2) LEN review. Allergy. 2014; 69:1275–9.

3. Jutel M, Akdis M, Budak F, Aebischer-Casaulta C, Wrzyszcz M, Blaser K, Akdis CA. IL-10 and TGF-beta cooperate in the regulatory T cell response to mucosal allergens in normal immunity and specific immunotherapy. Eur J Immunol. 2003; 33:1205–14.

4. Akdis M, Akdis CA. Mechanisms of allergen-specific immunotherapy: multiple suppressor factors at work in immune tolerance to allergens. J Allergy Clin Immunol. 2014; 133:621–31.

5. van de Veen W, Stanic B, Yaman G, Wawrzyniak M, Söllner S, Akdis DG, Rückert B, Akdis CA, Akdis M. IgG4 production is confined to human IL-10-producing regulatory B cells that suppress antigen-specific immune responses. J Allergy Clin Immunol. 2013; 131:1204–12.

6. Akdis CA, Akdis M. Mechanisms of allergen-specific immunotherapy. J Allergy Clin Immunol. 2011; 127:18–27.

7. Tophof MA, Hermanns A, Adelt T, Eberle P, Gronke C, Friedrichs F, Knecht R, Mönter E, Schöpfer H, Schwerk N, Steinbach J, Umpfenbach HU, Weißhaar C, Wilmsmeyer B, Bufe A. Side effects during subcutaneous immunotherapy in children with allergic diseases. Pediatr Allergy Immunol. 2017 Dec 16. [Epub].https://doi.org/10.1111/pai.12847.

8. Pajno GB, Caminiti L, Chiera F, Crisafulli G, Salzano G, Arasi S, Passalacqua G. Safety profile of oral immunotherapy with cow's milk and hen egg: A 10-year experience in controlled trials. Allergy Asthma Proc. 2016; 37:400–3.

9. Kulmala P, Pelkonen AS, Kuitunen M, Paassilta M, Remes S, Schultz R, Dunder T, Turunen S, Mäkelä MJ. Wheat oral immunotherapy was moderately successful but was associated with very frequent adverse events in children aged 6-18 years. Acta Paediatr. 2018 Jan 18. [Epub].https://doi.org/10.1111/apa.14226.

10. Di Costanzo M, Paparo L, Cosenza L, Di Scala C, Nocerino R, Aitoro R, Canani RB. Food allergies: novel mechanisms and therapeutic perspectives. Methods Mol Biol. 2016; 1371:215–21.

11. Jongejan L, van Ree R. Modified allergens and their potential to treat allergic disease. Curr Allergy Asthma Rep. 2014; 14:478.

12. Casanovas M, Gómez MJ, Carnés J, Fernández-Caldas E. Skin tests with native, depigmented and glutaraldehyde polymerized allergen extracts. J Investig Allergol Clin Immunol. 2005; 15:30–6.

13. Gallego MT, Iraola V, Himly M, Robinson DS, Badiola C, García-Robaina JC, Briza P, Carnés J. Depigmented and polymerised house dust mite allergoid: allergen content, induction of IgG4 and clinical response. Int Arch Allergy Immunol. 2010; 153:61–9.

14. Henmar H, Lund G, Lund L, Petersen A, Würtzen PA. Allergenicity, immunogenicity and dose-relationship of three intact allergen vaccines and four allergoid vaccines for subcutaneous grass pollen immunotherapy. Clin Exp Immunol. 2008; 153:316–23.

15. Würtzen PA, Lund L, Lund G, Holm J, Millner A, Henmar H. Chemical modification of birch allergen extract leads to a reduction in allergenicity as well as immunogenicity. Int Arch Allergy Immunol. 2007; 144:287–95.

16. Lund L, Henmar H, Würtzen PA, Lund G, Hjortskov N, Larsen JN. Comparison of allergenicity and immunogenicity of an intact allergen vaccine and commercially available allergoid products for birch pollen immunotherapy. Clin Exp Allergy. 2007; 37:564–71.

17. Heydenreich B, Bellinghausen I, Lorenz S, Henmar H, Strand D, Würtzen PA, Saloga J. Reduced in vitro T-cell responses induced by glutaraldehyde-modified allergen extracts are caused mainly by retarded internalization of dendritic cells. Immunology. 2012; 136:208–17.

