Intralymphatic Immunotherapy Research Articles

Intralymphatic Immunotherapy (ILIT) With Bee Venom Allergens: A Clinical Proof-of-Concept Study and the Very First ILIT in Humans.

BackgroundSubcutaneous venom immunotherapy (VIT) represents an effective treatment against bee venom allergy. However, it involves long treatment times, high costs, and the risk of adverse events (AEs). Shorter, safer, and cheaper treatment options are therefore pursued.ObjectiveTo determine the safety, immunogenicity, and efficacy of bee venom intralymphatic immunotherapy (ILIT).MethodsIn an open pilot study, 12 patients received bee venom ILIT in three sessions with 14-day intervals: 0.1–5 μg/dose. Ultrasound imaging was applied to guide an injection and to document the lymph node structure. In a second study, 67 patients from 15 centers in Europe and Australia were randomized to receive four doses of either 10- or 20-μg bee venom ILIT with 28-day intervals. Clinical endpoints included specific IgE and IgG and protection after a bee sting challenge. These studies were performed in the years 2000–2003.ResultsIn a proof-of-concept study, no serious AEs were observed. An increase in allergen-specific IgG1 but no IgG4 and IgE was observed. ILIT induced the protection against a bee sting challenge in 7 out of 8 challenged patients. In a multicenter study, an increase in allergen-specific IgG and IgE was observed, with the highest increase in patients receiving a higher ILIT dose. The study was terminated due to several serious AEs upon the sting challenge provocation after the completion of treatment. However, out of 45 patients challenged, 15 (65%) and 18 (82%) patients in the 10- and 20-μg group, respectively, showed an improvement of two grades or more. No correlation was observed between antibody levels and sting protection.ConclusionsWhile a pilot study suggested the safety and efficacy of bee venom ILIT, a high number of AEs seen after the sting challenge following a randomized study indicate that the immunology protection offered by bee venom ILIT is insufficient. Of note, the bee venom allergen extract used in the two studies were from the two different providers. While the first study used a formulation approved for use in subcutaneous VIT, the second study used a nonapproved formulation never tested in humans. Further studies on approved formulations should be performed to generate conclusive results regarding the safety and efficacy of bee venom ILIT.

Alternatives to Subcutaneous Immunotherapy for Allergic Rhinitis

Allergic rhinitis (AR) is an important public health issue worldwide due to its increasing prevalence and impact on quality of life, school performance, and work productivity. Subcutaneous immunotherapy (SCIT) is used to treat AR and involves repeated injections of allergen extracts. SCIT is used for cases of severe AR with symptoms that are not adequately controlled by medication, when the side effects of medication limit treatment options, or where the aim is to cure rather than symptomatically treat. Although SCIT is effective, it is not necessarily curative. Furthermore, there is also a low but present risk of systemic allergic reactions, with systemic side effects occurring in less than 0–1% of treated patients. Sublingual immunotherapy (SLIT) has emerged as an effective and safe alternative to SCIT. SCIT and SLIT are the only immunotherapies currently available for AR. In addition to sublingual administration as an alternative to SCIT, other routes of antigen administration have been attempted with the goal of increasing safety while maintaining efficacy. This review discusses the efficacies of SCIT and SLIT, their mechanisms, the utility of intralymphatic immunotherapy (ILIT) as an alternative route of antigen administration, and the potential for immunotherapy using other routes of antigen administration.

High-dose pollen intralymphatic immunotherapy: Two RDBPC trials question the benefit of dose increase.

