Skip to main content

Basic principles of intravenous immunoglobulin (IVIg) treatment

An Erratum to this article was published on 01 February 2008

Abstract

The original rationale for the therapeutic application of immunoglobulins was prevention and treatment of infectious diseases. With the description of agammaglobulinemia, substitution therapy became the primary indication for the use of immunoglobulins. Limitations and side effects of the intramuscular administration of immunoglobulins led to the development of preparations for intravenous use (IVIg). In the early 1980s an immunomodulatory effect of IVIg was described. Since then, the efficacy of IVIg has been established in controlled trials for diseases like idiopathic thrombocytopenic purpura, Kawasaki disease, Guillain-Barré syndrome, dermatomyositis, and many others. There is a large body of evidence that IVIg can modulate an immune reaction at the level of T cells, B cells, and macrophages, interferes with antibody production and degradation, modulates the complement cascade, and has effects on the cytokine network. However, the precise mechanism of action is not yet clear.

This is a preview of subscription content, access via your institution.

References

  1. 1.

    Andersson J, Skansén-Saphir U, Sparrelid E, Andersson U (1996) Intravenous immune globulin affects cytokine production in T lymphocytes and monocytes/macrophages. Clin Exp Immunol 104(Suppl 1):10–20

    PubMed  CAS  Google Scholar 

  2. 2.

    Aukrust P, Froland SS, Liabakk N-B, Müller F, Nordoy I, Haug C, Espevik T (1994) Release of cytokines, soluble cytokine receptors, and interleukin-1 receptor antagonist after intravenous immunoglobulin administration in vivo. Blood 84:2136–2143

    PubMed  CAS  Google Scholar 

  3. 3.

    Barandun S, Kistler P, Jeunet F, Isliker H (1962) Intravenous administration of human g-globulin. Vox Sang 7:157–174

    PubMed  CAS  Google Scholar 

  4. 4.

    Basta M, Dalakas MC (1994) High-dose intravenous immunoglobulin exerts its beneficial effect in patients with dermatomyositis by blocking endomysial deposition of activated complement fragments. J Clin Invest 94:1729–1735

    PubMed  CAS  Google Scholar 

  5. 5.

    Basta M, van Goor F, Luccioli S, Billings EM, Vortmeyer AO, Baranyi L, Szebeni J, Alving CR, Carroll MC, Berkower I, Stojilkovic SS, Metcalfe DD (2003) F(ab)’2-mediated neutralization of C3a and C3b anaphylatoxins: a novel effector function of immunoglobulins. Nature Med 9:431–438

    PubMed  CAS  Article  Google Scholar 

  6. 6.

    Bayry J, Lacroix-Desmazes S, Carbonneil C, Misra N, Donkova V, Pashov A, Chevailler A, Mouthon L, Weill B, Bruneval P, Kazatchkine MD, Kaveri SV (2003) Inhibition of maturation and function of dendritic cells by intravenous immunoglobulin. Blood 101:758–765

    PubMed  CAS  Article  Google Scholar 

  7. 7.

    Behring E, Kitasato S (1890) Über das Zustandekommen der Diphtherie-Immunität und der Tetanus-Immunität bei Thieren. Dtsch Med Wochenschr 16:1113–1114

    Article  Google Scholar 

  8. 8.

    Berkman SA, Lee ML, Gale RP (1990) Clinical uses of intravenous immunoglobulins. Ann Intern Med 112:278–292

    PubMed  CAS  Google Scholar 

  9. 9.

    Bieber AJ, Warrington A, Pease LR, Rodriguez M (2001) Humoral autoimmunity as a mediator of CNS repair. Trends Neurosci 24(Suppl):S39–S44

    PubMed  CAS  Article  Google Scholar 

  10. 10.

    Bouhlal H, Hocini H, Quillent-Grégoire C, Donkova V, Rose S, Amara A, Longhi R, Haeffner-Cavaillon N, Beretta A, Kaveri SV, Kazatchkine MD (2001) Antibodies to C-C chemokine receptor 5 in normal human IgG block infection of macrophages and lymphocytes with primary R5-tropic strains of HIV-1. J Immunol 166:7606–7611

    PubMed  CAS  Google Scholar 

  11. 11.

    Bruton OC (1952) Agammaglobulinemia. Pediatrics 9:722–728

    PubMed  CAS  Google Scholar 

  12. 12.

