Intramuscular administration of autologous total immunoglobulin G induces immunomodulatory effects on T cells in healthy human subjects: An open-labeled prospective single-arm trial

Byul Kwon, Seung-Jung Yang, Su-Mi Cho, Myoung-Eun Kim, Dong-Ho Nahm, Byul Kwon, Seung-Jung Yang, Su-Mi Cho, Myoung-Eun Kim, Dong-Ho Nahm

Abstract

Background: We hypothesized that intramuscular administration of autologous total immunoglobulin G (IgG) could induce an immunomodulatory effect in human subjects. In our previous studies, we showed that intramuscular administration of autologous total IgG could induce significant clinical improvements and increases of the serum levels of interleukin-10 (IL-10) and interferon-gamma (IFN-γ) in patients with atopic dermatitis.

Objective: To investigate the mechanism of immunomodulation induced by intramuscular administration of autologous total IgG, we evaluated changes in T cells before and after intramuscular administrations of autologous total IgG in this study.

Methods: Thirteen healthy adults received 8 intramuscular injections of 50 mg autologous total IgG for 4 weeks (from week 0 to week 4). The percentages of IL-10- or IFN-γ-producing peripheral blood T cells, as well as serum levels of IL-10, IFN-γ, and immunoglobulins, were measured at baseline (week 0) and at weeks 4, 8, and 12.

Results: The percentage of IL-10-producing CD4+ T cells was significantly increased at weeks 8 and 12 compared to baseline (P < .05), while the percentage of IFN-γ-producing CD3+ T cells was significantly increased at week 12 compared to baseline (P < .05). There were no significant differences in the serum levels of IL-10, IFN-γ, and immunoglobulins before and after intramuscular administration of autologous total IgG (P > .05). No serious adverse events were observed.

Conclusion: Intramuscular administration of autologous total IgG induced immunomodulatory effects on T cells in healthy human subjects. This simple intervention could be a safe, effective, and economical T cell immunomodulation method for human subjects (NCT03695757).

Conflict of interest statement

The authors have no conflicts of interest to disclose.

Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.

Figures

Figure 1
Figure 1
The study design.
Figure 2
Figure 2
The percentages of IL-10- or IFN-γ-producing peripheral blood CD3+ (A), CD4+ (B), CD8+ (C), and CD4+CD25+ (D) T cells in 13 healthy human subjects who received 8 intramuscular administrations of 50 mg autologous total IgG twice a week for 4 wk (from week 0 to week 4) during the 12-wk study period. P values were calculated using the Wilcoxon signed-rank test with Bonferroni correction. Each symbol and connecting line in the graphs represents an individual healthy subject. ∗P < .05, ∗∗P < .01 compared to baseline.
Figure 3
Figure 3
Representative flow cytometric analysis data on the percentages of IL-10- or IFN-γ-producing peripheral blood CD4+ T cells at baseline (week 0) and week 12 in 2 healthy human subjects who received 8 intramuscular administrations of 50 mg autologous total IgG twice a week for 4 wk (from week 0 to week 4) during the 12-wk study period.
Figure 4
Figure 4
Subpopulations of peripheral blood lymphocytes cultured for 20 h with non-specific cell stimulants in 13 healthy human subjects who received 8 intramuscular administrations of 50 mg autologous total IgG twice a week for 4 wk (from week 0 to week 4) during the 12-wk study period. P values were calculated using Wilcoxon's signed-rank test with Bonferroni correction. Each symbol and connecting line in the graphs represents an individual healthy subject. ∗P < .05 compared to baseline.
Figure 5
Figure 5
Serum levels of IL-10 and IFN-γ in 13 healthy human subjects who received 8 intramuscular administrations of 50 mg autologous total IgG twice a week for 4 wk (from week 0 to week 4) during the 12-wk study period. Each symbol and connecting line in the graphs represents an individual healthy subject.
Figure 6
Figure 6
Serum levels of IgG antibodies to pneumococcal capsular polysaccharide antigens (A), influenza antigens (B), house dust mite antigens (C), and extractable nuclear antigens (D) in 13 healthy human subjects who received 8 intramuscular administrations of 50 mg autologous total IgG twice a week for 4 wk (from week 0 to week 4) during the 12-wk study period. Each symbol and connecting line in the graphs represents an individual healthy subject.