18. Reinhold T, Brüggenjürgen B. Cost-effectiveness of grass pollen SCIT compared with SLIT and symptomatic treatment. Allergo J Int. 2017; 26:7–15.

19. Rosewich M, Lee D, Zielen S. Pollinex Quattro: an innovative four injections immunotherapy in allergic rhinitis. Hum Vaccin Immunother. 2013; 9:1523–31.

20. Carnés J, Himly M, Gallego M, Iraola V, Robinson DS, Fernández-Caldas E, Briza P. Detection of allergen composition and in vivo immunogenicity of depigmented allergoids of Betula alba. Clin Exp Allergy. 2009; 39:426–34.

21. Heydenreich B, Bellinghausen I, Lund L, Henmar H, Lund G, Adler Würtzen P, Saloga J. Adjuvant effects of aluminium hydroxide-adsorbed allergens and allergoids – differences in vivo and in vitro. Clin Exp Immunol. 2014; 176:310–9.

22. Higgins D, Marshall JD, Traquina P, Van Nest G, Livingston BD. Immunostimulatory DNA as a vaccine adjuvant. Expert Rev Vaccines. 2007; 6:747–59.

23. Creticos PS, Schroeder JT, Hamilton RG, Balcer-Whaley SL, Khattignavong AP, Lindblad R, Li H, Coffman R, Seyfert V, Eiden JJ. Broide DImmune Tolerance Network Group. Immunotherapy with a ragweed-toll-like receptor 9 agonist vaccine for allergic rhinitis. N Engl J Med. 2006; 355:1445–55.

24. Tulic MK, Fiset PO, Christodoulopoulos P, Vaillancourt P, Desrosiers M, Lavigne F, Eiden J, Hamid Q. Amb a 1-immunostimulatory oligodeoxynucleotide conjugate immunotherapy decreases the nasal inflammatory response. J Allergy Clin Immunol. 2004; 113:235–41.

25. Zhu FG, Kandimalla ER, Yu D, Agrawal S. Oral administration of a synthetic agonist of Toll-like receptor 9 potently modulates peanut-induced allergy in mice. J Allergy Clin Immunol. 2007; 120:631–7.

26. Mantel PY, Kuipers H, Boyman O, Rhyner C, Ouaked N, Rückert B, Karagiannidis C, Lambrecht BN, Hendriks RW, Crameri R, Akdis CA, Blaser K, Schmidt-Weber CB. GATA3-driven Th2 responses inhibit TGF-beta1-induced FOXP3 expression and the formation of regulatory T cells. PLoS Biol. 2007; 5:e329.

27. Rosewich M, Girod K, Zielen S, Schubert R, Schulze J. Induction of bronchial tolerance after 1 cycle of monophosphoryl-a-adjuvanted specific immunotherapy in children with grass pollen allergies. Allergy Asthma Immunol Res. 2016; 8:257–63.

28. Musarra A, Bignardi D, Troise C, Passalacqua G. Long-lasting effect of a monophosphoryl lipid-adjuvanted immunotherapy to parietaria. A controlled field study. Eur Ann Allergy Clin Immunol. 2010; 42:115–9.

29. Dardalhon V, Awasthi A, Kwon H, Galileos G, Gao W, Sobel RA, Mitsdoerffer M, Strom TB, Elyaman W, Ho IC, Khoury S, Oukka M, Kuchroo VK. IL-4 inhibits TGF-beta-induced Foxp3+ T cells and, together with TGF-beta, generates IL-9+IL-10+ Foxp3 (-) effector T cells. Nat Immunol. 2008; 9:1347–55.

30. Chaker AM, Shamji MH, Dumitru FA, Calderon MA, Scadding GW, Makatsori M, Jones I, He QA, Subramanian KK, Arm JP, Durham SR, Schmidt-Weber CB. Short-term subcutaneous grass pollen immunotherapy under the umbrella of anti-IL-4: A randomized controlled trial. J Allergy Clin Immunol. 2016; 137:452–61.

31. Prussin C, Griffith DT, Boesel KM, Lin H, Foster B, Casale TB. Omalizumab treatment downregulates dendritic cell FcepsilonRI expression. J Allergy Clin Immunol. 2003; 112:1147–54.

