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Background Allergen-specific immunotherapy represents the only disease-modifying treatment for allergic diseases. We and others have previously demonstrated that intralymphatic immunotherapy (ILIT), a less time-consuming alternative to conventional subcutaneous immunotherapy (SCIT), is safe and effective. However, this has recently been disputed. The aim of this study was therefore to expand our previous trial, further assessing the safety and efficacy of ILIT. Methods Thirty-six patients with pollen-induced rhinoconjunctivitis were randomised to receive three intralymphatic inguinal injections of active allergen (1000 SQ-U birch- or grass-pollen) or placebo. Clinical effects, safety and circulating immunological markers were assessed before, 4 weeks after treatment and at the end of the consecutive pollen season. Results No moderate or severe reactions were recorded following ILIT. Patients receiving active ILIT experienced a significant improvement in self-recorded seasonal allergic symptoms, as compared to placebo ( p  = 0.05). In a subgroup of these patients (“improved”), a reduction in nasal symptoms following nasal allergen provocation was also demonstrated. No changes in total IgE or IgG 4 were found. However, the affinity of allergen specific IgG 4 following active treatment was significantly increased, as compared to non-improved patients ( p  = 0.04). This could be correlated with clinical improvement, on an individual level. Conclusions This double-blinded placebo-controlled study confirms that ILIT is a safe and effective treatment for pollen-induced rhinoconjunctivitis, markedly reducing seasonal allergic symptoms. Trial registration EudraCT: 2009-016815-39

Background Intralymphatic immunotherapy (ILIT) is a potential treatment option for allergic rhinitis (AR). We aimed to determine the efficacy (primary outcomes) and safety (secondary outcomes) of ILIT in treating patients with AR. Methods An electronic literature search was performed using MEDLINE and Cochrane Central Register of Controlled Trials CENTRAL (from their inception to December 2020). A random‐effects model was used to estimate the pooled prevalence with 95% confidence intervals. This study is registered with PROSPERO (CRD42019126271). Results We retrieved a total of 285 articles, of which 11 satisfied our inclusion criteria. There were 452 participants with age ranged from 15 to 58 years old. Intralymphatic immunotherapy was given in three doses with intervals of four weeks between doses in 10 trials. One trial gave three and six doses with an interval of two weeks. Both primary and secondary outcomes showed no difference between ILIT and placebo for all trials. There was no difference in the combined symptoms and medication score (SMD ‐0.51, 95% CI −1.31 to 0.28), symptoms score (SMD −0.27, 95% CI −0.91 to 0.38), medication score (SMD −6.56, 95% CI −21.48 to 8.37), rescue medication (RR 12.32, 95% CI 0.72–211.79) and the overall improvement score (MD −0.07, 95% CI −2.28 to 2.14) between ILIT and placebo. No major adverse events noted. Conclusions Intralymphatic immunotherapy possibly has a role in the treatment of AR patients. This review found it is safe but not effective, which could be contributed by the high variation amongst the trials. Future trials should involve larger numbers of participants and report standardized administration of ILIT and outcome measures.

Background: Intralymphatic immunotherapy (ILIT) has been used successfully in both human and veterinary medicine as a safe and effective treatment for allergic diseases. Initially, ILIT was administered by ultrasound guidance, but palpation-based injections have become more popular among veterinary dermatologists. Data from human medicine, however, show that precise injection into the lymph node is mandatory, and injection quality clearly correlates with clinical response. Hypothesis: Our aim was to assess the impact of the injection method (ultrasound guidance versus palpation-based guidance) on clinical response in dogs with atopic dermatitis. Methods: A total of 129 canine atopic dermatitis (CAD) cases treated with ILIT between 2014 and 2022 were retrieved from the hospital clinical database. The included dogs had to receive at least three intralymphatic injections administered either by palpation or ultrasound guidance. Those cases were retrospectively assessed and compared regarding clinical response to ILIT. Results: In total, 84 dogs received ILIT by ultrasound guidance, and in 25 dogs, ILIT was injected based on palpation. The success rate of ILIT was significantly higher in the ultrasound guidance group when compared to palpation-based injections. Conclusions: Low-quality injections must be considered as a possible reason for ILIT failure in dogs. Further prospective and controlled studies are necessary to confirm these results.

