Current Treatment Options in Allergy

, Volume 5, Issue 4, pp 415–423 | Cite as

What Do We Really Know About Intralymphatic Immunotherapy?

  • L. KlimekEmail author
  • G. Senti
  • H. J. Hoffmann
  • T. Kündig
Specific Immunotherapy (L Cox, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Specific Immunotherapy


Purpose of review

Allergen-specific immunotherapy (AIT) is the only causal treatment method of IgE-mediated allergies that may lead to long-term symptom amelioration even after the end of treatment, positively interfere with the course of disease, and improve the immunological situation of the patient. While AIT in general requires treatment periods over 3 up to 5 years, intralymphatic immunotherapy (ILIT) needs only three ultrasound-guided injections of low allergen doses into inguinal lymph nodes with 4-week time interval making the entire treatment possible within 2 months.

Recent findings

The number of published ILIT trials is continuously increasing and it has been mainly used for the indication of allergic rhinitis using commercially available grass pollen and birch extracts and Dermatophagoides farinae, Dermatophagoides pteronyssinus, dog or cat allergens, and moreover a recombinant MAT-Fel d 1 vaccine and autologous semen from a patient with post-orgasmic illness syndrome.


ILIT is a very promising AIT technique that could widely improve patient treatment However, there is not enough convincing evidence for a routine use of ILIT and no authorized commercial allergen extracts exist for this approach, so far. Dose-escalation studies and prospective DBPC efficacy trials need to be performed in diverse allergens like insect venom. Moreover, pediatric populations have not been present in former ILIT studies.


Intralymphatic immunotherapy ILIT Allergen-specific immunotherapy AIT Allergic rhinitis 


Compliance with ethical standards

Conflict of interest

Dr. Kündig reports grants from AlleCure Corp. USA, grants from ImVision AG, during the conduct of the study. In addition, Dr. Kündig has patents on intralymphatic immunotherapy where he is named as inventor. These patents, however, are owned by the University of Zurich. Dr. Klimek reports grants and personal fees from ALK-Abelló, Denmark; personal fees from MEDA, Sweden; grants and personal fees from Novartis, Switzerland; grants and personal fees from Allergopharma, Germany; grants and personal fees from Bionorica, Germany; personal fees from Boehringer Ingelheim, Germany; grants and personal fees from GSK, Great Britain; grants and personal fees from Lofarma, Italy; grants from Biomay, Austria; grants from HAL, Netherlands; grants from LETI, Spain; grants from Roxall, Germany; and grants from Bencard, Great Britain, outside the submitted work. Dr. Senti declares that she has no conflict of interest. Dr. Hoffmann declares that he has no conflict of interest.

Human and animal rights and informed consent

This article does contain studies with human subjects performed by GS, TK and HJH.

These studies have been performed according to the Declaration of Helsinki in its actual version and a positive vote of the responsible Ethical Committee was given before start of the study.

