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Comparison of different IVIg preparations on IL-17 production by human Th17 cells
Autoimmunity Reviews 10 (2011) 809–810
Contents lists available at ScienceDirect
Autoimmunity Reviews j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / a u t r ev
Comparison of different IVIg preparations on IL-17 production by human Th17 cells Mohan S. Maddur a,b,c, Srini V. Kaveri a,b,c,d,⁎, Jagadeesh Bayry a,b,c,d,⁎ a
Unité 872, Institut National de la Santé et de la Recherche Médicale Paris, F-75006, France Centre de Recherche des Cordeliers, Equipe 16, Immunopathology and Therapeutic Immunointervention, Université Pierre et Marie Curie - Paris 6, UMR S 872, 15 rue de l'Ecole de Médicine, Paris, F-75006, France c Université Paris Descartes, UMR S 872, Paris, F-75006, France d International Associated Laboratory IMPACT, Institut National de la Santé et de la Recherche Médicale -France and Indian Council of Medical Research - India, National Institute of Immunohaemotology, Mumbai, India b
a r t i c l e
i n f o
Available online 2 March 2011
a b s t r a c t Variations in intravenous immunoglobulin (IVIg) products are a common feature. In this report, we compared the effect of different IVIg products on IL-17 production by human Th17 cells. We found that irrespective of products, IgGs of all IVIg preparations were equally effective in inhibiting the production of IL-17A from Th17 cells. © 2011 Elsevier B.V. All rights reserved.
Intravenous immunoglobulin (IVIg) is a therapeutic preparation of pooled normal polyspecific IgG obtained from plasma pools of thousands of healthy blood donors. In addition to patients with primary immunodeficiencies, IVIg is used as a therapeutic agent in large number of autoimmune, allergic and inflammatory diseases [1-3]. Several mutually nonexclusive mechanisms have been described for the therapeutic efficacy of IVIg [1,2,4-6]. Unlike recombinant proteins, variations in IVIg products are a common feature. A recent article by Ahmed R et al., elegantly outlines the differences between commercially available IVIg products with respect to various parameters including stabilizing agents and formulation [7]. The variations in the source of plasma and IgG purification methods have been shown to influence the immunoglobulin content to infectious agents and the outcome of infection rate in immunodeficiency patients [8-10]. However, much data is not available on comparison of immunoregulatory properties of IVIg in the context of autoimmune and inflammatory conditions. Since, IgG molecules are the principal components of IVIg that mediate therapeutic effect, we compared the effect of IgG molecules of different IVIg products on IL-17A production by human Th17 cells. Th17 cells, a recently identified subset of Th cells that produce IL-17, mediate the clearance of extracellular pathogens such as Klebsiella and Candida. In addition, several reports also demonstrate that Th17 cells and IL-17 play a crucial role in the pathogenesis of various autoimmune, allergy and inflammatory conditions [11-17]. Since IVIg is beneficial in diseases such as Kawasaki disease, systemic lupus erythematosus, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, derma-
tomyositis and pemphigus, where Th17 cells are also implicated in the pathogenesis [1,18,19], we aimed at comparing the effect of various IVIg preparations on the production of IL-17A by Th17 cells. CD4+ Th cells were purified from peripheral blood mononuclear cells of healthy blood donors. For differentiation of Th17 cells, CD45RA+CD25− naïve Th cells were stimulated in X-VIVO serum-free medium with antiCD3 and anti-CD28 monoclonal antibodies and cytokines TGF-β (5 ng/ ml) and IL-21 (25 ng/ml) for 6 days. For amplification of Th17 cells, CD45RO+ memory Th cells were stimulated in X-VIVO serum-free medium with anti-CD3 and anti-CD28 monoclonal antibodies and cytokines IL-1β (12.5 ng/ml) and IL-6 (25 ng/ml) for 6 days [20]. Various IVIg preparations (Sandoglobulin, Gamunex, Privigen, Octagam, and Tegeline) were dialyzed in large volumes of PBS and RPMI-1640 medium and were added at a concentration of 25 mg/ml/0.25 million cells after 12 h initiation of culture as described previously [20]. Sandoglobulin and Tegeline are freeze-dried IVIg products while others are liquid preparations. The stabilizing agents are sucrose in Sandoglobulin, maltose in Octagam, L-proline in Privigen, glycine in Gamunex and saccharose in Tegeline. As shown in Fig. 1A and B, we found that irrespective of products, IgGs of all IVIg preparations were equally effective in inhibiting the production of IL-17A either from differentiating or expanding Th17 cells. The effect of IVIg was more prominent on inhibition of IL-17 from differentiating Th17 cells. Together, our data indicate that under ex-vivo experimental conditions, the IVIg products are similar in their mechanisms. However, data from patients are warranted to corroborate these experimental results that will help to formulate the guidelines for the use of specific IVIg preparations in various autoimmune diseases.
