Enhanced Pro-apoptotic Effects of Fe(II)-Modified IVIG on Human Neutrophils

Overview

Journal Front Immunol

Specialty Allergy & Immunology

Date 2020 Jun 9

PMID 32508840

Citations 4

Authors

Stefanie Graeter

Christoph Schneider

Danielle Verschoor

Sandro von Daniken

Frank Seibold

Nikhil Yawalkar

Peter Villiger

Jordan D Dimitrov

David F Smith

Richard D Cummings

Hans-Uwe Simon

Tchavdar Vassilev

Stephan von Gunten

Affiliations

Soon will be listed here.

Abstract

Mild modification of intravenous immunoglobulin (IVIG) has been reported to result in enhanced polyspecificity and leveraged therapeutic effects in animal models of inflammation. Here, we observed that IVIG modification by ferrous ions, heme or low pH exposure, shifted the repertoires of specificities in different directions. Ferrous ions exposed Fe(II)-IVIG, but not heme or low pH exposed IVIG, showed increased pro-apoptotic effects on neutrophil granulocytes that relied on a FAS-dependent mechanism. These effects were also observed in human neutrophils primed by inflammatory mediators or rheumatoid arthritis joint fluid , or patient neutrophils from acute Crohn's disease. These observations indicate that IVIG-mediated effects on cells can be enhanced by IVIG modification, yet specific modification conditions may be required to target specific molecular pathways and eventually to enhance the therapeutic potential.

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References

Joao C, Negi V, Kazatchkine M, Bayry J, Kaveri S . Passive Serum Therapy to Immunomodulation by IVIG: A Fascinating Journey of Antibodies. J Immunol. 2018; 200(6):1957-1963. DOI: 10.4049/jimmunol.1701271. View

Schneider C, Smith D, Cummings R, Boligan K, Hamilton R, Bochner B . The human IgG anti-carbohydrate repertoire exhibits a universal architecture and contains specificity for microbial attachment sites. Sci Transl Med. 2015; 7(269):269ra1. PMC: 4864610. DOI: 10.1126/scitranslmed.3010524. View

Schaub A, von Gunten S, Vogel M, Wymann S, Ruegsegger M, Stadler B . Dimeric IVIG contains natural anti-Siglec-9 autoantibodies and their anti-idiotypes. Allergy. 2011; 66(8):1030-7. DOI: 10.1111/j.1398-9995.2011.02579.x. View

Blixt O, Head S, Mondala T, Scanlan C, Huflejt M, Alvarez R . Printed covalent glycan array for ligand profiling of diverse glycan binding proteins. Proc Natl Acad Sci U S A. 2004; 101(49):17033-8. PMC: 534418. DOI: 10.1073/pnas.0407902101. View

Pearce O, Laubli H, Verhagen A, Secrest P, Zhang J, Varki N . Inverse hormesis of cancer growth mediated by narrow ranges of tumor-directed antibodies. Proc Natl Acad Sci U S A. 2014; 111(16):5998-6003. PMC: 4000847. DOI: 10.1073/pnas.1209067111. View

von Gunten S, Yousefi S, Seitz M, Jakob S, Schaffner T, Seger R . Siglec-9 transduces apoptotic and nonapoptotic death signals into neutrophils depending on the proinflammatory cytokine environment. Blood. 2005; 106(4):1423-31. DOI: 10.1182/blood-2004-10-4112. View

Schneider C, Wicki S, Graeter S, Timcheva T, Keller C, Quast I . IVIG regulates the survival of human but not mouse neutrophils. Sci Rep. 2017; 7(1):1296. PMC: 5430961. DOI: 10.1038/s41598-017-01404-0. View

Djoumerska-Alexieva I, Dimitrov J, Nacheva J, Kaveri S, Vassilev T . Protein destabilizing agents induce polyreactivity and enhanced immunomodulatory activity in IVIg preparations. Autoimmunity. 2009; 42(4):365-7. DOI: 10.1080/08916930902832181. View

Newburger J, Takahashi M, Burns J, Beiser A, Chung K, Duffy C . The treatment of Kawasaki syndrome with intravenous gamma globulin. N Engl J Med. 1986; 315(6):341-7. DOI: 10.1056/NEJM198608073150601. View

10.

