Dong-Ho Nahm

Chronic spontaneous urticaria (CSU) remains challenging to manage in patients who do not respond adequately to antihistamines or currently available immunomodulatory therapies. Intramuscular injection of autologous total IgG (autologous immunoglobulin therapy: AIGT) has demonstrated clinical efficacy, safety and immunomodulatory effects in patients with moderate‐to‐severe atopic dermatitis in a randomized placebo‐controlled clinical trial. However, the clinical usefulness of AIGT in patients with CSU has not been evaluated. We conducted a prospective open‐label pilot study to assess the efficacy and safety of AIGT in antihistamine‐refractory CSU. Fifteen adults with CSU received nine weekly intramuscular injections of 100 mg autologous IgG from Week 0 through Week 8 (inclusive). The primary outcome was the change in Urticaria Activity Score over 7 days (UAS7) at Week 12 from baseline. Secondary outcomes included the Urticaria Control Test (UCT), chronic urticaria‐specific quality of life (CU‐QoL) scores and patient‐reported disease burden using a visual analogue scale (VAS). The median change in UAS7 at Week 12 from baseline was −13.0 ( p < 0.001). Significant improvements in UCT, CU‐QoL and VAS were also observed at Week 12 from baseline ( p < 0.05). In longitudinal analyses, improvements in symptom burden and quality of life were detectable from Week 4 and were maintained through Week 24. Serum total IgG increased by a median of +68.0 mg/dL from baseline to Week 12 ( p < 0.05). No serious adverse events occurred. In conclusion, AIGT improved disease activity, urticaria control, quality of life and patient‐reported burden in patients with antihistamine‐refractory CSU. Further studies are needed to evaluate the clinical usefulness of AIGT in CSU.

Nahm DH, et al. Allergy Asthma Immunol Res. 2026 Mar;18(2):313-317. https://doi.org/10.4168/aair.2026.18.2.313

Lee HY, et al. Allergy Asthma Immunol Res. 2025 Mar;17(2):271-284. https://doi.org/10.4168/aair.2025.17.2.271

Interleukin‐33 (IL‐33) is a proinflammatory alarmin cytokine released by damaged epithelial tissue cells that initiates and amplifies both type 1 and type 2 inflammatory cascades. A role for IL‐33 in atopic dermatitis (AD; a chronic, relapsing type 2 inflammatory disease of the skin) has been proposed. Itepekimab is a novel human IgG4P monoclonal antibody against IL‐33, currently in clinical development for chronic obstructive pulmonary disease (COPD). Two global phase II studies—a dose‐ranging itepekimab monotherapy study (NCT03738423) and a proof‐of‐concept study of itepekimab alone and in combination with dupilumab (NCT03736967)—were conducted in patients with moderate‐to‐severe AD to assess safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy; both studies were terminated following an interim analysis of the proof‐of‐concept study, which failed to demonstrate the efficacy of itepekimab. In these two studies, itepekimab exhibited linear and dose‐proportional pharmacokinetics. Pharmacodynamics of total IL‐33 indicated that itepekimab saturated binding to the target in serum at 300 mg q2w and q4w doses, and decreased blood eosinophil counts. Concentration–time profiles of itepekimab and total IL‐33 were similar for itepekimab with or without dupilumab, and between East Asian and non‐East Asian subgroups. Itepekimab was generally well tolerated, both alone and in combination with dupilumab. The lack of clinical efficacy for itepekimab observed in these studies suggests that IL‐33 may not be a key pathogenic driver in moderate‐to‐severe AD.