⁎ Corresponding authors at: INSERM U 872, Equipe 16-Centre de Recherche des Cordeliers, 15 rue de l'Ecole de Médicine, Paris, F-75006, France. Tel.: +33 1 55 42 82 66; fax: +33 1 55 42 82 62. E-mail addresses: [email protected] (S.V. Kaveri), [email protected] (J. Bayry).
Acknowledgements
1568-9972/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.autrev.2011.02.007
Supported by grants from the Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche
810
M.S. Maddur et al. / Autoimmunity Reviews 10 (2011) 809–810
References
Fig. 1. Comparison of inhibitory effect of various IVIg preparations on human Th17 cell differentiation and amplification as analyzed by IL-17A production. CD4+ Th cells were stimulated with anti-CD3 and anti-CD28 alone in X-VIVO serum-free medium (Medium) or in the presence of cytokines. (A) Naïve CD4+ Th cells were stimulated in the presence of TGFβ and IL-21 for differentiation of Th17 cells. (B) Memory Th cells were stimulated in the presence of IL-1β and IL-6 for amplification of Th17 cells. Various IVIg preparations (Sandoglobulin, Gamunex, Privigen, Octagam and Tegeline) were added following 12 h of initiation of culture and supernatant was collected after 6 days to analyze the amount IL-17A secretion by ELISA (DuoSet ELISA kit, R&D Systems, France). Data from up to five donors are presented (mean ± SEM). *Statistical significance as determined by Student-t-test, where P b 0.05.
Scientifique (CNRS), Université Pierre et Marie Curie, Université Paris Descartes and European Community's Seventh Framework Programme [FP7-2007-2013] under Grant Agreement No. HEALTH-F2-2010260338-ALLFUN.
[1] Tha-In T, Bayry J, Metselaar HJ, Kaveri SV, Kwekkeboom J. Modulation of the cellular immune system by intravenous immunoglobulin. Trends Immunol 2008;29:608–15. [2] Seite JF, Shoenfeld Y, Youinou P, Hillion S. What is the contents of the magic draft IVIg? Autoimmun Rev 2008;7:435–9. [3] Danieli MG, Calcabrini L, Calabrese V, Marchetti A, Logullo F, Gabrielli A. Intravenous immunoglobulin as add on treatment with mycophenolate mofetil in severe myositis. Autoimmun Rev 2009;9:124–7. [4] Nimmerjahn F, Ravetch JV. Anti-inflammatory actions of intravenous immunoglobulin. Annu Rev Immunol 2008;26:513–33. [5] Kaveri SV, Lacroix-Desmazes S, Bayry J. The antiinflammatory IgG. N Engl J Med 2008;17(359):307–9. [6] Schwartz-Albiez R, Monteiro RC, Rodriguez M, Binder CJ, Shoenfeld Y. Natural antibodies, intravenous immunoglobulin and their role in autoimmunity, cancer and inflammation. Clin Exp Immunol 2009;158(Suppl 1):43–50. [7] Gurcan HM, Keskin DB, Ahmed AR. Information for healthcare providers on general features of IGIV with emphasis on differences between commercially available products. Autoimmun Rev 2010;9:553–9. [8] Krause I, Wu R, Sherer Y, Patanik M, Peter JB, Shoenfeld Y. In vitro antiviral and antibacterial activity of commercial intravenous immunoglobulin preparations—a potential role for adjuvant intravenous immunoglobulin therapy in infectious diseases. Transfus Med 2002;12:133–9. [9] Roifman CM, Schroeder H, Berger M, Sorensen R, Ballow M, Buckley RH, et al. Comparison of the efficacy of IGIV-C, 10% (caprylate/chromatography) and IGIVSD, 10% as replacement