Patients with severe birch and timothy allergy were randomized to receive 3 monthly injections of 0.1 ml of birch and 5-grass allergen extracts (10,000 SQ units/ml, ALK-Abelló) placebo, or 5-grass and placebo via ultrasound-guided injections into inguinal lymph nodes. For a study, the researchers assessed the Total Symptom Score, Medication Score, and Rhinoconjunctivitis Quality of Life Questionnaire before and after each birch and grass pollen season over 3 years. Flow cytometry and Luminex were used to examine the proportions of T helper subsets in circulation and allergen-induced cytokine and chemokine production. During the birch and grass pollen seasons each year after treatment, all 3 groups reported fewer symptoms, decreased medication use, and improved quality of life at nearly the same rate, regardless of whether they were treated with 1 or 2 allergens. The most prevalent side effect was mild local soreness. In all 3 groups, IgE levels to birch dropped, whereas birch-induced IL-10 production rose. IgG4 levels to birch and timothy mainly were unaltered, as was skin prick test reactivity. Conjunctival challenge experiments using timothy extract revealed a more significant allergen threshold. Furthermore, 3 years following therapy, regulatory T cell frequencies increased in all 3 groups. Intralymphatic immunotherapy with 1 or 2 allergens was safe and helpful in patients with grass and birch pollen allergies, and it was linked to immunological modulatory responses in bystanders.