    Ciric B, Van Keulen V, Paz Soldan M, Rodriguez M, Pease LR (2004) Antibody-mediated remyelination operates through mechanism independent of immunomodulation. J Neuroimmunol 146:153–161

    PubMed  CAS  Article  Google Scholar 

  13. 13.

    Devathasan G, Kueh YK, Chong PN (1984) High-dose intravenous gammaglobulin for myasthenia gravis. Lancet 2:809–810

    Google Scholar 

  14. 14.

    Dwyer JM (1992) Manipulating the immune system with immune globulins. N Engl J Med 326:107–116

    PubMed  CAS  Article  Google Scholar 

  15. 15.

    Fateh-Moghadam A, Besinger U, Geursen RG (1982) Ein klinisches Modell zur Regulation der humoralen Immunantwort: Infusionstherapie. Beitr Infusionsther Klin Ernähr 9:69–79

    CAS  Google Scholar 

  16. 16.

    Fateh-Moghadam A, Wick M, Besinger U, Geursen RG (1984) High-dose intravenous gammaglobulin for myasthenia gravis. Lancet 1:848–845

    PubMed  CAS  Article  Google Scholar 

  17. 17.

    Frank MM, Basta M, Fries LF (1992) The effect of intravenous immune globulin on complement-dependent immune damage of cells and tissues. Clin Immunol Immunopathol 62:S82–S86

    PubMed  CAS  Article  Google Scholar 

  18. 18.

    Gajdos P, Outin H, Elkharrat D, Brunel D, de Rohan-Chabot P, Raphael JC, Goulon M, Goulon-Goeau C, Morel E (1984) High-dose intravenous gammaglobulin for myasthenia gravis. Lancet 1:406–407

    PubMed  CAS  Article  Google Scholar 

  19. 19.

    Grosse-Wilde H, Blasczyk R, Westhoff U (1992) Soluble HLA class I and class II concentrations in commercial immunoglobulin preparations. Tissue Antigens 39:74–77

    PubMed  CAS  Article  Google Scholar 

  20. 20.

    Hansi W, Kratzsch G, Heimpel H (1980) Klinische Erfahrungen mit einem neuen intravenöse applizierbaren Immunglobulin-Präparat. Dtsch Med Wschr 105:1675–1680

    PubMed  CAS  Article  Google Scholar 

  21. 21.

    Heiken H, Schmidt RE (2003) Indications for the use of immunoglobulin therapy. Dtsch Med Wochenschr 128:1665–1669

    PubMed  CAS  Article  Google Scholar 

  22. 22.

    Hurez V, Kaveri SV, Mouhoub A, Dietrich G, Mani J-C, Klatzmann D, Kazatchkine MD (1994) Anti-CD4 activity of normal human immunoglobulin G for therapeutic use (Intravenous immunoglobulin, IVIg). Ther Immunol 1:269–277

    PubMed  CAS  Google Scholar 

  23. 23.

    Imbach P, Barandun S, d’Apuzzo V, Baumgartner C, Hirt A, Morell A, Rossi E, Schöni M, Vest M, Wagner HP (1981) High-dose intravenous gammaglobulin for idiopathic thrombocytopenic purpura in childhood. Lancet 1:1228–1231

    PubMed  CAS  Article  Google Scholar 

  24. 24.

    Ippoliti G, Cosi V, Piccolo G, Lombardi M, Mantegaz R (1984) High-dose intravenous gammaglobulin for myasthenia gravis. Lancet 2:809–809

    Article  Google Scholar 

  25. 25.

    Jungi TW, Brcic M, Kuhnert P, Spycher MO, Li F, Nydegger UE (1990) Effect of IgG for intravenous use on Fc receptor-mediated phagocytosis by human monocytes. Clin Exp Immunol 82:163–169

    PubMed  CAS  Article  Google Scholar 

  26. 26.

    Kaveri S, Vassilev T, Hurez V, Lengagne R, Lefranc C, Cot S, Pouletty P, Glotz D, Kazatchkine MD (1996) Antibodies to a conserved region of HLA class I molecules, capable of modulating CD8 T cell-mediated function, are present in pooled normal immunoglobulin for therapeutic use. J Clin Invest 97:865–869

    PubMed  CAS  Google Scholar 

  27. 27.

    Kazatchkine MD, Kaveri SV (2001) Immunomodulation of autoimmune and inflammatory diseases with intravenous immune globulin. N Engl J Med 345:747–755

    PubMed  CAS  Article  Google Scholar 

  28. 28.