therapy in primary immune deficiency. A randomized double-blind trial. Int Immunopharmacol 2003;3:1325–33. [10] Gelfand EW. Differences between IGIV products: impact on clinical outcome. Int Immunopharmacol 2006 Apr;6:592–9. [11] Louten J, Boniface K, de Waal Malefyt R. Development and function of TH17 cells in health and disease. J Allergy Clin Immunol 2009;123:1004–11. [12] Annunziato F, Cosmi L, Liotta F, Maggi E, Romagnani S. Type 17 T helper cells-origins, features and possible roles in rheumatic disease. Nat Rev Rheumatol 2009;5:325–31. [13] Yang K, Vega JL, Hadzipasic M, Schatzmann Peron JP, Zhu B, Carrier Y, et al. Deficiency of thrombospondin-1 reduces Th17 differentiation and attenuates experimental autoimmune encephalomyelitis. J Autoimmun 2009;32:94–103. [14] Mucida D, Salek-Ardakani S. Regulation of TH17 cells in the mucosal surfaces. J Allergy Clin Immunol 2009;123:997–1003. [15] Lan RY, Salunga TL, Tsuneyama K, Lian ZX, Yang GX, Hsu W, et al. Hepatic IL-17 responses in human and murine primary biliary cirrhosis. J Autoimmun 2009;32: 43–51. [16] Selmi C. Autoimmunity in 2009. Autoimmun Rev 2010;9:795–800. [17] Baraut J, Michel L, Verrecchia F, Farge D. Relationship between cytokine profiles and clinical outcomes in patients with systemic sclerosis. Autoimmun Rev 2010;10:65–73. [18] Galeotti C, Bayry J, Kone-Paut I, Kaveri SV. Kawasaki disease: aetiopathogenesis and therapeutic utility of intravenous immunoglobulin. Autoimmun Rev 2010;9:441–8. [19] Ballow M. The IgG molecule as a biological immune response modifier: mechanisms of action of intravenous immune serum globulin in autoimmune and inflammatory disorders. J Allergy Clin Immunol 2011;127:315–23. [20] Maddur MS, Vani J, Hegde P, Lacroix-Desmazes S, Kaveri SV, Bayry J. Inhibition of differentiation, amplification and function of human TH17 cells by intravenous immunoglobulin. J Allergy Clin Immunol 2011;127:823–30.e7.
Contents lists available at ScienceDirect
Autoimmunity Reviews j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / a u t r ev
Comparison of different IVIg preparations on IL-17 production by human Th17 cells Mohan S. Maddur a,b,c, Srini V. Kaveri a,b,c,d,⁎, Jagadeesh Bayry a,b,c,d,⁎ a
Unité 872, Institut National de la Santé et de la Recherche Médicale Paris, F-75006, France Centre de Recherche des Cordeliers, Equipe 16, Immunopathology and Therapeutic Immunointervention, Université Pierre et Marie Curie - Paris 6, UMR S 872, 15 rue de l'Ecole de Médicine, Paris, F-75006, France c Université Paris Descartes, UMR S 872, Paris, F-75006, France d International Associated Laboratory IMPACT, Institut National de la Santé et de la Recherche Médicale -France and Indian Council of Medical Research - India, National Institute of Immunohaemotology, Mumbai, India b
a r t i c l e
i n f o
Available online 2 March 2011
a b s t r a c t Variations in intravenous immunoglobulin (IVIg) products are a common feature. In this report, we compared the effect of different IVIg products on IL-17 production by human Th17 cells. We found that irrespective of products, IgGs of all IVIg preparations were equally effective in inhibiting the production of IL-17A from Th17 cells. © 2011 Elsevier B.V. All rights reserved.