Min JY, et al. Allergy Asthma Immunol Res. 2024 Jan;16(1):9-21. https://doi.org/10.4168/aair.2024.16.1.9

The regulatory T (Treg) cells constitute a functionally defined subpopulation of T cells that modulate the immune system and maintain immune tolerance through suppression of the development of autoimmune responses to self-antigens and allergic reactions to external antigens. Reduction in the number or function of Treg cells has been suggested as a key immune abnormality underlying the development of autoimmune and allergic diseases. In vitro studies have demonstrated that purified polyvalent immunoglobulin G (IgG) from multiple healthy blood donors can exert immunomodulatory effects on Treg cells. Incubation of polyvalent human IgG with purified CD4⁺CD25^high T cells increased the intracellular expression of interleukin (IL)-10. Intravenous administration of polyvalent human IgG induced significant expansions of CD4⁺ Foxp3⁺ Treg cells and clinical improvements in patients with autoimmune diseases. In human clinical trials, intramuscular administration of autologous total IgG significantly increased the percentage of IL-10-producing CD4⁺ Treg cells in the peripheral blood of healthy subjects and provided significant clinical improvements in patients with atopic dermatitis. These results suggest a clinical usefulness of polyvalent IgG-induced activation of Treg cells in human subjects. This review proposes a new hypothesis for immune tolerance mechanism by integrating the pre-existing “idiotypic network theory” and “Treg cell theory” into an “anti-idiotypic Treg cell theory.” Based on this hypothesis, an “active anti-idiotypic therapy” for allergic and autoimmune diseases using autologous polyvalent IgG (as immunizing antigens) is suggested as follows: (1) Intramuscular or subcutaneous administration of autologous polyvalent IgG produces numerous immunogenic peptides derived from idiotypes of autologous IgG through processing of dendritic cells, and these peptides activate anti-idiotypic Treg cells in the same subject. (2) Activated anti-idiotypic Treg cells secrete IL-10 and suppress Th2 cell response to allergens and autoimmune T cell response to self-antigens. (3) These events can induce a long-term clinical improvements in patients with allergic and autoimmune diseases. Further studies are needed to evaluate the detailed molecular mechanism underlying polyvalent IgG-induced Treg cell activation and the clinical usefulness of this immunomodulatory therapy for autoimmune and allergic diseases.

Atopic dermatitis (AD) is a chronically relapsing inflammatory skin disorder characterized by itching and eczematous lesions. It is often associated with a personal or familial history of allergic diseases. Allergic inflammation induced by immunoglobulin E and T-helper type 2 (Th2) cell responses to common environmental agents has been suggested to play an essential role in AD pathogenesis. The standard therapies for AD, including topical or systemic agents, focus on controlling skin inflammation. Recently developed monoclonal antibody to interleukin-4 receptor alpha or Janus kinase inhibitors can provide significant clinical improvements in patients with AD by inhibiting Th2 cell-mediated skin inflammation. However, the clinical efficacy of the Th2 cell-targeted therapy is transient and incomplete in patients with AD. Patients with AD are seeking a permanent cure. Therefore, the development of novel immunomodulatory strategies that can improve a long-term clinical outcome and provide a long-term treatment-free clinical remission of AD (disease-modifying therapy) is needed. Regulatory T (Treg) cells play a critical role in the maintenance of immune tolerance and suppress the development of autoimmune and allergic diseases. This review provides three working hypotheses and perspectives for the treatment of AD by Treg cell activation. (1) A decreased number or function of Treg cells is a critical event that causes the activation of Th2 cells, leading to the development and maintenance of AD. (2) Activation of Treg cells is an effective therapeutic approach for AD. (3) Many different immunomodulatory strategies activating Treg cells can provide a long-term clinical improvement of AD by induction of immune tolerance. The Treg cell-targeted immunomodulatory therapies for AD include allergen immunotherapy, microbiota, vitamin D, polyvalent human immunoglobulin G, monoclonal antibodies to the surface antigens of T cell or antigen-presenting cell, and adoptive transfer of autologous Treg cells or genetically engineered Treg cells expanded in vitro.

Lee HY, et al. Allergy Asthma Immunol Res. 2023 Nov;15(6):725-756. https://doi.org/10.4168/aair.2023.15.6.725

Nahm DH, et al. Yonsei Med J. 2023 Jul;64(7):423-432. https://doi.org/10.3349/ymj.2022.0559