The same dosing schedule, 1000 SQ-U times three, with one-month intervals, have been evaluated in most trials of intralymphatic immunotherapy (ILIT) for the treatment of allergic rhinitis (AR). The present studies evaluated if a dose escalation in ILIT can enhance the clinical and immunological effects, without compromising safety. Two randomized double-blind placebo-controlled trials of ILIT for grass pollen-induced AR were performed. The first included 29 patients that had recently ended 3years of SCIT and the second contained 39 not previously vaccinated patients. An up-dosage of 1000-3000-10,000 (5000+5000 with 30minutes apart) SQ-U with 1month in between was evaluated. Doses up to 10,000 SQ-U were safe after recent SCIT. The combined symptom-medication scores (CSMS) were reduced by 31% and the grass-specific IgG4 levels in blood were doubled. In ILIT de novo, the two first patients that received active treatment developed serious adverse reactions at 5000 SQ-U. A modified up-dosing schedule; 1000-3000-3000 SQ-U appeared to be safe but failed to improve the CSMS. Flow cytometry analyses showed increased activation of lymph node-derived dendritic but not T cells. Quality of life and nasal provocation response did not improve in any study. Intralymphatic immunotherapy in high doses after SCIT appears to further reduce grass pollen-induced seasonal symptoms and may be considered as an add-on treatment for patients that do not reach full symptom control after SCIT. Up-dosing schedules de novo with three monthly injections that exceeds 3000 SQ-U should be avoided.

The route is the destination-novel forms of application of allergen immunotherapy

Allergen immunotherapy (AIT) is the only causal therapy of IgE-mediated allergies if allergen avoidance is not feasible. Already well established are subcutaneous (SCIT) and sublingual (SLIT) allergen application, and recently the first oral immunotherapy (OIT) for treating peanut allergy was approved. Interesting and promising new forms of allergen administration are intralymphatic (ILIT) and epicutaneous (EPIT) immunotherapy. Immunologic and clinical efficiency in terms of tolerance induction have been investigated in animal and clinical studies, including the first phase 3studies. The findings as well as advantages and disadvantages, potential risks and challenges that still have to be addressed before routine clinical application can be envisioned will be comprehensively presented and discussed.

Efficacy and safety of intralymphatic immunotherapy in allergic rhinitis: A systematic review and meta-analysis.

BackgroundIntralymphatic 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.MethodsAn 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).ResultsWe 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.ConclusionsIntralymphatic 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.

Intralymphatic immunotherapy for allergic rhinitis: A systematic review and meta-analysis.

Background: Only a fraction of patients with allergic rhinitis receive allergen-specific immunotherapy (AIT). AIT is most commonly delivered subcutaneously in a series of injections over 3-5 years. Common obstacles to completing this therapy include cost and inconvenience. Intralymphatic immunotherapy (ILIT) has been proposed as a faster alternative, which requires as few as three injections spaced 4 weeks apart. Objective: This systematic review and meta-analysis evaluated the current evidence that supports the use of ILIT for allergic rhinitis. Methods: Clinical trials were identified in the published literature by using an electronic search strategy and were evaluated by using a risk of bias tool. Treatment outcome (symptom scores, medication scores, and combined symptom and medication scores) and provocation testing results (nasal provocation and skin-prick testing) were included in a meta-analysis of standardized mean difference with subgrouping by using a random-effects model. Overall adverse event rates were tabulated, and overall risk ratios were calculated by using a random-effects model. Results: We identified 17 clinical trials that met eligibility criteria. The standardized mean difference of ILIT on the symptom and medication score was -0.72 (95% confidence interval [CI], -0.98 to -0.46; p < 0.0001) (n = 10). The standardized mean difference of ILIT on nasal provocation and skin-prick testing was -1.00 (95% CI, -1.38 to -0.61; p < 0.0001) (n = 7) and -0.73 (95% CI, -0.99 to -0.47; p < 0.0001) (n = 7), respectively. No statistically significant heterogeneity was detected. The overall adverse event rate was 39.5% for ILIT and 23.5% for placebo. Also, 98.4% of adverse events were mild. Conclusion: Our meta-analysis demonstrated that ILIT was safe, conferred desensitization to seasonal and nonseasonal allergens, alleviated allergic rhinitis symptoms, and reduced medication use. A larger randomized, double-blind, placebo controlled trial will be necessary for wider adaptation of this form of AIT.