Intravenous immunoglobulin (IVIg) is a therapeutic preparation of pooled normal polyspecific IgG obtained from plasma pools of thousands of healthy blood donors. In addition to patients with primary immunodeficiencies, IVIg is used as a therapeutic agent in large number of autoimmune, allergic and inflammatory diseases [1-3]. Several mutually nonexclusive mechanisms have been described for the therapeutic efficacy of IVIg [1,2,4-6]. Unlike recombinant proteins, variations in IVIg products are a common feature. A recent article by Ahmed R et al., elegantly outlines the differences between commercially available IVIg products with respect to various parameters including stabilizing agents and formulation [7]. The variations in the source of plasma and IgG purification methods have been shown to influence the immunoglobulin content to infectious agents and the outcome of infection rate in immunodeficiency patients [8-10]. However, much data is not available on comparison of immunoregulatory properties of IVIg in the context of autoimmune and inflammatory conditions. Since, IgG molecules are the principal components of IVIg that mediate therapeutic effect, we compared the effect of IgG molecules of different IVIg products on IL-17A production by human Th17 cells. Th17 cells, a recently identified subset of Th cells that produce IL-17, mediate the clearance of extracellular pathogens such as Klebsiella and Candida. In addition, several reports also demonstrate that Th17 cells and IL-17 play a crucial role in the pathogenesis of various autoimmune, allergy and inflammatory conditions [11-17]. Since IVIg is beneficial in diseases such as Kawasaki disease, systemic lupus erythematosus, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, derma-
tomyositis and pemphigus, where Th17 cells are also implicated in the pathogenesis [1,18,19], we aimed at comparing the effect of various IVIg preparations on the production of IL-17A by Th17 cells. CD4+ Th cells were purified from peripheral blood mononuclear cells of healthy blood donors. For differentiation of Th17 cells, CD45RA+CD25− naïve Th cells were stimulated in X-VIVO serum-free medium with antiCD3 and anti-CD28 monoclonal antibodies and cytokines TGF-β (5 ng/ ml) and IL-21 (25 ng/ml) for 6 days. For amplification of Th17 cells, CD45RO+ memory Th cells were stimulated in X-VIVO serum-free medium with anti-CD3 and anti-CD28 monoclonal antibodies and cytokines IL-1β (12.5 ng/ml) and IL-6 (25 ng/ml) for 6 days [20]. Various IVIg preparations (Sandoglobulin, Gamunex, Privigen, Octagam, and Tegeline) were dialyzed in large volumes of PBS and RPMI-1640 medium and were added at a concentration of 25 mg/ml/0.25 million cells after 12 h initiation of culture as described previously [20]. Sandoglobulin and Tegeline are freeze-dried IVIg products while others are liquid preparations. The stabilizing agents are sucrose in Sandoglobulin, maltose in Octagam, L-proline in Privigen, glycine in Gamunex and saccharose in Tegeline. As shown in Fig. 1A and B, we found that irrespective of products, IgGs of all IVIg preparations were equally effective in inhibiting the production of IL-17A either from differentiating or expanding Th17 cells. The effect of IVIg was more prominent on inhibition of IL-17 from differentiating Th17 cells. Together, our data indicate that under ex-vivo experimental conditions, the IVIg products are similar in their mechanisms. However, data from patients are warranted to corroborate these experimental results that will help to formulate the guidelines for the use of specific IVIg preparations in various autoimmune diseases.
⁎ Corresponding authors at: INSERM U 872, Equipe 16-Centre de Recherche des Cordeliers, 15 rue de l'Ecole de Médicine, Paris, F-75006, France. Tel.: +33 1 55 42 82 66; fax: +33 1 55 42 82 62. E-mail addresses: [email protected] (S.V. Kaveri), [email protected] (J. Bayry).
Acknowledgements
1568-9972/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.autrev.2011.02.007
Supported by grants from the Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche
810
M.S. Maddur et al. / Autoimmunity Reviews 10 (2011) 809–810
References
Fig. 1. Comparison of inhibitory effect of various IVIg preparations on human Th17 cell differentiation and amplification as analyzed by IL-17A production. CD4+ Th cells were stimulated with anti-CD3 and anti-CD28 alone in X-VIVO serum-free medium (Medium) or in the presence of cytokines. (A) Naïve CD4+ Th cells were stimulated in the presence of TGFβ and IL-21 for differentiation of Th17 cells. (B) Memory Th cells were stimulated in the presence of IL-1β and IL-6 for amplification of Th17 cells. Various IVIg preparations (Sandoglobulin, Gamunex, Privigen, Octagam and Tegeline) were added following 12 h of initiation of culture and supernatant was collected after 6 days to analyze the amount IL-17A secretion by ELISA (DuoSet ELISA kit, R&D Systems, France). Data from up to five donors are presented (mean ± SEM). *Statistical significance as determined by Student-t-test, where P b 0.05.
Scientifique (CNRS), Université Pierre et Marie Curie, Université Paris Descartes and European Community's Seventh Framework Programme [FP7-2007-2013] under Grant Agreement No. HEALTH-F2-2010260338-ALLFUN.
