Intramuscular administration of autologous total immunoglobulin G induces immunomodulatory effects on T cells in healthy human subjects

Kwon, Byul; Yang, Seungjung; Cho, Su-Mi; Kim, Myoung-Eun; Nahm, Dong-Ho

doi:10.1097/md.0000000000029486

Cited by 6 publications

(13 citation statements)

References 39 publications

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“…Previously, our research group demonstrated that the human thymus can generate IL-10-producing regulatory B cells (B10) in response to stimulation with polyclonal IgG from individuals with allergies 18 . In recent years, the immunomodulatory effects of polyclonal IgG have been observed both in vitro 30 – 34 and in vivo 35 – 38 , primarily focusing on T cell populations in murine and human systems.…”

Section: Discussionmentioning

confidence: 99%

IgG from Dermatophagoides pteronyssinus (Der p)-atopic individuals modulates non-atopic thymic B cell phenotype (alfa-4/beta-7) and cytokine production (IFN-γ, IL-9, and IL-10) with direct membrane interaction

de-Apoena Reche,

Machado,

Fagundes

et al. 2024

Sci Rep

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Studies about thymic B cells are scarce in the literature, but it was suggested that they can exert modulatory and regulatory functions on the immune system. Thymic B cells can play some role in regulating the most frequent allergic background worldwide, the atopy induced by the mite Dermatophagoides pteronyssinus (Der p). Here, we aimed to evaluate if the polyclonal IgG repertoire produced by Der p-atopic individuals can influence the homing and cytokine profile of human thymic B derived from non-atopic children aged less than seven days. With this purpose, we produced polyclonal IgG formulations and cultivated human thymocytes in their presence. We also assessed IgG subclasses and the direct interaction of IgG with thymic B cell membranes. Our results could demonstrate that Der p-atopic IgG could not reduce the expression of α4β7 homing molecule as observed in response to the other IgG formulations and could reduce the frequency of IFN-γ- and IL-9-producing thymic B cells compared to the mock condition. Der p-atopic IgG could also induce thymic IL-10-producing B cells compared to control conditions. The IgG derived from Der p-atopic individuals failed to diminish the population of IL-13-producing thymic B cells, unlike the reduction observed with other IgG formulations when compared to the mock condition. All IgG formulations had similar levels of IgG subclasses and directly interacted with thymic B cell membranes. Finally, we performed experiments using peripheral non-atopic B cells where IgG effects were not observed. In conclusion, our observation demonstrates that IgG induced in allergic individuals can modulate non-atopic thymic B cells, potentially generating thymic B cells prone to allergy development, which seems to not occur in mature B cells.

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Section: Discussionmentioning

confidence: 99%

IgG from Dermatophagoides pteronyssinus (Der p)-atopic individuals modulates non-atopic thymic B cell phenotype (alfa-4/beta-7) and cytokine production (IFN-γ, IL-9, and IL-10) with direct membrane interaction

de-Apoena Reche,

Machado,

Fagundes

et al. 2024

Sci Rep

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“…In this study, 13 healthy adults were submitted to an intramuscular administration of total autologous IgG in the same protocol used in the above AD patients’ studies (50 mg for 4 weeks). These individuals demonstrate an increase in the percentage of peripheral CD4+ T cells producing IL-10 and CD3+ T cells producing IFN-γL-10 compared to baseline [ 43 ]. Unfortunately, the researchers did not evaluate complex intracellular and phenotypic molecules to generate more analytical aspects that may be compared or corroborated with the complexity of experimental evidence.…”

Section: In Vivo Approaches To the Immune Tolerance Induced ...mentioning

confidence: 99%

Immune modulation and possible pathological implications mediated by naturally produced immunoglobulin G idiotypes: from historical to recent experimental and clinical studies focused on atopic dermatitis

Santander,

Machado,

Fagundes

et al. 2024

Clin Exp Vaccine Res

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Since the 1950s decade, it has been suggested that a naturally produced or induced repertoire of immunoglobulin G (IgG) idiotypes may exert some immunoregulatory functions. In the last decades, some more advanced theories have suggested that the repertoire of IgG idiotypes may influence the development or control of some atopic diseases. In atopic dermatitis (AD), some evidence indicated that the IgG repertoire obtained from these patients could effectively mediate regulatory functions on thymic and peripheral CD4+ and CD8+ T cells. Furthermore, some recent clinical trials have corroborated the hypothesis that IgG from AD patients can exert regulatory functions in vivo . Here, we revised some historical aspects that yield current approaches developed in vitro and in vivo to elucidate a recently proposed theory termed “hooks without bait” that can strengthen the broad spectrum of research about evaluating different sets of IgG idiotypes and determine their immunological effects.

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“…In humans, an author of this review (Nahm DH) reported that the intramuscular administration of autologous total IgG increased the percentage of IL-10-producing CD4 + T cells in the peripheral blood in 13 healthy human subjects ( 46 ). However, this report could not provide a detailed molecular mechanism underlying the autologous polyvalent IgG-mediated immunomodulation or the subpopulation of Treg cells activated by autologous polyvalent IgG.…”

Section: Four Hypothetical Models For the Mechanism Underlying Polyva...mentioning

confidence: 99%

“…In a clinical trial, IVIg therapy in patients with common variable immunodeficiency significantly increased the number of peripheral Treg cells (expressing CD4, CD25, and low levels of CD127) and plasma levels of IL-10 within 30 minutes after the infusion of IVIg, suggesting a highly efficient interaction between polyvalent IgG and Treg cells ( 64 ). This review provides a summary of study results (subpopulation of Treg cells and mechanism) on the polyvalent IgG-induced activation of Treg cells in human clinical trials ( Table 3 ) ( 46 , 57 – 65 ).…”

Section: Evidence Supporting Activation Of Treg Cells By Polyvalent I...mentioning

confidence: 99%

“…An author (Nahm DH) of this review has tried to develop a new anti-idiotypic therapy through intramuscular injection of autologous total IgG purified from autologous blood via affinity-chromatography using protein A bead in patients with atopic dermatitis (AD) and healthy human subjects ( 46 , 66 – 70 ). From clinical trials in patients with AD and healthy human subjects, the novel concept of an “active anti-idiotypic therapy” was developed as described in the following sections.…”

Section: Evidence Supporting Activation Of Treg Cells By Polyvalent I...mentioning

confidence: 99%

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Mechanism underlying polyvalent IgG-induced regulatory T cell activation and its clinical application: Anti-idiotypic regulatory T cell theory for immune tolerance

Victor,

Nahm

2023

Front. Immunol.

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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+CD25high 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.

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Intramuscular administration of autologous total immunoglobulin G induces immunomodulatory effects on T cells in healthy human subjects

Cited by 6 publications

References 39 publications

IgG from Dermatophagoides pteronyssinus (Der p)-atopic individuals modulates non-atopic thymic B cell phenotype (alfa-4/beta-7) and cytokine production (IFN-γ, IL-9, and IL-10) with direct membrane interaction

IgG from Dermatophagoides pteronyssinus (Der p)-atopic individuals modulates non-atopic thymic B cell phenotype (alfa-4/beta-7) and cytokine production (IFN-γ, IL-9, and IL-10) with direct membrane interaction

Immune modulation and possible pathological implications mediated by naturally produced immunoglobulin G idiotypes: from historical to recent experimental and clinical studies focused on atopic dermatitis

Mechanism underlying polyvalent IgG-induced regulatory T cell activation and its clinical application: Anti-idiotypic regulatory T cell theory for immune tolerance

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