Differences in Anti-Inflammatory Actions of Intravenous Immunoglobulin Between Mice and Men: More Than Meets the Eye

Overview

Journal Front Immunol

Specialty Allergy & Immunology

Date 2015 May 15

PMID 25972869

Citations 15

Authors

Angela S W Tjon

Rogier van Gent

Teunis B Geijtenbeek

Jaap Kwekkeboom

Affiliations

Soon will be listed here.

Abstract

Intravenous immunoglobulin (IVIg) is a therapeutic preparation of polyspecific human IgGs purified from plasma pooled from thousands of individuals. When administered at a high dose, IVIg inhibits inflammation and has proven efficacy in the treatment of various autoimmune and systemic inflammatory diseases. Importantly, IVIg therapy can ameliorate both auto-antibody-mediated and T-cell mediated immune pathologies. In the last few decades, extensive research in murine disease models has resulted in the elucidation of two novel anti-inflammatory mechanisms-of-action of IVIg: induction of FcγRIIB expression by sialylated Fc, and stimulation of regulatory T cells. Whereas controversial findings in mice studies have recently inspired intense scientific debate regarding the validity of the sialylated Fc-FcγRIIB model, the most fundamental question is whether these anti-inflammatory mechanisms of IVIg are operational in humans treated with IVIg. In this review, we examine the evidence for the involvement of these anti-inflammatory mechanisms in the therapeutic effects of IVIg in humans. We demonstrate that although several elements of both immune-modulatory pathways of IVIg are activated in humans, incorrect extrapolations from mice to men have been made on the molecular and cellular components involved in these cascades that warrant for critical re-evaluation of these anti-inflammatory mechanisms of IVIg in humans.

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References

Seite J, Cornec D, Renaudineau Y, Youinou P, Mageed R, Hillion S . IVIg modulates BCR signaling through CD22 and promotes apoptosis in mature human B lymphocytes. Blood. 2010; 116(10):1698-704. DOI: 10.1182/blood-2009-12-261461. View

Lux A, Nimmerjahn F . Of mice and men: the need for humanized mouse models to study human IgG activity in vivo. J Clin Immunol. 2012; 33 Suppl 1:S4-8. DOI: 10.1007/s10875-012-9782-0. View

Othy S, Hegde P, Topcu S, Sharma M, Maddur M, Lacroix-Desmazes S . Intravenous gammaglobulin inhibits encephalitogenic potential of pathogenic T cells and interferes with their trafficking to the central nervous system, implicating sphingosine-1 phosphate receptor 1-mammalian target of rapamycin axis. J Immunol. 2013; 190(9):4535-41. DOI: 10.4049/jimmunol.1201965. View

Samuelsson A, Towers T, Ravetch J . Anti-inflammatory activity of IVIG mediated through the inhibitory Fc receptor. Science. 2001; 291(5503):484-6. DOI: 10.1126/science.291.5503.484. View

Pack M, Trumpfheller C, Thomas D, Park C, Granelli-Piperno A, Munz C . DEC-205/CD205+ dendritic cells are abundant in the white pulp of the human spleen, including the border region between the red and white pulp. Immunology. 2007; 123(3):438-46. PMC: 2433334. DOI: 10.1111/j.1365-2567.2007.02710.x. View

Kaneko Y, Nimmerjahn F, Ravetch J . Anti-inflammatory activity of immunoglobulin G resulting from Fc sialylation. Science. 2006; 313(5787):670-3. DOI: 10.1126/science.1129594. View

Nimmerjahn F, Ravetch J . Divergent immunoglobulin g subclass activity through selective Fc receptor binding. Science. 2005; 310(5753):1510-2. DOI: 10.1126/science.1118948. View

Maddur M, Vani J, Hegde P, Lacroix-Desmazes S, Kaveri S, Bayry J . Inhibition of differentiation, amplification, and function of human TH17 cells by intravenous immunoglobulin. J Allergy Clin Immunol. 2011; 127(3):823-30.e1-7. DOI: 10.1016/j.jaci.2010.12.1102. View

Hirabayashi Y, Takahashi Y, Xu Y, Akane K, Villalobos I, Okuno Y . Lack of CD4⁺CD25⁺FOXP3⁺ regulatory T cells is associated with resistance to intravenous immunoglobulin therapy in patients with Kawasaki disease. Eur J Pediatr. 2013; 172(6):833-7. DOI: 10.1007/s00431-013-1937-3. View

10.