32. Rolinck-Werninghaus C, Hamelmann E, Keil T, Kulig M, Koetz K, Gerstner B, Kuehr J, Zielen S, Schauer U, Kamin W, Von Berg A, Hammermann J, Weinkauf B, Weidinger G, Stenglein S. Wahn UOmalizumab Rhinitis Study Group. The co-seasonal application of anti-IgE after preseasonal specific immunotherapy decreases ocular and nasal symptom scores and rescue medication use in grass pollen allergic children. Allergy. 2004; 59:973–9.

33. Braido F, Corsico A, Rogkakou A, Ronzoni V, Baiardini I, Canonica GW. The relationship between allergen immunotherapy and omalizumab for treating asthma. Expert Rev Respir Med. 2015; 9:129–34.

34. Lambert N, Guiddir T, Amat F, Just J. Pre-treatment by omalizumab allows allergen immunotherapy in children and young adults with severe allergic asthma. Pediatr Allergy Immunol. 2014; 25:829–32.

35. Boni E, Incorvaia C, Mauro M. Dose-dependence of protection from systemic reactions to venom immunotherapy by omalizumab. Clin Mol Allergy. 2016; 14:14.

36. Ricciardi L. Omalizumab: A useful tool for inducing tolerance to bee venom immunotherapy. Int J Immunopathol Pharmacol. 2016; 29:726–8.

37. Palgan K, Bartuzi Z, Gotz-Zbikowska M. Treatment with a combination of omalizumab and specific immunotherapy for severe anaphylaxis after a wasp sting. Int J Immunopathol Pharmacol. 2014; 27:109–12.

38. Rafi A, Do LT, Katz R, Sheinkopf LE, Simons CW, Klaustermeyer W. Effects of omalizumab in patients with food allergy. Allergy Asthma Proc. 2010; 31:76–83.

39. Schneider LC, Rachid R, LeBovidge J, Blood E, Mittal M, Umetsu DT. A pilot study of omalizumab to facilitate rapid oral desensitization in high-risk peanut-allergic patients. J Allergy Clin Immunol. 2013; 132:1368–74.

40. 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. Omalizumab facilitates rapid oral desensitization for peanut allergy. J Allergy Clin Immunol. 2017; 139:873–81.

41. Nadeau KC, Schneider LC, Hoyte L, Borras I, Umetsu DT. Rapid oral desensitization in combination with omalizumab therapy in patients with cow's milk allergy. J Allergy Clin Immunol. 2011; 127:1622–4.

42. Sampson HA, Leung DY, Burks AW, Lack G, Bahna SL, Jones SM, Wong DA. A phase II, randomized, double blind, parallel group, placebo controlled oral food challenge trial of Xolair (omalizumab) in peanut allergy. J Allergy Clin Immunol. 2011; 127:1309–10.

43. Wood RA, Sicherer SH, Burks AW, Grishin A, Henning AK, Lindblad R, Stablein D, Sampson HA. 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. 2013; 68:803–8.

44. Brandström J, Vetander M, Lilja G, Johansson SG, Sundqvist AC, Kalm F, Nilsson C, Nopp A. Individually dosed omalizumab: an effective treatment for severe peanut allergy. Clin Exp Allergy. 2017; 47:540–50.

45. Frischmeyer-Guerrerio PA, Masilamani M, Gu W, Brittain E, Wood R, Kim J, Nadeau K, Jarvinen KM, Grishin A, Lindblad R, Sampson HA. Mechanistic correlates of clinical responses to omalizumab in the setting of oral immunotherapy for milk allergy. J Allergy Clin Immunol. 2017; 140:1043–53.

46. Bégin P, Dominguez T, Wilson SP, Bacal L, Mehrotra A, Kausch B, Trela A, Tavassoli M, Hoyte E, O'Riordan G, Blakemore A, Seki S, Hamilton RG, Nadeau KC. Phase 1 results of safety and tolerability in a rush oral immunotherapy protocol to multiple foods using Omalizumab. Allergy Asthma Clin Immunol. 2014; 10:7.

47. Kramer MF, Heath MD. Aluminium in allergen-specific subcutaneous immunotherapy: a German perspective. Vaccine. 2014; 32:4140–8.

48. Arora N, Gangal SV. Efficacy of liposome entrapped allergen in down regulation of IgE response in mice. Clin Exp Allergy. 1992; 22:35–42.