References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Brehler R, Klimek L, Vogelberg C, Werfel T, Pfaar O, Hamelmann E. Evidence vs. efficacy in allergen-specific immunotherapy: considerations using the example of tradable products in Germany. Allergo J Int. 2016;25:38–43.CrossRefGoogle Scholar
  2. 2.
    Pfaar O, Bonini S, Cardona V, Demoly P, Jakob T, Jutel M, et al. Perspectives in allergen immunotherapy: 2017 and beyond. Allergy. 2018;73(Suppl 104):5–23.CrossRefGoogle Scholar
  3. 3.
    Pfaar O, Bachert C, Bufe A, Buhl R, Ebner C, Eng P, et al. Guideline on allergen-specific immunotherapy in IgE-mediated allergic diseases: S2k Guideline of the German Society for Allergology and Clinical Immunology (DGAKI), the Society for Pediatric Allergy and Environmental Medicine (GPA), the Medical Association of German Allergologists (AeDA), the Austrian Society for Allergy and Immunology (OGAI), the Swiss Society for Allergy and Immunology (SGAI), the German Society of Dermatology (DDG), the German Society of Oto- Rhino-Laryngology, Head and Neck Surgery (DGHNO-KHC), the German Society of Pediatrics and Adolescent Medicine (DGKJ), the Society for Pediatric Pneumology (GPP), the German Respiratory Society (DGP), the German Association of ENT Surgeons (BV-HNO), the Professional Federation of Paediatricians and Youth Doctors (BVKJ), the Federal Association of Pulmonologists (BDP) and the German Dermatologists Association (BVDD). Allergo J Int. 2014;23(8):282–319.CrossRefGoogle Scholar
  4. 4.
    Nurmatov U, Dhami S, Arasi S, Roberts G, Pfaar O, Muraro A, et al. Allergen immunotherapy for allergic rhinoconjunctivitis: a systematic overview of systematic reviews. Clin Transl Allergy. 2017;7:24.CrossRefGoogle Scholar
  5. 5.
    Hoffmann HJ, Valovirta E, Pfaar O, Moingeon P, Schmid JM, Skaarup SH, et al. Novel approaches and perspectives in allergen immunotherapy. Allergy. 2017;72(7):1022–34.CrossRefGoogle Scholar
  6. 6.
    Klimek L, Kundig T, Senti G. Allergen specific immunotherapy for rhinitis allergica: new applications. Hno. 2015;63(5):343–51.CrossRefGoogle Scholar
  7. 7.
    Jin JJ, Li JT, Klimek L, Pfaar O. Sublingual immunotherapy dosing regimens: what is ideal? J Allergy Clin Immunol Pract. 2017;5(1):1–10.CrossRefGoogle Scholar
  8. 8.
    Klimek L, Brehler R, Hamelmann E, Kopp M, Ring J, Treudler R, et al. Development of subcutaneous immunotherapy in over 100 years: from beginning to immunologically-oriented therapy concepts. Part 1: Immunological mechanisms, efficacy and indications. Allergo J Int. 2018 (in press).Google Scholar
  9. 9.
    Klimek L, Brehler R, Hamelmann E, Kopp M, Ring J, Treudler R, et al. Development of subcutaneous immunotherapy in over 100 years: from beginning to immunologically-oriented therapy concepts. Part 2: preventive aspects and innovations. Allergo J Int. 2018 (in press).Google Scholar
  10. 10.
    Rotiroti G, Shamji M, Durham SR, Till SJ. Repeated low-dose intradermal allergen injection suppresses allergen-induced cutaneous late responses. J Allergy Clin Immunol. 2012;130(4):918–924 e1.CrossRefGoogle Scholar
  11. 11.
    Passalacqua G, Canonica GW. Local nasal specific immunotherapy for allergic rhinitis. Allergy, Asthma, Clin Immunol: Off J Can Soc Allergy Clin Immunol. 2006;2(3):117–23.CrossRefGoogle Scholar
  12. 12.
    •• Senti G, Prinz Vavricka BM, Erdmann I, Diaz MI, Markus R, McCormack SJ, et al. Intralymphatic allergen administration renders specific immunotherapy faster and safer: a randomized controlled trial. Proc Natl Acad Sci U S A. 2008;105(46):17908–12 This publication describes the first application of ILIT in men.CrossRefGoogle Scholar
  13. 13.
