[Skip to Content]
Sign In
Individual Sign In
Create an Account
Institutional Sign In
OpenAthens Shibboleth
[Skip to Content Landing]
Download PDF
1.
Plasma Exchange/Sandoglobulin Guillain-Barré Syndrome Trial Group, Randomized trial of plasma exchange, intravenous immunoglobulin, and combined treatments in Guillain-Barré syndrome. Lancet. 1997;349225- 230Article
2.
Hahn  AFBolton  CFZochodne  DFeasby  TE Intravenous immunoglobulin treatment in chronic inflammatory demyelinating polyneuropathy: a double-blind, placebo-controlled, cross-over study. Brain. 1996;1191067- 1077Article
3.
Nobile-Orazio  E Multifocal motor neuropathy. J Neurol Neurosurg Psychiatry. 1996;60599- 603Article
4.
Fazekas  FDeisenhammer  FStrasser-Fuchs  SNahler  GMamoli  Bfor the Austrian Immunoglobulin in Multiple Sclerosis Study Group, Randomised placebo-controlled trial of monthly intravenous immunoglobulin therapy in relapsing-remitting multiple sclerosis. Lancet. 1997;349589- 593Article
5.
Rodriguez  MLennon  VA Immunoglobulins promote remyelination in the central nervous system. Ann Neurol. 1990;2712- 17Article
6.
Basta  MDalakas  MC High-dose intravenous immunoglobulin exerts its beneficial effect in patients with dermatomyositis by blocking endomysial deposition of activated complement fragments. J Clin Invest. 1994;941729- 1735Article
7.
Hartung  H-PToyka  KVGriffin  JW Guillain-Barré syndrome and chronic inflammatory demyelinating polyradiculoneuropathy. Antel  JBirnbaum  GHartung  H-Peds.Clinical Neuroimmunology. Blackwell Science Malden, Mass1998;294- 306
8.
Lutz  HUStammler  PJelezarova  ENater  MSpath  PJ High doses of immunoglobulin G attenuate immune aggregate-mediated complement activation by enhancing physiologic cleavage of C3b in C3bn-IgG complexes. Blood. 1996;88184- 193
9.
Kaveri  SVassilev  THurez  V  et al.  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. 1996;97865- 869Article
10.
Kondo  NKasahara  KKameyama  T  et al.  Intravenous immunoglobulins suppress immunoglobulin productions by suppressing Ca2+-dependent signal transduction through Fcg receptors in B lymphocytes. Scand J Immunol. 1994;4037- 42Article
11.
Kazatchkine  MDDietrich  GHurez  V  et al.  V region-mediated selection of autoreactive repertoires by intravenous immunoglobulin (i.v.Ig). Immunol Rev. 1994;13979- 107Article
12.
Debré  MBonnet  M-CFridman  W-H  et al.  Infusion of Fc-gamma fragments for treatment of children with acute immune thrombocytopenic purpura. Lancet. 1993;342945- 949Article
13.
Yu  ZLennon  VA Mechanism of intravenous immune globulin therapy in antibody-mediated autoimmune diseases. N Engl J Med. 1999;340227- 228Article
14.
Miyagi  FHoriuchi  HNagata  I  et al.  Fc portion of intravenous immunoglobulins suppresses the induction of experimental allergic neuritis. J Neuroimmunol. 1997;78127- 131Article
15.
Silvestris  FD'Amore  OCafforio  PSavino  LDammacco  F Intravenous immune globulin therapy of lupus nephritis: use of pathogenic anti-DNA-reactive IgG. Clin Exp Immunol. 1996;104(suppl 1)91- 97
16.
van Doorn  PABrand  AVermeulen  M Anti-neuroblastoma cell line antibodies in inflammatory demyelinating polyneuropathy: inhibition in vitro and in vivo by IV immunoglobulin. Neurology. 1988;381592- 1595Article
17.
Andersson  JSkansén-Saphir  USparrelid  EAndersson  U Intravenous immune globulin affects cytokine production in T lymphocytes and monocytes/macrophages. Clin Exp Immunol. 1996;104(suppl 1)10- 20
18.
Ross  CSvenson  MHansen  MBVejlsgaard  GLBendtzen  K High avidity IFN-neutralizing antibodies in pharmaceutically prepared human IgG. J Clin Invest. 1995;951974- 1978Article
19.
Stangel  MSchumacher  HCRuprecht  KBoegner  FMarx  P Immunoglobulins for intravenous use inhibit TNF α cytotoxicity in vitro. Immunol Invest. 1997;26569- 578Article
20.
Pavelko  KDvan Engelen  BGMRodriguez  M Acceleration in the rate of CNS remyelination in lysolecithin-induced demyelination. J Neurosci. 1998;182498- 2505
21.
Dalakas  MCQuarles  RHFarrer  RG  et al.  A controlled study of intravenous immunoglobulin in demyelinating neuropathy with IgM gammopathy. Ann Neurol. 1996;40792- 795Article
Neurological Review
June 1999

Mechanisms of High-Dose Intravenous Immunoglobulins in Demyelinating Diseases

Author Affiliations

From the MRC Centre for Brain Repair, Cambridge University, Cambridge, England (Dr Stangel); and the Department of Neurology and the Clinical Research Group for Multiple Sclerosis and Neuroimmunology, Julius Maximilians Universität, Würzburg, Germany (Drs Toyka and Gold).