Intralymphatic immunotherapy with tyrosine-adsorbed allergens: a double-blind, placebo-controlled trial

BackgroundMost previous studies used aluminum hydroxide-absorbed allergen extracts in evaluating the potential therapeutic roles of intralymphatic allergen-specific immunotherapy (ILAIT). In this study, we evaluated the therapeutic efficacy and safety of ILAIT with L-tyrosine-adsorbed allergen extracts of Dermatophagoides farinae, D. pteronyssinus, cat, dog, or mixtures thereof, in patients with allergic rhinitis induced by these allergens.MethodsIn this randomized, double-blind, placebo-controlled trial, study subjects received three intralymphatic injections of L-tyrosine-adsorbed allergen extracts (active group) or saline (placebo group) at 4-week intervals.ResultsAlthough ILAIT reduced daily medication use and skin reactivity to HDM and cat allergens at 4 months after treatment, overall symptom score on a visual analog scale (VAS), sinonasal outcome test-20 (SNOT-20), rhinoconjunctivitis quality of life questionnaire (RQLQ), daily symptom score (dSS), daily medication score (dMS), daily symptom medication score (dSMS), nasal reactivity to HDM allergen, and basophil activity to HDM, cat, and dog allergens at 4 months and 1 year after treatment were similar between the treatment and control groups. Intralymphatic injection was more painful than a venous puncture, and pain at the injection site was the most frequent local adverse event (12.8%); dyspnea and wheezing were the most common systemic adverse events (5.3%).ConclusionsILAIT with L-tyrosine-adsorbed allergen extracts does not exhibit profound therapeutic efficacy in allergic rhinitis and can provoke moderate-to-severe systemic reactions and cause pain at the injection site.Trial registration: clinicaltrials.gov: NCT02665754; date of registration: 28 January 2016

Intralymphatic immunotherapy for allergic rhinoconjunctivitis: a systematic review and meta-analysis.

Intralymphatic immunotherapy (ILIT) is a new route of allergen-specific immunotherapy. Data confirming its effect is restricted to a small number of studies. A systematic review with meta-analysis was conducted. The short-term (less than 24 weeks), medium-term (24-52 weeks), and long-term (more than 52 weeks) effects of ILIT in patients with allergic rhinoconjunctivitis (ARC) were assessed. The outcomes were combined symptom and medication scores (CSMS), symptoms visual analog scale (VAS), disease-specific quality of life (QOL), specific IgG4 level, specific IgE level, and adverse events. Eleven randomized controlled trials and 2 cohorts (483 participants) were included. Compared with placebo, short term benefits of ILIT for seasonal ARC improved CSMS, improved VAS and increased specific IgG4 level but did not change QOL or specific IgE level. Medium-term effect improved VAS. Data on the long-term benefit of ILIT remain unavailable and require longer term follow-up studies. There were no clinical benefits of ILIT for perennial ARC. ILIT was safe and well-tolerated. ILIT showed short-term benefits for seasonal ARC. The sustained effects of ILIT were inconclusive. It was well tolerated.

Intralymphatic immunotherapy improves grass pollen allergic rhinoconjunctivitis: A 3-year randomized placebo-controlled trial