49. Tasaniyananda N, Chaisri U, Tungtrongchitr A, Chaicumpa W, Sookrung N. Mouse model of cat allergic rhinitis and intranasal liposome-adjuvanted refined fel d 1 vaccine. PLoS One. 2016; 11:e0150463.

50. Meechan P, Tungtrongchitr A, Chaisri U, Maklon K, Indrawattana N, Chaicumpa W, Sookrung N. Intranasal, liposome-adjuvanted cockroach allergy vaccines made of refined major allergen and whole-body extract of Periplaneta americana. Int Arch Allergy Immunol. 2013; 161:351–62.

51. Sehra S, Chugh L, Gangal SV. Polarized TH1 responses by liposome-entrapped allergen and its potential in immunotherapy of allergic disorders. Clin Exp Allergy. 1998; 28:1530–7.

52. Valenta R, Linhart B, Swoboda I, Niederberger V. Recombinant allergens for allergen-specific immunotherapy: 10 years anniversary of immunotherapy with recombinant allergens. Allergy. 2011; 66:775–83.

53. Focke M, Marth K, Flicker S, Valenta R. Heterogeneity of commercial timothy grass pollen extracts. Clin Exp Allergy. 2008; 38:1400–8.

54. Vrtala S, Fohr M, Campana R, Baumgartner C, Valent P, Valenta R. Genetic engineering of trimers of hypoallergenic fragments of the major birch pollen allergen, Bet v 1, for allergy vaccination. Vaccine. 2011; 29:2140–8.

55. Pichler U, Hauser M, Hofer H, Himly M, Hoflehner E, Steiner M, Mutschlechner S, Hufnagl K, Ebner C, Mari A, Briza P, Bohle B, Wiedermann U, Ferreira F, Wallner M. Allergen hybrids – next generation vaccines for Fagales pollen immunotherapy. Clin Exp Allergy. 2014; 44:438–49.

56. Spertini F, Perrin Y, Audran R, Pellaton C, Boudousquié C, Barbier N, Thierry AC, Charlon V, Reymond C. Safety and immunogenicity of immunotherapy with Bet v 1-derived contiguous overlapping peptides. J Allergy Clin Immunol. 2014; 134:239–40.

57. Zieglmayer P, Focke-Tejkl M, Schmutz R, Lemell P, Zieglmayer R, Weber M, Kiss R, Blatt K, Valent P, Stolz F, Huber H, Neubauer A, Knoll A, Horak F, Henning R, Valenta R. Mechanisms, safety and efficacy of a B cell epitope-based vaccine for immunotherapy of grass pollen allergy. EBioMedicine. 2016; 11:43–57.

58. Klimek L, Bachert C, Lukat KF, Pfaar O, Meyer H, Narkus A. Allergy immunotherapy with a hypoallergenic recombinant birch pollen allergen rBet v 1-FV in a randomized controlled trial. Clin Transl Allergy. 2015; 5:28.

59. Wood RA, Kim JS, Lindblad R, Nadeau K, Henning AK, Dawson P, Plaut M, Sampson HA. 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. 2016; 137:1103–10.

60. Wai CY, Leung NY, Leung PS, Chu KH. T cell epitope immunotherapy ameliorates allergic responses in a murine model of shrimp allergy. Clin Exp Allergy. 2016; 46:491–503.

61. Rupa P, Mine Y. Oral immunotherapy with immunodominant T-cell epitope peptides alleviates allergic reactions in a Balb/c mouse model of egg allergy. Allergy. 2012; 67:74–82.

62. Yang M, Yang C, Mine Y. Multiple T cell epitope peptides suppress allergic responses in an egg allergy mouse model by the elicitation of forkhead box transcription factor 3- and transforming growth factor-beta-associated mechanisms. Clin Exp Allergy. 2010; 40:668–78.

63. Liu Y, Sun Y, Chang LJ, Li N, Li H, Yu Y, Bryce PJ, Grammer LC, Schleimer RP, Zhu D. Blockade of peanut allergy with a novel Ara h 2-Fcγ fusion protein in mice. J Allergy Clin Immunol. 2013; 131:213–21.

64. Freidl R, Gstoettner A, Baranyi U, Swoboda I, Stolz F, Focke-Tejkl M, Wekerle T, van Ree R, Valenta R, Linhart B. Blocking antibodies induced by immunization with a hypoallergenic parvalbumin mutant reduce allergic symptoms in a mouse model of fish allergy. J Allergy Clin Immunol. 2017; 139:1897–905.