    Senti G, Crameri R, Kuster D, Johansen P, Martinez-Gomez JM, Graf N, et al. Intralymphatic immunotherapy for cat allergy induces tolerance after only 3 injections. J Allergy Clin Immunol. 2012;129(5):1290–6.CrossRefGoogle Scholar
  14. 14.
    • Senti G, Kundig TM. Intralymphatic immunotherapy. World Allergy Organ J. 2015;8(1):9 Excellent review of ILIT.CrossRefGoogle Scholar
  15. 15.
    Hylander T, Larsson O, Petersson-Westin U, Eriksson M, Kumlien Georen S, Winqvist O, et al. Intralymphatic immunotherapy of pollen-induced rhinoconjunctivitis: a double-blind placebo-controlled trial. Respir Res. 2016;17:10.CrossRefGoogle Scholar
  16. 16.
    Hylander T, Latif L, Petersson-Westin U, Cardell LO. Intralymphatic allergen-specific immunotherapy: an effective and safe alternative treatment route for pollen-induced allergic rhinitis. J Allergy Clin Immunol. 2013;131(2):412–20.CrossRefGoogle Scholar
  17. 17.
    • Schmid JM, Nezam H, Madsen HH, Schmitz A, Hoffmann HJ. Intralymphatic immunotherapy induces allergen specific plasmablasts and increases tolerance to skin prick testing in a pilot study. Clin Transl Allergy. 2016;6:19 This study provides new insights into possible immunological mechanisms of ILIT.CrossRefGoogle Scholar
  18. 18.
    Akdis CA, Akdis M. Advances in allergen immunotherapy: aiming for complete tolerance to allergens. Sci Transl Med. 2015;7(280):280ps6.CrossRefGoogle Scholar
  19. 19.
    Klimek L, Bachmann MF, Senti G, Kundig TM. Immunotherapy of type-1 allergies with virus-like particles and CpG-motifs. Expert Rev. Clin Immunol. 2014;10(8):1059–67.CrossRefGoogle Scholar
  20. 20.
    Klimek L, Schmidt-Weber CB, Kramer MF, Skinner MA, Heath MD. Clinical use of adjuvants in allergen-immunotherapy. Expert Rev. Clin Immunol. 2017;13(6):599–610.CrossRefGoogle Scholar
  21. 21.
    Klimek L, Pfaar O, Bousquet J, Senti G, Kundig T. Allergen immunotherapy in allergic rhinitis: current use and future trends. Expert Rev. Clin Immunol. 2017;13(9):897–906.CrossRefGoogle Scholar
  22. 22.
    Kundig TM, Bachmann MF, DiPaolo C, Simard JJ, Battegay M, Lother H, et al. Fibroblasts as efficient antigen-presenting cells in lymphoid organs. Science. 1995;268(5215):1343–7.CrossRefGoogle Scholar
  23. 23.
    Senti G, Johansen P, Kundig TM. Intralymphatic immunotherapy: from the rationale to human applications. Curr Top Microbiol Immunol. 2011;352:71–84.PubMedGoogle Scholar
  24. 24.
    Klimek L, Bergmann KC, Biedermann T, Bousquet J, Hellings P, Jung K, et al. Visual analogue scales (VAS): measuring instruments for the documentation of symptoms and therapy monitoring in cases of allergic rhinitis in everyday health care: position Paper of the German Society of Allergology (AeDA) and the German Society of Allergy and Clinical Immunology (DGAKI), ENT Section, in collaboration with the working group on Clinical Immunology, Allergology and Environmental Medicine of the German Society of Otorhinolaryngology, Head and Neck Surgery (DGHNOKHC). Allergo J Int. 2017;26(1):16–24.CrossRefGoogle Scholar
  25. 25.
    Zaleska A, Eiwegger T, Soyer O, van de Veen W, Rhyner C, Soyka MB, et al. Immune regulation by intralymphatic immunotherapy with modular allergen translocation MAT vaccine. Allergy. 2014;69(9):1162–70.CrossRefGoogle Scholar
  26. 26.
    Patterson AM, Bonny AE, Shiels WE 2nd, Erwin EA. Three-injection intralymphatic immunotherapy in adolescents and young adults with grass pollen rhinoconjunctivitis. Ann Allergy Asthma Immunol. 2016;116(2):168–70.CrossRefGoogle Scholar
  27. 27.
    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(5):1248–1252 e5.CrossRefGoogle Scholar
  28. 28.