 

DAVID E.PLEASUREMD

Arch Neurol. 1999;56(6):661-663. doi:10.1001/archneur.56.6.661
Abstract

Administration of high-dose intravenous immunoglobulins has become one of the most successful new treatment regimens for demyelinating diseases. In a decade of molecular medicine, it came as a surprise that a natural blood product would prove effective in several disorders, including Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, multifocal motor neuropathy, and, probably, multiple sclerosis. Many experimental studies, both in vivo and in vitro, have shown that intravenous immunoglobulins can interfere with the immune system at several levels. In addition, intravenous immunoglobulins may promote remyelination in demyelinating disease associated with viral infections. At present, no single mode of action has been identified as the crucial mechanism, which leads us to suggest that multiple effects may act in concert.

Intravenous immunoglobulin (IVIg) treatment now has an established role in the therapy of immunologically mediated demyelinating disorders, including Guillain-Barré syndrome,1chronic inflammatory demyelinating polyneuropathy,2and multifocal motor neuropathy.3In multiple sclerosis, studies support a therapeutic role in inflammatory demyelination in the central nervous system.4While the immunomodulating capacity of IVIgs has been studied extensively over the past 15 years, their remyelination potential has been recognized only recently.5

EFFECTS OF IVIgs ON COMPONENTS OF THE IMMUNE SYSTEM
Complement

Immunoglobulins can bind complement components with their constant domain and thus prevent tissue damage caused by the complement activation cascade. This mechanism in humans has been demonstrated in an inflammatory disease of muscle (dermatomyositis) by specimens obtained from serial muscle biopsies and in vitro complement uptake studies, where C3b and the membrane attack complex disappeared under IVIg treatment.6One possible mechanism may be the inactivation of C3b2-IgG complexes, which are milestones in the process of membrane-attack-complex (C5b-9) formation.7Complement deposition in situ is also of prime pathogenic importance in inflammatory demyelinating disorders, eg, Guillain-Barré syndrome.8

T Cells

At present, most of our knowledge of the influence of IVIgs on T cells is derived from in vitro studies. Changes in both CD8+suppressor or cytotoxic cells and CD4+helper T cells were demonstrated after IVIg treatment. Antibodies directed against several T-cell surface molecules are present in IVIgs, including the T-cell receptor, CD4, and major histocompatibility complex.9Neutralizing antibodies against bacterial or viral superantigens that stimulate T cells unspecifically are also contained in IVIgs. Furthermore, soluble CD4 or CD4-like activity and soluble HLA molecules are found in trace amounts in IVIgs. The implications of these contaminations comigrating with IVIgs is uncertain because successful treatment trials have been reported with different preparations containing variable amounts of these factors.

B Cells

Many in vitro studies have shown the potential of IVIgs to inhibit antibody production and B-cell differentiation.10This could be mediated by anti-idiotypic antibodies directed against the surface-bound idiotypes on B cells producing pathogenic antibodies (see below), or by antibodies directed against the CD5 antigen that is expressed on the subpopulation of B cells thought to produce low-affinity natural autoantibodies. Anti-idiotypes have indeed been shown to be present in IVIg preparations.11Finally, IVIgs can inhibit the production of interleukin 6, a cytokine needed for the secretion of IgG by plasma cells.

Fc Receptor

The Fc portion of immunoglobulins interacts with many phagocytic cells expressing appropriate Fc receptors on their cell surfaces. Pathogenic antibodies can bind to the Fc receptor and thereby target macrophages. Excess amounts of immunoglobulins may compete with this binding and block the damaging effects of inflammatory effector cells. Modulation of Fc receptor–mediated functions has been shown in vitro, and administration of purified Fc fragments was indeed effective in children with idiopathic thrombocytopenic purpura.12Another beneficial Fc-mediated effect is through Fc receptor neonate binding protein (FcRn), which, after excess binding to therapeutic IVIg, speeds up IgG autoantibody catabolism and elimination.13For neurologic disorders, there is evidence from experimental autoimmune neuritis in rats that intact human IVIgs, but not F(ab′)2fragments, can reduce disease severity, suggesting that their effect is mediated via the Fc portion.14

Anti-idiotypes

Immunoglobulins that recognize and attach to the antigen-binding region of the F(ab) part of another immunoglobulin are called anti-idiotypic antibodies. These antibodies may occur naturally or may be driven by antigenic challenge with subsequent formation of autoantibodies. It is thought that a network of these various antibodies may play a role in the regulation of autoimmunity.11The therapeutic relevance of this mechanism in human disease was demonstrated by the successful treatment of 2 patients with systemic lupus erythematosus with purified anti-idiotypic antibodies.15This mechanism has been suggested to play a role in Guillain-Barré syndrome and chronic inflammatory demyelinating polyneuropathy.16