65. Ueno HM, Kato T, Ohnishi H, Kawamoto N, Kato Z, Kaneko H, Kondo N, Nakano T. T-cell epitope-containing hypoallergenic β-lactoglobulin for oral immunotherapy in milk allergy. Pediatr Allergy Immunol. 2016; 27:818–24.

66. Liu J, Chen FH, Qiu SQ, Yang LT, Zhang HP, Liu JQ, Geng XR, Yang G, Liu ZQ, Li J, Liu ZG, Li HB, Yang PC. Probiotics enhance the effect of allergy immunotherapy on regulating antigen specific B cell activity in asthma patients. Am J Transl Res. 2016; 8:5256–70.

67. Christensen HR, Frøkiaer H, Pestka JJ. Lactobacilli differentially modulate expression of cytokines and maturation surface markers in murine dendritic cells. J Immunol. 2002; 168:171–8.

68. de Roock S, van Elk M, van Dijk ME, Timmerman HM, Rijkers GT, Prakken BJ, Hoekstra MO, de Kleer IM. Lactic acid bacteria differ in their ability to induce functional regulatory T cells in humans. Clin Exp Allergy. 2010; 40:103–10.

69. Berni Canani R, Nocerino R, Terrin G, Coruzzo A, Cosenza L, Leone L, Troncone R. Effect of Lactobacillus GG on tolerance acquisition in infants with cow's milk allergy: a randomized trial. J Allergy Clin Immunol. 2012; 129:580–2.

70. Hol J, van Leer EH, Elink Schuurman BE, de Ruiter LF, Samsom JN, Hop W, Neijens HJ, de Jongste JC. Nieuwenhuis EECow's Milk Allergy Modified by Elimination and Lactobacilli study group. The acquisition of tolerance toward cow's milk through probiotic supplementation: a randomized, controlled trial. J Allergy Clin Immunol. 2008; 121:1448–54.

71. Jerzynska J, Stelmach W, Balcerak J, Woicka-Kolejwa K, Rychlik B, Blauz A, Wachulec M, Stelmach P, Majak P, Stelmach I. Effect of Lactobacillus rhamnosus GG and vitamin D supplementation on the immunologic effectiveness of grass-specific sublingual immunotherapy in children with allergy. Allergy Asthma Proc. 2016; 37:324–34.

72. Borchers AT, Krishnamurthy A, Keen CL, Meyers FJ, Gershwin ME. The immunobiology of mushrooms. Exp Biol Med (Maywood). 2008; 233:259–76.

73. Hsieh KY, Hsu CI, Lin JY, Tsai CC, Lin RH. Oral administration of an edible-mushroom-derived protein inhibits the development of food-allergic reactions in mice. Clin Exp Allergy. 2003; 33:1595–602.

74. Gomez-Escobar N, van den Biggelaar A, Maizels R. A member of the TGF-beta receptor gene family in the parasitic nematode Brugia pahangi. Gene. 1997; 199:101–9.

75. Gomez-Escobar N, Gregory WF, Maizels RM. Identification of tgh-2, a filarial nematode homolog of Caenorhabditis elegans daf-7 and human transforming growth factor beta, expressed in microfilarial and adult stages of Brugia malayi. Infect Immun. 2000; 68:6402–10.

76. Hirata M, Hirata K, Hara T, Kawabuchi M, Fukuma T. Expression of TGF-beta-like molecules in the life cycle of Schistosoma japonicum. Parasitol Res. 2005; 95:367–73.

77. Urry ZL, Richards DF, Black C, Morales M, Carnés J, Hawrylowicz CM, Robinson DS. Depigmented-polymerised allergoids favour regulatory over effector T cells: enhancement by 1α, 25-dihydroxyvitamin D3. BMC Immunol. 2014; 15:21.

78. Grundström J, Neimert-Andersson T, Kemi C, Nilsson OB, Saarne T, Andersson M, van Hage M, Gafvelin G. Covalent coupling of vitamin D3 to the major cat allergen Fel d 1 improves the effects of allergen-specific immunotherapy in a mouse model for cat allergy. Int Arch Allergy Immunol. 2012; 157:136–46.