    Kundig TM, Johansen P, Bachmann MF, Cardell LO, Senti G. Intralymphatic immunotherapy: time interval between injections is essential. J Allergy Clin Immunol. 2014;133(3):930–1.CrossRefGoogle Scholar
  29. 29.
    Malling HJ, Witten M, Poulsen LK. Reply: To J Allergy Clin Immunol. 2014;133(3):931–932.Google Scholar
  30. 30.
    Graf N, Dinkel B, Rose H, Hothorn LA, Gerhard D, Johansen P, et al. A critical appraisal of analyzing nasal provocation test results in allergen immunotherapy trials. Rhinology. 2014;52(2):137–41.CrossRefGoogle Scholar
  31. 31.
    Hellkvist L, Hjalmarsson E, Georen SK, Karlsson A, Lundkvist K, Winqvist O, et al. Intralymphatic immunotherapy with two concomitant allergens, birch and grass - a RDBPC trial. J Allergy Clin Immunol. 2018.Google Scholar
  32. 32.
    Lee SP, Jung JH, Lee SM, Joe E, Kang IG, Kim ST, et al. Intralymphatic immunotherapy alleviates allergic symptoms during allergen exposure in daily life. Allergy Asthma Immunol Res. 2018;10(2):180–1.CrossRefGoogle Scholar
  33. 33.
    Senti G, Johansen P, Kundig T. Intralymphatic immunotherapy: from the rationale to human applications. In: Valenta R, Coffman R, editors. Vaccines against Allergies. Berlin: Springer-Verlag Berlin; 2011. p. 71–84.CrossRefGoogle Scholar
  34. 34.
    Mueller RS, Jensen-Jarolim E, Roth-Walter F, Marti E, Janda J, Seida AA, et al. Allergen immunotherapy in people, dogs, cats and horses - differences, similarities and research needs. Allergy. 2018.Google Scholar
  35. 35.
    Fischer N, Rostaher A, Favrot C. Intralymphatic immunotherapy: an effective and safe alternative route for canine atopic dermatitis. Schweiz Arch Tierheilkd. 2016;158(9):646–52.CrossRefGoogle Scholar
  36. 36.
    Timm K, Mueller RS, Nett-Mettler CS. Long-term effects of intralymphatic immunotherapy (ILIT) on canine atopic dermatitis. Vet Dermatol. 2018;29(2):123–e49.CrossRefGoogle Scholar
  37. 37.
    Kim ST, Park SH, Lee SM, Lee SP. Allergen-specific intralymphatic immunotherapy in human and animal studies. Asia Pac Allergy. 2017;7(3):131–7.CrossRefGoogle Scholar
  38. 38.
    Martinez-Gomez JM, Johansen P, Erdmann I, Senti G, Crameri R, Kundig TM. Intralymphatic injections as a new administration route for allergen-specific immunotherapy. Int Arch Allergy Immunol. 2009;150(1):59–65.CrossRefGoogle Scholar
  39. 39.
    Jonsdottir S, Hamza E, Janda J, Rhyner C, Meinke A, Marti E, et al. Developing a preventive immunization approach against insect bite hypersensitivity using recombinant allergens: a pilot study. Vet Immunol Immunopathol. 2015;166(1–2):8–21.CrossRefGoogle Scholar
  40. 40.
    Jonsdottir S, Svansson V, Stefansdottir SB, Schupbach G, Rhyner C, Marti E, et al. A preventive immunization approach against insect bite hypersensitivity: intralymphatic injection with recombinant allergens in alum or alum and monophosphoryl lipid A. Vet Immunol Immunopathol. 2016;172:14–20.CrossRefGoogle Scholar
  41. 41.
    Weschenfelder AK, Klimek L, Mulleneisen N, Renz H, Wehrmann W, Werfel T, et al. Course of respiratory allergy by treatment strategy based on German routine data. Allergo J Int. 2017;26(6):195–203.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  • L. Klimek
    • 1
    Email author
  • G. Senti
    • 2
  • H. J. Hoffmann
    • 3
  • T. Kündig
    • 4
  1. 1.Center for Rhinology and AllergologyWiesbadenGermany
  2. 2.Clinical Trials CenterUniversity Hospital ZurichZurichSwitzerland
  3. 3.Department of Clinical Medicine, Department of Respiratory Diseases and AllergyAarhus UniversityAarhusDenmark
  4. 4.Department of DermatologyUniversity Hospital ZurichZurichSwitzerland

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