    Kleyweg RP, van der Meche FGA, Meulstee J (1988) Treatment of Guillain-Barré syndrome with high-dose gammaglobulin. Neurology 38:1639–1641

    PubMed  CAS  Google Scholar 

  29. 29.

    Knecht H, Baumberger M, Tobòn A, Steck A (2004) Sustained remission of CIDP associated with Evans syndrome. Neurology 63:730–732

    PubMed  Google Scholar 

  30. 30.

    Kondo N, Kasahara K,Kameyama T, Suzuki Y, Shimozawa N, Tomatsu S, Nakashima Y, Hori T, Yamagishi A, Ogawa T, Iwata H, Takahashi Y, Takenaka R, Watanabe K, Haga M, Orii T (1994) Intravenous immunoglobulins suppress immunoglobulin productions by suppressing Ca2+-dependent signal transduction through Fcg receptors in B lymphocytes. Scand J Immunol 40:37–42

    PubMed  CAS  Article  Google Scholar 

  31. 31.

    Kornhuber B (1971) Intravenöse g-Globulin-Therapie. Erfahrungen mit einer neuartigen Präparation. Mschr Kinderheilk 119:528–530

    Google Scholar 

  32. 32.

    Lapointe BM, Herx LM, Gill V, Metz LM, Kubes P (2004) IVIg therapy in brain inflammation: etiology-dependent differential effects on leucocyte recruitment. Brain 127:2649–2656

    PubMed  Article  Google Scholar 

  33. 33.

    Lenercept Multiple Sclerosis Study Group, University of British Columbia MS/MRI Analysis Group (1999) TNF neutralization in MS. Results of a randomized, placebo-controlled multicenter study. Neurology 53:457–465

    Google Scholar 

  34. 34.

    Luthardt T (1980) Intravenöse Immunglobulinsubstitution bei Antikörpermangelsyndrom. Dtsch Med Wochenschr 105:993–997

    PubMed  CAS  Google Scholar 

  35. 35.

    Lutz HU, Stammler P, Jelezarova E, Nater M, Späth PJ (1996) High doses of immunoglobulin G attenuate immune aggregate-mediated complement activation by enhancing physiologic cleavage of C3b in C3bn-IgG complexes. Blood 88:184–193

    PubMed  CAS  Google Scholar 

  36. 36.

    Marchalonis JJ, Kaymaz H, Dedeoglu F, Schluter SF, Yocum DE, Edmundson AB (1992) Human autoantibodies reactive with synthetic autoantigens from T-cell receptor b chain. Proc Natl Acad Sci 89:3325–3329

    PubMed  CAS  Article  Google Scholar 

  37. 37.

    Miller DH, Khan OA, Sheremata WA, Blumhardt LD, Rice GPA, Libonati MA, Willmer-Hulme AJ, Dalton CM, Miszkiel KA, O’Conner PW, for the International Natalizumab Multiple Sclerosis Trial Group (2003) A controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 348:15–23

    PubMed  CAS  Article  Google Scholar 

  38. 38.

    Mollnes TE, Hogasen K,Hoaas BF, Michaelsen TE, Garred P, Harboe M (1995) Inhibition of complement-mediated red cell lysis by immunoglobulins is dependent on the Ig isotype and its C1 binding properties. Scand J Immunol 41:449–456

    PubMed  CAS  Article  Google Scholar 

  39. 39.

    Morell A, Skvaril F (1980) Struktur und biologische Eigenschaften von Immunglobulinen und g-Globulin-Präparaten. Schweiz med Wschr 110:80–85

    PubMed  CAS  Google Scholar 

  40. 40.

    NIH consensus conference (1990) Intravenous immunoglobulin. Prevention and treatment of disease. JAMA 264:3189–3193

    Article  Google Scholar 

  41. 41.

    Nobile-Orazio E (2005) Treatment of dysimmune neuropathies. J Neurol 252:385–395

    PubMed  CAS  Article  Google Scholar 

  42. 42.

    Nolte MT, Pirofsky B, Gerritz GA, Golding B (1979) Intravenous immunoglobulin therapy for antibody deficiency. Clin Exp Immunol 36:237–243

    PubMed  CAS  Google Scholar 

  43. 43.