[1] Tha-In T, Bayry J, Metselaar HJ, Kaveri SV, Kwekkeboom J. Modulation of the cellular immune system by intravenous immunoglobulin. Trends Immunol 2008;29:608–15. [2] Seite JF, Shoenfeld Y, Youinou P, Hillion S. What is the contents of the magic draft IVIg? Autoimmun Rev 2008;7:435–9. [3] Danieli MG, Calcabrini L, Calabrese V, Marchetti A, Logullo F, Gabrielli A. Intravenous immunoglobulin as add on treatment with mycophenolate mofetil in severe myositis. Autoimmun Rev 2009;9:124–7. [4] Nimmerjahn F, Ravetch JV. Anti-inflammatory actions of intravenous immunoglobulin. Annu Rev Immunol 2008;26:513–33. [5] Kaveri SV, Lacroix-Desmazes S, Bayry J. The antiinflammatory IgG. N Engl J Med 2008;17(359):307–9. [6] Schwartz-Albiez R, Monteiro RC, Rodriguez M, Binder CJ, Shoenfeld Y. Natural antibodies, intravenous immunoglobulin and their role in autoimmunity, cancer and inflammation. Clin Exp Immunol 2009;158(Suppl 1):43–50. [7] Gurcan HM, Keskin DB, Ahmed AR. Information for healthcare providers on general features of IGIV with emphasis on differences between commercially available products. Autoimmun Rev 2010;9:553–9. [8] Krause I, Wu R, Sherer Y, Patanik M, Peter JB, Shoenfeld Y. In vitro antiviral and antibacterial activity of commercial intravenous immunoglobulin preparations—a potential role for adjuvant intravenous immunoglobulin therapy in infectious diseases. Transfus Med 2002;12:133–9. [9] Roifman CM, Schroeder H, Berger M, Sorensen R, Ballow M, Buckley RH, et al. Comparison of the efficacy of IGIV-C, 10% (caprylate/chromatography) and IGIVSD, 10% as replacement therapy in primary immune deficiency. A randomized double-blind trial. Int Immunopharmacol 2003;3:1325–33. [10] Gelfand EW. Differences between IGIV products: impact on clinical outcome. Int Immunopharmacol 2006 Apr;6:592–9. [11] Louten J, Boniface K, de Waal Malefyt R. Development and function of TH17 cells in health and disease. J Allergy Clin Immunol 2009;123:1004–11. [12] Annunziato F, Cosmi L, Liotta F, Maggi E, Romagnani S. Type 17 T helper cells-origins, features and possible roles in rheumatic disease. Nat Rev Rheumatol 2009;5:325–31. [13] Yang K, Vega JL, Hadzipasic M, Schatzmann Peron JP, Zhu B, Carrier Y, et al. Deficiency of thrombospondin-1 reduces Th17 differentiation and attenuates experimental autoimmune encephalomyelitis. J Autoimmun 2009;32:94–103. [14] Mucida D, Salek-Ardakani S. Regulation of TH17 cells in the mucosal surfaces. J Allergy Clin Immunol 2009;123:997–1003. [15] Lan RY, Salunga TL, Tsuneyama K, Lian ZX, Yang GX, Hsu W, et al. Hepatic IL-17 responses in human and murine primary biliary cirrhosis. J Autoimmun 2009;32: 43–51. [16] Selmi C. Autoimmunity in 2009. Autoimmun Rev 2010;9:795–800. [17] Baraut J, Michel L, Verrecchia F, Farge D. Relationship between cytokine profiles and clinical outcomes in patients with systemic sclerosis. Autoimmun Rev 2010;10:65–73. [18] Galeotti C, Bayry J, Kone-Paut I, Kaveri SV. Kawasaki disease: aetiopathogenesis and therapeutic utility of intravenous immunoglobulin. Autoimmun Rev 2010;9:441–8. [19] Ballow M. The IgG molecule as a biological immune response modifier: mechanisms of action of intravenous immune serum globulin in autoimmune and inflammatory disorders. J Allergy Clin Immunol 2011;127:315–23. [20] Maddur MS, Vani J, Hegde P, Lacroix-Desmazes S, Kaveri SV, Bayry J. Inhibition of differentiation, amplification and function of human TH17 cells by intravenous immunoglobulin. J Allergy Clin Immunol 2011;127:823–30.e7.