Allergic rhinoconjunctivitis is a global health problem. Different allergen immunotherapy regimes are marketed but have low adherence because they are expensive, complex, and time-consuming. New allergen immunotherapy forms are needed. In a 3-year follow-up double-blind randomized placebo-controlled trial, we aimed to investigate the effect of intralymphatic allergen immunotherapy (ILIT). Patients with grass pollen rhinoconjunctivitis were treated with 3 ILIT injections and an ILIT booster 1 year later, 3 ILIT injections and a placebo booster, or 3 placebo injections and a placebo booster. Primary outcome was improvement in a combined symptom and medication score (cSMS). Anovel evaluation tool with a linear regression model of cSMS and grass pollen counts was developed. Secondary outcomes were changes in grass specific immunoglobulins and skin and nasal provocation tests to grass pollen. A total of 36 patients were included. Log10-transformed cSMS was reduced by 0.30 (95% CI, 0.11-0.49; P= .002), equaling 48.5% (95% CI, 24.5%-62%), in the entire 3-year follow-up period, significant only in the first follow-up season but not in the second and third seasons. The regression model showed a 37% (P< .001) reduction in cSMS. The booster injection 1 year later had no additional effect. Secondary, repeated measures of IgE and IgG4 to grass showed significant between-group difference and within-group change in the ILIT groups. No change in provocation test results was found. ILIT gives a substantial reduction in grass pollen allergy symptoms and use of rescue medication, significant in the first season after treatment. Abooster injection had no additional effect.

A comparative study of subcutaneous, intralymphatic and sublingual immunotherapy for the long-term control of dogs with nonseasonal atopic dermatitis.

Allergen-specific immunotherapy (ASIT) is the only causative treatment of canine atopic dermatitis (cAD). Different routes for administration of ASIT have been used; however, comparative studies are lacking. The present study compared the efficacy and safety of subcutaneous (SCIT), intralymphatic (ILIT) and sublingual (SLIT) immunotherapy. 30 atopic dogs were included and allocation to three groups (SCIT, n=8; ILIT, n=12; SLIT, n=10) was determined by the owners. ASIT was administered using routine protocols. The pruritus Visual Analog Scale (PVAS), canine atopic dermatitis extent and severity index (CADESI), concurrent medications and adverse events were recorded initially and one, three, six and 12 months later. The main outcome measure was return to a normal status, which included CADESI <12, PVAS <2.5 and medication score <10. Drop-outs were distributed evenly and 23 dogs finished the study (SCIT, n=6; ILIT, n=10; SLIT, n=7). Adverse reactions to treatment were rare. At the start of the study, the three groups were homogeneous with respect to clinical signs and concurrent medications. After 12 months of ASIT, the CADESI and PVAS had decreased with a stable medication score in the ILIT and SCIT groups (P < 0.05), while all three scores had increased in the SLIT group. Return to normal state was achieved in one of six (17%) dogs receiving SCIT, in six of 10 (60%) dogs receiving ILIT and in one of seven (14%) dogs receiving SLIT. These findings suggest that SCIT and ILIT improved clinical signs of cAD, whereas ILIT had a much higher return to normal rate.

Intralymphatic immunotherapy for mountain cedar pollinosis: A randomized, double-blind, placebo-controlled trial

BackgroundAllergen immunotherapy can provide long-term benefits, including symptomatic relief and reduced disease progression, but it requires a lengthy regimen that presents barriers to patient adherence. Thus, there is a need for improved approaches to immunotherapy. Recently, several clinical trials have reported successful results from intralymphatic immunotherapy. ObjectiveTo evaluate the efficacy, safety, and tolerability of intralymphatic immunotherapy for allergies caused by mountain cedar pollen in a proof-of-concept study. MethodsA total of 21 patients with allergic rhinoconjunctivitis because of mountain cedar pollen were randomized to receive 3 monthly intralymphatic injections of allergenic extract or placebo before the 2018-2019 mountain cedar pollen season. Safety was monitored during treatment to the end of the pollen season using structured and spontaneous reports. Clinical efficacy information was collected using a daily electronic diary of symptoms and allergy medication. Allergen-specific serum immunoglobulin E was assessed before treatment and at the end of the study. ResultsThere were no serious adverse events or systemic reactions in either group. A total of 4 patients experienced mild injection-site reactions. Patients receiving intralymphatic immunotherapy experienced a significant improvement in allergy symptoms and medication use relative to patients receiving placebo (P < .001), and the active treatment group had lower average total combined scores on 20 of 27 days during the peak pollen season (P < .05). There was no significant difference among groups in changes to mean mountain cedar-specific serum immunoglobulin E levels. ConclusionIn this proof-of-concept trial, intralymphatic immunotherapy was well tolerated and improved the symptoms and medication use associated with allergic rhinoconjunctivitis caused by mountain cedar pollen. Trial RegistrationThis study was registered at ClinicalTrials.gov under the registration number NCT03682965 before the enrollment of the first subject.