    Noseworthy JH, O’Brien PC, Weinshenker BG, Weis JA, Petterson TM, Erickson BJ, Windebank AJ, Whisnant JP, Stolp-Smith KA, Harper CM, Low PA, Romme LJ, Johnson M, An K-N, Rodriguez M (2000) IV immunoglobulin does not reverse established weakness in MSA double-blind, placebo-controlled trial. Neurology 55:1135–1143

    PubMed  CAS  Google Scholar 

  44. 44.

    Otten A, Vermeulen M, Bossuyt PMM (1995) Intravenous immunoglobulin treatment in neurological diseases. J Neurol Neurosurg Psychiatry 59:359–361

    Google Scholar 

  45. 45.

    Plasma Exchange/Sandoglobulin Guillain-Barré Syndrome Trial Group (1997) Randomized trial of plasma exchange, intravenous immunoglobulin, and combined treatments in Guillain-Barré syndrome. Lancet 349:225–230

    Article  Google Scholar 

  46. 46.

    Prasad NKA, Papoff G, Zeuner A, Bonnin E, Kazatchkine MD, Ruberti G, Kaveri SV (1998) Therapeutic preparations of normal polyspecific IgG (IVIg) induce apoptosis in human lymphocytes and monocytes: A novel mechanism of action of IVIg involving the Fas apoptotic pathway. J Immunol 161:3781–3790

    PubMed  CAS  Google Scholar 

  47. 47.

    Pul R, Nguyen D, Schmitz U, Marx P, Stangel M (2002) Comparison of intravenous immunoglobulin preparations on microglial function in vitro: More potent immunomodulatory capacity of an IgM/IgA-enriched preparation. Clin Neuropharmacol 25:254–259

    PubMed  CAS  Article  Google Scholar 

  48. 48.

    Ratko TA, Burnett DA, Foulke GE, Matuszewski KA, Sacher RA, University consortium expert panel (1995) Recommendations for off-label use of intravenously administered immunoglobulin preparations. JAMA 273:1865–1870

    PubMed  CAS  Article  Google Scholar 

  49. 49.

    Rossi F, Kazatchkine MD (1989) Antiidiotypes against autoantibodies in pooled normal human polyspecific Ig. J Immunol 143:4104–4109

    PubMed  CAS  Google Scholar 

  50. 50.

    Rothfelder U, Neu I, Pelka R (1982) Therapie der Multiplen Sklerose mit Immunglobulin G Münch med Wschr 124:74–78

    CAS  Google Scholar 

  51. 51.

    Samuelsson A, Towers TL, Ravetch JV (2001) Anti-inflammatory activity of IVIG mediated through the inhibitory Fc receptor. Science 291:484–486

    PubMed  CAS  Article  Google Scholar 

  52. 52.

    Schuller E, Govaerts A (1983) First results of immunotherapy with immunoglobulin G in multiple sclerosis patients. Eur Neurol 22:205–212

    PubMed  CAS  Google Scholar 

  53. 53.

    Schultze HE, Schwick G (1962) Über neue Möglichkeiten intravenöser Gammaglobulin-Applikation. Dtsch Med Wschr 87:1643–1650

    PubMed  CAS  Article  Google Scholar 

  54. 54.

    Stangel M, Bernard D (2003) Polyclonal IgM influence oligodendrocyte precursor cells in mixed glial cell cultures: implications for remyelination. J Neuroimmunol 138:25–30

    PubMed  CAS  Article  Google Scholar 

  55. 55.

    Stangel M, Boegner F, Klatt CH, Hofmeister C, Seyfert S (2000) A placebo-controlled pilot trial to study the remyelinating potential of intravenous immunoglobulins in multiple sclerosis. J Neurol Neurosurg Psychiatry 68:89–92

    PubMed  CAS  Article  Google Scholar 

  56. 56.

    Stangel M, Compston A, Scolding NJ (1999) Polyclonal immunoglobulins for intravenous use do not influence the behaviour of cultured oligodendrocytes. J Neuroimmunol 96:228–233

    PubMed  CAS  Article  Google Scholar 

  57. 57.

    Stangel M, Gold R (2004) Use of i. v. immunoglobulins in neurology—evidence-based consensus. Nervenarzt 75:801–815

    PubMed  CAS  Article  Google Scholar 

  58. 58.

    Stangel M, Joly E, Scolding NJ, Compston DAS (2000) Normal polyclonal immunoglobulins (“IVIg”) inhibit microglial phagocytosis in vitro. J Neuroimmunol 106:137–144

    PubMed  CAS  Article  Google Scholar 

  59. 59.