79. Baris S, Kiykim A, Ozen A, Tulunay A, Karakoc-Aydiner E, Barlan IB. Vitamin D as an adjunct to subcutaneous allergen immunotherapy in asthmatic children sensitized to house dust mite. Allergy. 2014; 69:246–53.

80. Li XM, Zhang TF, Huang CK, Srivastava K, Teper AA, Zhang L, Schofield BH, Sampson HA. Food allergy herbal formula-1 (FAHF-1) blocks peanut-induced anaphylaxis in a murine model. J Allergy Clin Immunol. 2001; 108:639–46.

81. Srivastava KD, Kattan JD, Zou ZM, Li JH, Zhang L, Wallenstein S, Goldfarb J, Sampson HA, Li XM. The Chinese herbal medicine formula FAHF-2 completely blocks anaphylactic reactions in a murine model of peanut allergy. J Allergy Clin Immunol. 2005; 115:171–8.

82. Wang J, Patil SP, Yang N, Ko J, Lee J, Noone S, Sampson HA, Li XM. 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. 2010; 105:75–84.

83. Wang J, Jones SM, Pongracic JA, Song Y, Yang N, Sicherer SH, Makhija MM, Robison RG, Moshier E, Godbold J, Sampson HA, Li XM. Safety, clinical, and immunologic efficacy of a Chinese herbal medicine (food allergy herbal formula-2) for food allergy. J Allergy Clin Immunol. 2015; 136:962–70. e1.

84. Du Toit G, Roberts G, Sayre PH, Bahnson HT, Radulovic S, Santos AF, Brough HA, Phippard D, Basting M, Feeney M, Turcanu V, Sever ML, Gomez Lorenzo M, Plaut M. Lack GLEAP Study Team. Randomized trial of peanut consumption in infants at risk for peanut allergy. N Engl J Med. 2015; 372:803–13.

85. Perkin MR, Logan K, Tseng A, Raji B, Ayis S, Peacock J, Brough H, Marrs T, Radulovic S, Craven J, Flohr C. Lack GEAT Study Team. Randomized trial of introduction of allergenic foods in breast-fed infants. N Engl J Med. 2016; 374:1733–43.

86. Wei-Liang Tan J, Valerio C, Barnes EH, Turner PJ, Van Asperen PA, Kakakios AM. Campbell DEBeating Egg Allergy Trial (BEAT) Study Group. A randomized trial of egg introduction from 4 months of age in infants at risk for egg allergy. J Allergy Clin Immunol. 2017; 139:1621–8. e8.

87. Hamelmann E, Herz U, Holt P, Host A, Lauener RP, Matricardi PM, Wahn U, Wickman M. New visions for basic research and primary prevention of pediatric allergy: an iPAC summary and future trends. Pediatr Allergy Immunol. 2008; 19(Suppl 19):4–16.

88. Senti G, Prinz Vavricka BM, Erdmann I, Diaz MI, Markus R, McCormack SJ, Simard JJ, Wüthrich B, Crameri R, Graf N, Johansen P, Kündig TM. Intralymphatic allergen administration renders specific immunotherapy faster and safer: a randomized controlled trial. Proc Natl Acad Sci U S A. 2008; 105:17908–12.

89. Senti G, Crameri R, Kuster D, Johansen P, Martinez-Gomez JM, Graf N, Steiner M, Hothorn LA, Grönlund H, Tivig C, Zaleska A, Soyer O, van Hage M, Akdis CA, Akdis M, Rose H, Kündig TM. Intralymphatic immunotherapy for cat allergy induces tolerance after only 3 injections. J Allergy Clin Immunol. 2012; 129:1290–6.

90. Witten M, Malling HJ, Blom L, Poulsen BC, Poulsen LK. Is intralymphatic immunotherapy ready for clinical use in patients with grass pollen allergy? J Allergy Clin Immunol. 2013; 132:1248–1252. e5.

91. Lee SP, Choi SJ, Joe E, Lee SM, Lee MW, Shim JW, Kim YJ, Kyung SY, Park JW, Jeong SH, Jung JH. A pilot study of intralymphatic immunotherapy for house dust mite, cat, and dog allergies. Allergy Asthma Immunol Res. 2017; 9:272–7.