A preseason booster prolongs the increase of allergen specific IgG4 levels, after basic allergen intralymphatic immunotherapy, against grass pollen seasonal allergy

BackgroundAllergen 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.MethodsIntralymphatic 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.ResultsThe 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.ConclusionsIt 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

Sustained effects of intralymphatic pollen-specific immunotherapy on Japanese cedar pollinosis.

Intralymphatic immunotherapy (ILIT) for allergic patients requires only a few intralymphatic injections of the allergen. However, the effectiveness and safety for Japanese cedar pollinosis are unclear. The objectives of this study were to clarify whether and how long ILIT is effective for pollinosis, and its safety. In an open pilot investigation followed by a double-blind, placebo-controlled study, patients with Japanese cedar pollinosis received 3 intralymphatic inguinal injections of the pollen extracts before the first pollen season. The symptom medication score (SMS), nasal provocation testing and scoring visual analogue scale (VAS) were assessed after the first-third seasons. (1) Although mild adverse events were induced at the injected site, severe adverse events were not noted. (2) During the latter part of the first season, ILIT-treated patients (n=12) tended to show improved SMS compared to placebo-treated (n=6) without statistical significance. When assessed by nasal provocation testing and VAS scoring after the first season, the effectiveness of ILIT was significant. (3) The effects of ILIT continued until the second or third season. (4) Neither allergen-specific antibodies nor Treg/Breg cells changed in the peripheral blood. ILIT was safe and effective for Japanese cedar pollinosis. The clinical effects remained for 1-2 years.

Diverse Mechanisms of Allergen Specific Immunotherapy

Allergen immunotherapy (AIT) is widely used to establish a tolerant immune response and it is currently the only disease modifying treatment. There are different routes to administer the allergen, including subcutaneous, sublingual, intralymphatic, epicutaneous, intradermal, and oral and local nasal allergen immunotherapy. Although the optimal administration route depends on the type of allergen, some patients remain unresponsive and so it is important to predict the outcome before and during treatment. Therefore, there is a need to identify candidate prognostic markers for allergen immunotherapy. Herein, we discuss the recent literature on the molecular mechanisms of AIT.

Intralymphatic immunotherapy in pollen-allergic young adults with rhinoconjunctivitis and mild asthma: A randomized trial

Four intralymphatic allergen injections for treatment of pollen allergy reduce medication use, improve symptoms and have immune modulating effects in adolescents and young adults with rhinoconjunctivitis and mild asthma due to birch or grass pollen.

Research progress in the application of intralymphatic allergen immunotherapy in allergic diseases

SummaryAlthough subcutaneous immunotherapy （SCIT） and sublingual immunotherapy （SLIT） have a positive effect, there are drawbacks such as long treatment time period, frequent treatment times, and risk of adverse reactions. Peripheral superficial lymph node injection of allergen immunotherapy （ILIT） as an emerging specific immunotherapy method has the advantages of high safety, less adverse reactions, short treatment time, less treatment times, less patient pain, and exact curative effect. In recent years, more and more scholars have conducted extensive research on intra-lymphatic injection of immunotherapy for allergic diseases. This paper systematically summarizes the theoretical basis, method, safety, effectiveness and possible immune mechanism of ILIT.

Ocular allergy: update on clinical trials.