    Stangel M, Schumacher HC, Ruprecht K, Boegner F, Marx P (1997) Immunoglobulins for intravenous use inhibit TNFα cytotoxicity in vitro. Immunol Invest 26:569–578

    PubMed  CAS  Google Scholar 

  60. 60.

    Stephan W (1975) Undegraded human immunoglobulin for intravenous use. Vox Sang 28:422–437

    PubMed  CAS  Article  Google Scholar 

  61. 61.

    Stohl W, Elliot JE (1996) In vitro inhibition by intravenous immunoglobulin of human T cell-dependent B cell differentiation induced by staphylococcal superantigens. Clin Immunol Immunopathol 79:122–133

    PubMed  CAS  Article  Google Scholar 

  62. 62.

    Takei S, Arora YK, Walker SM (1993) Intravenous immunoglobulin contains specific antibodies inhibitory to activation of T cells by staphylococcal toxin superantigens. J Clin Invest 91:602–607

    PubMed  CAS  Article  Google Scholar 

  63. 63.

    Toungouz M, Denys CH, De Groote D, Dupont E (1995) In vitro inhibition of tumour necrosis factor-α and interleukin-6 production by intravenous immunoglobulins. B J Haematol 89:698–703

    CAS  Article  Google Scholar 

  64. 64.

    Toyoda M, Pao A, Petrosian A, Jordan SC (2003) Pooled human gammaglobulin modulates surface molecule expression and induces apoptosis in human B cells. Am J Transplant 3:156–166

    PubMed  CAS  Article  Google Scholar 

  65. 65.

    van der Meche FGA, Schmitz PIM, the Dutch Guillain-Barré study group. (1992) A randomized trial comparing intravenous immune globulin and plasma exchange in Guillain-Barré syndrome. N Engl J Med 326:1123–1129

    PubMed  CAS  Article  Google Scholar 

  66. 66.

    Vassilev T, Gelin C, Kaveri SV, Zilber M-T, Boumsell L, Kazatchkine MD (1993) Antibodies to the CD5 molecule in normal human immunoglobulins for therapeutic use (intravenous immunoglobulins, IVIg). Clin Exp Immunol 92:369–372

    PubMed  CAS  Article  Google Scholar 

  67. 67.

    Vassilev TL, Kazatchkine MD, Van Huyen JP, Mekrache M, Bonnin E, Mani JC, Lecoubier C, Korinth D, Baruch D, Schriever F, Kaveri SV (1999) Inhibition of cell adhesion by antibodies to Arg-Gly-Asp (RGD) in normal immunoglobulin for therapeutic use (intravenous immunoglobulin, IVIg). Blood 93:3624–3631

    PubMed  CAS  Google Scholar 

  68. 68.

    Vermeulen M, van der Meche FGA, Speelman JD, Weber A, Busch HFM (1985) Plasma and gamma-globulin infusion in chronic inflammatory polyneuropathy. J Neurol Sci 70:317–326

    PubMed  CAS  Article  Google Scholar 

  69. 69.

    Viard I, Wehrli P, Bullani R, Schneider P, Holler N, Salomon D, Hunziker T, Saurat J-H, Tschopp J, French LE (1998) Inhibition of toxic epidermal necrolysis by blockade of CD95 with human intravenous immunoglobulin. Science 282:490–493

    PubMed  CAS  Article  Google Scholar 

  70. 70.

    Xu C, Poirier B,Van Huyen J-PD, Lucciari N, Michel O, Chevalier J, Kaveri S (1998) Modulation of endothelial cell function by normal polyspecific human intravenous immunoglobulins. A possible mechanism of action in vascular diseases. Am J Pathol 153:1257–1266

    PubMed  CAS  Google Scholar 

  71. 71.

    Yu Z, Lennon VA (1999) Mechanism of intravenous immune globulin therapy in antibody-mediated diseases. N Engl J Med 340:227–228

    PubMed  CAS  Article  Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to Martin Stangel.

Additional information

An erratum to this article is available at http://dx.doi.org/10.1007/s00415-008-0881-z.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Stangel, M., Pul, R. Basic principles of intravenous immunoglobulin (IVIg) treatment. J Neurol 253, v18–v24 (2006). https://doi.org/10.1007/s00415-006-5003-1

Download citation

Key words

  • intravenous immunoglobulins
  • IVIg
  • mechanism of action
  • immunomodulation
  • immune treatment