References

    1. Buckley RH, Schiff RI. The use of intravenous immune globulin in immunodeficiency diseases. N Engl J Med 1991;325:110–7.
    1. Kazatchkine MD, Kaveri SV. Immunomodulation of autoimmune and inflammatory diseases with intravenous immune globulin. N Engl J Med 2001;345:747–55.
    1. Gelfand EW. Intravenous immune globulin in autoimmune and inflammatory diseases. N Engl J Med 2012;367:2015–25.
    1. Imbach P, Barandun S, d’Apuzzo V, et al. . High-dose intravenous gammaglobulin for idiopathic thrombocytopenic purpura in childhood. Lancet 1981;1:1228–31.
    1. Gilardin L, Bayry J, Kaveri SV. Intravenous immunoglobulin as clinical immune-modulating therapy. CMAJ 2015;187:257–64.
    1. Galeotti C, Kaveri SV, Bayry J. IVIG-mediated effector functions in autoimmune and inflammatory diseases. Int Immunol 2017;29:491–8.
    1. Kessel A, Ammuri H, Peri R, et al. . Intravenous immunoglobulin therapy affects T regulatory cells by increasing their suppressive function. J Immunol 2007;179:5571–5.
    1. Maddur MS, Kaveri SV, Bayry J. Circulating normal IgG as stimulator of regulatory T cells: lessons from intravenous immunoglobulin. Trends Immunol 2017;38:789–92.
    1. Ephrem A, Chamat S, Miquel C, et al. . Expansion of CD4+CD25+ regulatory T cells by intravenous immunoglobulin: a critical factor in controlling experimental autoimmune encephalomyelitis. Blood 2008;111:715–22.
    1. Seite JF, Shoenfeld Y, Youinou P, Hillion S. What is the contents of the magic draft IVIg? Autoimmun Rev 2008;7:435–9.
    1. Fuchs S, Feferman T, Meidler R, Brenner T, Laub O, Souroujon MC. The disease-specific arm of the therapeutic effect of intravenous immunoglobulin in autoimmune diseases: experimental autoimmune myasthenia gravis as a model. Isr Med Assoc J 2008;10:58–60.
    1. Wallmann J, Pali-Scholl I, Jensen-Jarolim E. Anti-ids in allergy: timeliness of a classic concept. World Allergy Organ J 2010;3:195–201.
    1. Shoenfeld Y. The idiotypic network in autoimmunity: antibodies that bind antibodies that bind antibodies. Nat Med 2004;10:17–8.
    1. Lopez-Requena A, Mateo De Acosta C, Vazquez AM, Perez R. Immunogenicity of autologous immunoglobulins: principles and practices. Mol Immunol 2007;44:3076–82.
    1. Schulz R, Werner B, Behn U. Self-tolerance in a minimal model of the idiotypic network. Front Immunol 2014;5:86.
    1. Nahm DH, Cho SM, Kim ME, Kim YJ, Jeon SY. Autologous immunoglobulin therapy in patients with severe recalcitrant atopic dermatitis: a preliminary report. Allergy Asthma Immunol Res 2014;6:89–94.
    1. Gottheil WS, Satenstein DL. The autoserum treatment in dermatology. JAMA 1914;63:1190–4.
    1. Mori O, Hashimoto T. Autologous whole blood intramuscular injection as a cure for chronic urticaria: report of a patient in whom intradermal injection of autologous serum continued to cause a weal-and-flare response. Br J Dermatol 1999;140:1192–3.
    1. Pittler MH, Armstrong NC, Cox A, Collier PM, Hart A, Ernst E. Randomized, double-blind, placebo-controlled trial of autologous blood therapy for atopic dermatitis. Br J Dermatol 2003;148:307–13.
    1. Debbarman P, Sil A, Datta PK, Bandyopadhyay D, Das NK. Autologous serum therapy in chronic urticaria: a promising complement to antihistamines. Indian J Dermatol 2014;59:375–82.
    1. Staubach P, Onnen K, Vonend A, et al. . Autologous whole blood injections to patients with chronic urticaria and a positive autologous serum skin test: a placebo-controlled trial. Dermatology 2006;212:150–9.
    1. Schafer T, Riehle A, Wichmann HE, Ring J. Alternative medicine in allergies – prevalence, patterns of use, and costs. Allergy 2002;57:694–700.