The purpose of this article is to provide an update on the advances made through recent clinical trials regarding the treatment of the signs and symptoms of allergic conjunctivitis and its associated conditions. Recent studies have demonstrated significant advancement in the various forms of immunotherapy treatments. Nutritional interventions such as probiotics have surfaced as a viable complementary treatment option. Novel delivery methods such as contact lenses have been further studied along with a new tacrolimus formulation to improve ocular levels of the drug. Currently, the primary advances in treatment for allergic conjunctivitis has shifted from new ophthalmic agents to immunotherapy and improvement of drug delivery. This includes the classic subcutaneous and sublingual and the novel epicutaneous and intralymphatic immunotherapy delivery systems as well as an edible rice vaccine. New targets for treatment have spurred research into new antagonist drugs such as (OC000459), a prostaglandin D2 antagonist. The Marinosolv formulation using tacrolimus shows promise and may be considered for other ophthalmic agents in the future. Other nonpharmacological treatments such as stenting and mechanical barrier gel have demonstrated their usefulness in treating ocular symptoms.

Clinical efficacy and safety of specific immunotherapy for allergic rhinitis with cervical lymph node injection

Objective: To evaluate the clinical efficacy and safety of intralymphatic immunotherapy with cervical lymph node injection for allergic rhinitis. Method: A retrospective analysis of 81 patients with allergic rhinitis(AR) who had received specific immunotherapy with cervical lymph node injection in 2016 in the first people's Hospital of Foshan was conducted. The neck lymph node immunotherapy under the guidance of color Doppler ultrasound consisted of three sessions, and in each session 50 Tu(Arog) was delivered. The scores of nasal and ocular symptoms, drug score and adverse reactions during treatment were recorded before and after treatment, and the efficacy and safety were observed. Result: Before treatment, the nasal symptoms score of 81 AR cases of mite allergy was 7.00±1.65. After 1,2 and 3 sessions of cervical lymph node immune therapy and 1 year after completion of treatment, the nasal symptom scores were 4.37±1.88, 4.26±1.80, 4.22±1.80, and 4.09±2.10,respectively, which were significantly lower than that before treatment(P<0.01). The quality of life score was 53.68±9.28 before treatment, which decreased to 23.01±13.28 one year after treatment, and the difference was statistically significant(P<0.01). The drug score was 3.27±1.17 before treatment, which decreased to 1.00±1.05 1 years after treatment, and the difference was statistically significant(P<0.01). During treatment and 1-year follow-up, only 8 cases had mild local reactions, and no systemic adverse reactions occurred. Conclusion: Cervical lymph node injection specific immunotherapy can significantly relieve the symptoms of dust mite allergic rhinitis. The treatment is effective and safe, and greatly shortens the duration of immune treatment.

Intralymphatic Immunotherapy for Peanut Allergy: A pilot study of three patients

Intralymphatic Immunotherapy for Peanut Allergy: A pilot study of three patients

Nasal challenges in allergen immunotherapy trials.

The nasal allergen challenge (NAC) model can be a valuable diagnostic tool for allergic rhinitis. Alongside its clinical use, NACs can be used as primary and secondary endpoints in studies evaluating allergen immunotherapy (AIT) products for allergic rhinitis treatment. This review will discuss the technical aspects of the NAC model and provide a summary of recent studies using NACs to assess existing and new AIT treatments. Over the last 2 years, both titrated and single-dose nasal challenge protocols have been used to evaluate immunotherapies targeting grass, birch, house dust mite, and cat allergens. Early efficacy and dose-finding trials showed improvements in allergic symptoms and nasal tolerance to allergens after AIT treatment with standardized extracts or modified forms of whole allergen. NACs were also used in two proof-of-concept studies to illustrate the efficacy of intralymphatic immunotherapy with two concomitant allergens and subcutaneous immunotherapy with Fel d 1-specific IgG-blocking antibodies. Along with existing therapies, nasal challenges are useful in evaluating AIT treatments in the very early stages of clinical development. However, because of the variety in challenge techniques and symptom assessments available, special attention must be placed in the protocol design in order to compare the study results with existing NAC publications.