Stowell S, Arthur C, McBride R, Berger O, Razi N, Heimburg-Molinaro J . Microbial glycan microarrays define key features of host-microbial interactions. Nat Chem Biol. 2014; 10(6):470-6. PMC: 4158828. DOI: 10.1038/nchembio.1525. View

11.

Djoumerska-Alexieva I, Roumenina L, Pashov A, Dimitrov J, Hadzhieva M, Lindig S . Intravenous Immunoglobulin with Enhanced Polyspecificity Improves Survival in Experimental Sepsis and Aseptic Systemic Inflammatory Response Syndromes. Mol Med. 2015; 21(1):1002-1010. PMC: 4982479. DOI: 10.2119/molmed.2014.00224. View

12.

Djoumerska-Alexieva I, Roumenina L, Stefanova T, Vassilev T, Dimitrov J . Heme-Exposed Pooled Therapeutic IgG Improves Endotoxemia Survival. Inflammation. 2016; 40(1):117-122. DOI: 10.1007/s10753-016-0460-x. View

13.

Pavlovic S, Zdravkovic N, Dimitrov J, Djukic A, Arsenijevic N, Vassilev T . Intravenous immunoglobulins exposed to heme (heme IVIG) are more efficient than IVIG in attenuating autoimmune diabetes. Clin Immunol. 2010; 138(2):162-71. DOI: 10.1016/j.clim.2010.10.010. View

14.

Casulli S, Topcu S, Fattoum L, von Gunten S, Simon H, Teillaud J . A differential concentration-dependent effect of IVIg on neutrophil functions: relevance for anti-microbial and anti-inflammatory mechanisms. PLoS One. 2011; 6(10):e26469. PMC: 3204983. DOI: 10.1371/journal.pone.0026469. View

15.

Altznauer F, von Gunten S, Spath P, Simon H . Concurrent presence of agonistic and antagonistic anti-CD95 autoantibodies in intravenous Ig preparations. J Allergy Clin Immunol. 2003; 112(6):1185-90. DOI: 10.1016/j.jaci.2003.09.045. View

16.

Gelfand E . Intravenous immune globulin in autoimmune and inflammatory diseases. N Engl J Med. 2012; 367(21):2015-25. DOI: 10.1056/NEJMra1009433. View

17.

Strom T, Tilney N, Carpenter C, BUSCH G . Identity and cytotoxic capacity of cells infiltrating renal allografts. N Engl J Med. 1975; 292(24):1257-63. DOI: 10.1056/NEJM197506122922402. View

18.

Graeter S, Simon H, von Gunten S . Granulocyte death mediated by specific antibodies in intravenous immunoglobulin (IVIG). Pharmacol Res. 2019; 154:104168. DOI: 10.1016/j.phrs.2019.02.007. View

19.

von Gunten S, Smith D, Cummings R, Riedel S, Miescher S, Schaub A . Intravenous immunoglobulin contains a broad repertoire of anticarbohydrate antibodies that is not restricted to the IgG2 subclass. J Allergy Clin Immunol. 2009; 123(6):1268-76.e15. PMC: 2777748. DOI: 10.1016/j.jaci.2009.03.013. View

20.

Djoumerska-Alexieva I, Dimitrov J, Voynova E, Lacroix-Desmazes S, Kaveri S, Vassilev T . Exposure of IgG to an acidic environment results in molecular modifications and in enhanced protective activity in sepsis. FEBS J. 2010; 277(14):3039-50. DOI: 10.1111/j.1742-4658.2010.07714.x. View