Background Allergen specific IgG4 levels have been monitored as a surrogate marker for the tolerance inducing effect of subcutaneous immunotherapy (SCIT) in many studies. Its accuracy at group level has been well established, but IgG4 has not yet found its place in the daily care of immunotherapy patients. Methods Intralymphatic immunotherapy (ILIT) is a novel route for allergy vaccination against pollen allergy, where an ultrasound-guided injection of 1000 SQ-U Alutard is given directly into a groin lymph node. The suggested standard dosing so far has been one injection with 4 weeks in-between. In total 3000 SQ-U with the treatment completed in 2 months. IgG4 was measured with Immulite technique and rhinoconjunctivitis symptoms were estimated with daily online questionnaires. Mann–Whitney U-test and Wilcoxon Signed Rank test were applied for comparisons between groups and within groups, respectively. Results The present study demonstrates that a single, preseason ILIT booster of 1000 SQ-U Alutard 5-grasses ® , re-increases the allergen specific timothy-IgG4 levels, in patients already treated with ILIT before the previous pollen season. It also shows the feasibility of the ILIT-route for allergy vaccination of rhinitis patients, with or without concomitant asthma, with low degree of side effects and reconfirms high and sustained patient satisfaction. Conclusions It is tempting to suggest that the allergen specific IgG4 levels can be used to build an intuitive algorithm for future clinical guidance of ILIT patients. Trial registration Is Intralymphatic Allergen Immunotherapy Effective and Safe?, ClinicalTrials.gov Identifier NCT04210193. Registered 24 December 2019—Retrospectively registered, https://clinicaltrials.gov/ct2/show/study/NCT04210193?term=NCT04210193&draw=2&rank=1

Conduct an overview of systematic reviews and meta-analyses on intralymphatic immunotherapy for allergic rhinitis, providing systematic evidence to optimize clinical practice and evidence-based decision-making. A computer-based retrieval system was used to comprehensively search databases such as PubMed, Embase, Cochrane Library, Web of Science, CNKI, VIP, WANFANG, and CBM. The retrieval time limit was set from the inception date of each database to August 14, 2025, aiming to obtain systematic review/Meta-analysis literatures on lymph node intralymphatic immunotherapy for the treatment of allergic rhinitis. Use evaluation tools such as ROBIS, AMSTAR-2, PRISMA 2020, and GRADE to perform quality re-evaluations on the systematic reviews/Meta-analyses of included studies from the aspects of bias risk, methodology, reporting, and evidence level, and conduct comprehensive re-evaluations on the outcome indicators of the included studies. A total of seven systematic reviews/meta-analyses were included. Risk of bias assessment indicated all studies had low risk. Methodological quality evaluation revealed six studies were of low quality and one was of very low quality. In terms of reporting quality, all included studies demonstrated high quality, with PRISMA scores ranging from 33 to 40. For outcome measures, evidence quality assessment identified 6 high-quality, 13 moderate-quality, 18 low-quality, and 27 very low-quality results. Quantitative analysis showed that intralymphatic immunotherapy not only improved subjective symptom scores in allergic rhinitis patients but also effectively induced immune tolerance. Qualitative analysis further confirmed that this targeted approach significantly enhanced allergen tolerance and reduced nasal symptom severity. The therapy demonstrated a favorable safety profile, primarily characterized by mild local adverse events, with substantially fewer systemic reactions compared to conventional subcutaneous immunotherapy. Intralymphatic immunotherapy demonstrates efficacy in improving symptoms and objective indicators of allergic rhinitis, particularly for grass pollen and mixed allergens, with acceptable short-to-medium term outcomes despite limited long-term effectiveness. The treatment exhibits a favorable safety profile dominated by mild local reactions. However, these findings are constrained by low evidence quality. Future studies should adhere to established guidelines to produce higher-quality evidence through systematic reviews and meta-analyses. The systematic review was registered on PROSPERO (https://www.crd.york.ac.uk/PROSPERO/) with the registration number CRD420251126501.