Schwab I, Biburger M, Kronke G, Schett G, Nimmerjahn F . IVIg-mediated amelioration of ITP in mice is dependent on sialic acid and SIGNR1. Eur J Immunol. 2012; 42(4):826-30. DOI: 10.1002/eji.201142260. View

11.

Sondermann P, Pincetic A, Maamary J, Lammens K, Ravetch J . General mechanism for modulating immunoglobulin effector function. Proc Natl Acad Sci U S A. 2013; 110(24):9868-72. PMC: 3683708. DOI: 10.1073/pnas.1307864110. View

12.

Ichiyama T, Ueno Y, Hasegawa M, Ishikawa Y, Matsubara T, Furukawa S . Intravenous immunoglobulin does not increase FcgammaRIIB expression on monocytes/macrophages during acute Kawasaki disease. Rheumatology (Oxford). 2004; 44(3):314-7. DOI: 10.1093/rheumatology/keh488. View

13.

Anthony R, Wermeling F, Karlsson M, Ravetch J . Identification of a receptor required for the anti-inflammatory activity of IVIG. Proc Natl Acad Sci U S A. 2008; 105(50):19571-8. PMC: 2604916. DOI: 10.1073/pnas.0810163105. View

14.

Suzukawa M, Iikura M, Koketsu R, Nagase H, Tamura C, Komiya A . An IL-1 cytokine member, IL-33, induces human basophil activation via its ST2 receptor. J Immunol. 2008; 181(9):5981-9. DOI: 10.4049/jimmunol.181.9.5981. View

15.

Brunner S, Schiechl G, Falk W, Schlitt H, Geissler E, Fichtner-Feigl S . Interleukin-33 prolongs allograft survival during chronic cardiac rejection. Transpl Int. 2011; 24(10):1027-39. DOI: 10.1111/j.1432-2277.2011.01306.x. View

16.

Ramakrishna C, Newo A, Shen Y, Cantin E . Passively administered pooled human immunoglobulins exert IL-10 dependent anti-inflammatory effects that protect against fatal HSV encephalitis. PLoS Pathog. 2011; 7(6):e1002071. PMC: 3107211. DOI: 10.1371/journal.ppat.1002071. View

17.

Bashirova A, Geijtenbeek T, van Duijnhoven G, van Vliet S, Eilering J, Martin M . A dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin (DC-SIGN)-related protein is highly expressed on human liver sinusoidal endothelial cells and promotes HIV-1 infection. J Exp Med. 2001; 193(6):671-8. PMC: 2193415. DOI: 10.1084/jem.193.6.671. View

18.

Steiniger B, Barth P, Herbst B, Hartnell A, Crocker P . The species-specific structure of microanatomical compartments in the human spleen: strongly sialoadhesin-positive macrophages occur in the perifollicular zone, but not in the marginal zone. Immunology. 1998; 92(2):307-16. PMC: 1364073. DOI: 10.1046/j.1365-2567.1997.00328.x. View

19.

Debre M, Bonnet M, Fridman W, Carosella E, Philippe N, Reinert P . Infusion of Fc gamma fragments for treatment of children with acute immune thrombocytopenic purpura. Lancet. 1993; 342(8877):945-9. DOI: 10.1016/0140-6736(93)92000-j. View

20.

Schwab I, Nimmerjahn F . Intravenous immunoglobulin therapy: how does IgG modulate the immune system?. Nat Rev Immunol. 2013; 13(3):176-89. DOI: 10.1038/nri3401. View