    1. Nahm DH, Kim ME, Cho SM. Effects of intramuscular injection of autologous immunoglobulin on clinical severity and serum IgE concentration in patients with atopic dermatitis. Dermatology 2015;231:145–51.
    1. Nahm DH, Ahn A, Kim ME, Cho SM, Park MJ. Autologous immunoglobulin therapy in patients with severe recalcitrant atopic dermatitis: long-term changes of clinical severity and laboratory parameters. Allergy Asthma Immunol Res 2016;8:375–82.
    1. Cho SM, Kim ME, Kwon B, Nahm DH. Immunomodulatory effects induced by intramuscular administration of autologous total immunoglobulin G in patients with atopic dermatitis. Int Immunopharmacol 2017;52:01–6.
    1. Nahm DH, Ye YM, Shin YS, et al. . Efficacy, safety, and immunomodulatory effect of the intramuscular administration of autologous total immunoglobulin G for atopic dermatitis: A randomized clinical trial. Allergy Asthma Immunol Res 2020;12:949–63.
    1. British Committee for Standards in Haematology Transfusion Task Force, Boulton FE, James S V. Guidelines for policies on alternatives to allogeneic blood transfusion. 1. Predeposit autologous blood donation and transfusion. Transfus Med 2007;17:354–65.
    1. Andrew SM, Titus JA. Purification of immunoglobulin G. Curr Protoc Immunol 2001;Chapter 2: Unit 2.7.
    1. Shin JU, Kim SH, Noh JY, et al. . Allergen-specific immunotherapy induces regulatory T cells in an atopic dermatitis mouse model. Allergy 2018;73:1801–11.
    1. Bruyn GA, Hiemstra PS, Matze-van der Lans A, van Furth R. Pneumococcal anticapsular antibodies in patients with chronic cardiovascular and obstructive lung disease in the Netherlands. J Infect Dis 1990;162:1192–4.
    1. Rowe T, Abernathy RA, Hu-Primmer J, et al. . Detection of antibody to avian influenza A (H5N1) virus in human serum by using a combination of serologic assays. J Clin Microbiol 1999;37:937–43.
    1. Nahm DH, Kim HY, Park HS. Elevation of specific immunoglobulin A antibodies to both allergen and bacterial antigen in induced sputum from asthmatics. Eur Respir J 1998;12:540–5.
    1. Ishaq M, Ali R. Enzyme-linked immunosorbent assay for detection of antibodies to extractable nuclear antigens in systemic lupus erythematosus, with nylon as solid phase. Clin Chem 1983;29:823–7.
    1. Agrawal R, Wisniewski JA, Woodfolk JA. The role of regulatory T cells in atopic dermatitis. Curr Probl Dermatol 2011;41:112–24.
    1. Eyerich K, Novak N. Immunology of atopic eczema: overcoming the Th1/Th2 paradigm. Allergy 2013;68:974–82.
    1. Wang SC, Yang KD, Lin CY, et al. . Intravenous immunoglobulin therapy enhances suppressive regulatory T cells and decreases innate lymphoid cells in children with immune thrombocytopenia. Pediatr Blood Cancer 2020;67:e28075.
    1. Tsurikisawa N, Saito H, Oshikata C, Tsuburai T, Akiyama K. High-dose intravenous immunoglobulin treatment increases regulatory T cells in patients with eosinophilic granulomatosis with polyangiitis. J Rheumatol 2012;39:1019–25.
    1. Perez EE, Orange JS, Bonilla F, et al. . Update on the use of immunoglobulin in human disease: a review of evidence. J Allergy Clin Immunol 2017;139:S1–46.
    1. Bretscher PA. On the mechanism determining the TH1/TH2 phenotype of an immune response, and its pertinence to strategies for the prevention, and treatment, of certain infectious diseases. Scand J Immunol 2014;79:361–76.
    1. Cook IF. Evidence based route of administration of vaccines. Hum Vaccin 2008;4:67–73.
    1. Mahadevia PJ. The pocketbook: pharmacoeconomic issues related to intravenous immunoglobulin therapy. Pharmacotherapy 2005;25:S94–100.

Source: PubMed

Szponzorok és közreműködők

Egészségi állapot

Kábítószer-beavatkozások

3
Iratkozz fel