Allergen immunotherapy (AIT) is effective in reducing the clinical symptoms associated with allergic rhinitis, asthma and venom-induced anaphylaxis. Subcutaneous (SCIT) and sublingual immunotherapy (SLIT) with unmodified allergen extracts are the most widely prescribed AIT regimens. The efficacy of these 2 routes appears comparable, but the safety profile with SLIT is more favorable allowing for home administration and requiring less patient time. However, both require that the treatment is taken regularly over several years, e.g., monthly in a supervised medical setting with SCIT and daily at home with SLIT. Despite the difference in treatment settings, poor adherence has been reported with both routes. Emerging evidence suggests that AIT may be effective in other allergic conditions such as atopic dermatitis, venom sting-induced large local reactions, and food allergy. Research with oral immunotherapy (OIT) for food allergies suggest that many patients can be desensitized during treatment, but questions remain about whether this can produce long term tolerance. Further studies are needed to identify appropriate patients and treatment regimens with these conditions. Efforts to develop safer and more effective AIT for inhalant allergies have led to investigations with modified allergens and alternate routes. Intralymphatic (ILIT) has been shown to produce long-lasting clinical benefits after three injections comparable to a 3-year course of SCIT. Epicutaneous (EPIT) has demonstrated promising results for food and inhalant allergies. Vaccine modifications, such as T cell epitopes or the use of viral-like particles as an adjuvant, have been shown to provide sustained clinical benefits after a relatively short course of treatment compared to the currently available AIT treatments, SLIT and SCIT. These newer approaches may increase the utilization and adherence to AIT because the multi-year treatment requirement of currently available AIT is a likely deterrent for initiating and adhering to treatment.

Background Allergen Immunotherapy is a promising treatment of allergy. Seven patients with rhinoconjunctivitis to grass allergen were treated with intralymphatic immunotherapy (ILIT) to explore whether this treatment could be performed. Effect of treatment was assessed as change in symptom medication score, response in skin prick test and nasal allergen provocation. ILIT deposits allergen in an inguinal lymph node to elicit a strong immune stimulus. This allowed us to monitor appearance of allergen specific plasmablasts 7 days after allergen injection. Findings In an open trial of seven patients with a history of symptomatic allergic rhinoconjunctivitis due to grass pollen, three injections of allergen into inguinal lymph nodes were performed with monthly intervals. Allergen injections induced grass allergen specific plasmablasts expressing other isotypes than IgE after 7 days, induced a trend toward improvement in symptom and medication score and rhinoconjunctivitis-related quality of life during the grass pollen season 2013 and significantly raised the threshold in nasal allergen challenge and titrated skin prick testing. Mild side-effects were recorded after 3 of the 21 of injections (14 %). Conclusions This pilot study shows that ILIT may induce allergen specific plasmablasts, and confirms an effect on provocation of mast cells in skin and nasal mucosa during the ensuing winter.

Die Allergenimmuntherapie (AIT) ist die einzig kausale Form der Behandlung Ig(Immunglobulin)E-vermittelter Allergien, sofern keine Allergenmeidung möglich ist. Bereits lange und gut etabliert sind subkutane (SCIT) und sublinguale (SLIT) Allergenapplikation, vor Kurzem wurde zudem die erste orale Immuntherapie (OIT) zur Behandlung der Erdnussallergie zugelassen. Interessante und vielversprechende weitere Administrationsformen sind die intralymphatische (ILIT) und epikutane (EPIT) Immuntherapie, deren immunologische und klinische Wirksamkeit bezüglich einer Toleranzinduktion sowohl in tierexperimentellen als auch klinischen Studien untersucht worden ist, Letztere auch bereits in ersten Phase-3-Studien. Die Ergebnisse der Prüfungen sowie Vor- und Nachteile dieser neuen Verfahren, auch im Hinblick auf mögliche Risiken und noch zu adressierende Herausforderungen vor einem zukünftigen routinemäßigen klinischen Einsatz sollen im Folgenden ausführlich dargelegt und diskutiert werden.

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. Summary 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.

Background: Allergic diseases are among the most common diseases in humans. Besides allergen avoidance, allergen-specific immunotherapy is the only causative treatment option. During recent years, many innovations of this therapy have emerged. Methods: Selective literature research in Medline and PubMed, under the inclusion of national and international guidelines and Cochrane meta analyses. Results: In several meta-analyses, the clinical efficacy of subcutaneous immunotherapy (SCIT) has been largely demonstrated. Recently, major research activities in mucosal immunotherapies focused on the sublingual application route. There are well-documented clinical data on the efficacy and safety of this form of immunotherapy. New application routes as well as new immune-modifying agents such as virus-like particles or CpG-motifs have also been investigated. Conclusion: SIT is accepted to be the only causative treatment option for allergies. New application routes and new immune-modifying agents will allow for different delivery methods in the future.