92. Lee SP, Jung JH, Lee SM, Joe E, Kang IG, Kim ST, Lee MW, Park SH, Choi SJ. Intralymphatic immunotherapy alleviates allergic symptoms during allergen exposure in daily life. Allergy Asthma Immunol Res. 2018; 10:180–1.

93. Kim ST, Park SH, Lee SM, Lee SP. Allergen-specific intralymphatic immunotherapy in human and animal studies. Asia Pac Allergy. 2017; 7:131–7.

94. Senti G, von Moos S, Tay F, Graf N, Johansen P, Kündig TM. Determinants of efficacy and safety in epicutaneous allergen immunotherapy: summary of three clinical trials. Allergy. 2015; 70:707–10.

95. Senti G, von Moos S, Tay F, Graf N, Sonderegger T, Johansen P, Kündig TM. Epicutaneous allergen-specific immunotherapy ameliorates grass pollen-induced rhinoconjunctivitis: A double-blind, placebo-controlled dose escalation study. J Allergy Clin Immunol. 2012; 129:128–35.

96. Dupont C, Kalach N, Soulaines P, Legoué-Morillon S, Piloquet H, Benhamou PH. Cow's milk epicutaneous immunotherapy in children: a pilot trial of safety, acceptability, and impact on allergic reactivity. J Allergy Clin Immunol. 2010; 125:1165–7.

97. Kitaoka M, Shin Y, Kamiya N, Kawabe Y, Kamihira M, Goto M. Transcutaneous peptide immunotherapy of japanese cedar pollinosis using solid-in-oil nanodispersion technology. AAPS PharmSciTech. 2015; 16:1418–24.

Table 1.

Summary table of novel strategies in immunotherapy (IT)

Novel strategies	Mode of action	Results and recommendations
Allergoids	Extracts which have been modified chemically by substances such as glutaraldehyde or formaldehyde.	Extract dependent with one study showing clinical efficacy [13], but mostly demonstrate both reduced allergenicity and immunogenicity [14, 15, 17].
Immunostimulatory sequences	Induce strong Th1 response.	Small scale clinical studies show improved rhinitis symptom scores [23, 24]. In vitro studies using food sequences also show suppression of allergen-specific IgE levels [25, 26].
Epitope modification	Modification of IgE-binding epitopes to reduce allergenicity.	Protein oligomerization [55-57] and hybrid molecules [59, 63] increase immunogenicity.
Peptide-based immunotherapy	Use of short sequence tolerogenic epitopes which prevent cross-linking of IgE and hence reduce allergenicity.	Positive studies in vivo and mouse models studies [39-41].
Monoclonal antibodies	(1) Anti-IL 4: Suppression of inhibition of FOXP3+ T regulatory cells. (2) Anti-IgE monoclonal antibody: Prevents binding of free IgE to high affinity Fcε R1 IgE receptor.	(1) No additional benefit conferred when used together with SCIT [30]. (2) Improved efficacy with grass and pollen SCIT [32] and cow's milk and peanut OIT [41-43] with improved safety profile.
Carriers	Aluminium hydroxide that induce strong Th2 responses by stimulating antigen-presenting cells. Newer lipid based carriers improve stability and drug delivery, also act as immunomodulators.	Greater immunogenicity and reduced allergenicity in mouse models [21, 48, 49].
Probiotics	Tolerogenic effect via dendritic cell and T-cell responses.	Improved clinical efficacy in grass pollen SLIT [69]. Overall lack of studies.
Earlier timing of introduction	Early and controlled introduction of allergens at an optimally defined timing may induce long-term tolerance starting from an early age in predisposed individuals (87).	The optimal timing for introduction of IT is yet to be determined.
Alternative routes of IT	Administration of allergens via tissues which have a high density of antigen-presenting cells such as via the skin and lymphatics may improve efficacy.	Outcomes of efficacy using the intralymphatic route vary between studies. Some report improved efficacy requiring a shorter duration of treatment [88, 89] while others do not report therapeutic efficacy [90]. Some studies have reported increased adverse effects and recommend dose reductions [91, 92]. Treatment via the epicutaneous route has been shown to be effective but only with high doses of IT [94, 95].

IL, interleukin; SCIT, subcutaneous immunotherapy; SLIT, sublingual immunotherapy; Fc_Ɛ R1, high-affinity IgE receptor; OIT, oral immunotherapy.

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