Cytokines

Clinical studies have demonstrated that the cytokine profile of patients is altered by the administration of IVIgs, and this is supported by studies showing that cytokine production can be modulated by IVIgs in cultured mononuclear cells.17It has not been proved, however, that this mechanism plays a major role in the pathologic situation. Intravenous immunoglobulins contain trace amounts of interferon gamma and transforming growth factor beta. While interferon gamma is thought to activate an ongoing immune response in the peripheral nervous system, transforming growth factor beta seems to be associated with clinical recovery. On the other hand, antibodies directed against interleukin 1α, interleukin 6, and the class I and II interferons (alfa, beta, and gamma) have been found in IVIgs,18which may also have a regulatory role in the cytokine network. In experimental autoimmune encephalomyelitis, human IVIgs are thought to act via down-regulation of tumor necrosis factor α secretion. Indeed a protective effect of IVIgs on tumor necrosis factor–α mediated cell damage has been shown in vitro.19It seems not an easy task to formulate a unifying hypothesis based on these multiple observations.

EFFECTS OF IVIgs ON REMYELINATION

The concept that IVIgs may have the potential to remyelinate axons originated from the observation that polyclonal immunoglobulins against spinal cord homogenate were able to increase remyelination in the inflammatory model of Theiler virus encephalitis.5A monoclonal IgMκ antibody was identified that could promote remyelination, suppress inflammation, and also have some effect in a toxic model of demyelination.20This monoclonal antibody was shown to be polyreactive, recognizing antigens present on oligodendrocytes and other cells. Extrapolating from these experimental observations, IVIgs may have a beneficial effect if they contain such autoantibodies. This intriguing concept challenges the traditional view of antimyelin antibodies as essentially detrimental. Besides their immunomodulatory role (see above) antimyelin antibodies may stimulate oligodendrocyte precursors or mature oligodendrocytes to proliferate or differentiate.

CONCLUSIONS

Treatment with IVIgs has shown a positive effect in conditions of both the peripheral and central nervous systems. As a first-line treatment for Guillain-Barré syndrome, it has demonstrated efficacy in 2 large controlled trials.1Used alternatively to plasma exchange and standard immunosuppression (steroids and azathioprine), IVIgs have shown efficacy in controlled trials against chronic inflammatory demyelinating polyneuropathy.2 Used as a first-line treatment, either alone or in combination with cyclophosphamide to halt progression, IVIg therapy has demonstrated efficacy, again in controlled trials, for the treatment of multifocal motor neuropathy,3and has shown a positive effect in single cases against neuropathy with IgM paraproteinemia (though a controlled trial failed to demonstrate efficacy).21In 3 controlled trials with multiple sclerosis, IVIg therapy has shown a positive effect on relapse rate.4

There is overwhelming evidence that IVIgs can manipulate the immune system at several levels. The capacity of immunoglobulins to promote remyelination has been demonstrated in experimental models, but it remains to be shown whether this is a direct effect on myelin or is secondary to immunomodulation. A general restorative action of IVIgs is less likely, since not all demyelinating immunoneuropathies respond favorably,21nor was there a protective effect in adrenoleukodystrophy, a peroxisomal dysmyelinating disorder.

The history of IVIg treatments is a telling example of how much empirical knowledge can contribute to medical progress even in the realm of molecular medicine. Elucidation of both the pathophysiological mechanisms in the various diseases and the mode of action of IVIgs may eventually lead to more specific immunoglobulin preparations, including the generation of recombinant humanized immunoglobulin fractions.

Back to top
Article Information

Accepted for publication July 17, 1998.

Dr Stangel is the recipient of a Deutsche Forschungsgemeinschaft scholarship, Bonn, Germany. The Clinical Research Group for Multiple Sclerosis (Drs Toyka and Gold) is supported by the Deutsche Forschungsgemeinschaft, Gemeinnützige Hertiestiftung, Wilhelm-Sander Stiftung, German Multiple Sclerosis Society, and funds from the State of Bavaria.

We would like to thank Marinos C. Dalakas, MD, for many helpful discussions.

We apologize to all scientists, clinical and experimental, whose work has not been cited due to space limitations in this short review.

Reprints: Ralf Gold, MD, Neurologische Universitätsklinik, Josef-Schneider-Strasse 11, D-97080 Würzburg, Germany (e-mail: r.gold@mail.uni-wuerzburg.de).

References
1.
Plasma Exchange/Sandoglobulin Guillain-Barré Syndrome Trial Group, Randomized trial of plasma exchange, intravenous immunoglobulin, and combined treatments in Guillain-Barré syndrome. Lancet. 1997;349225- 230Article
2.
Hahn  AFBolton  CFZochodne  DFeasby  TE Intravenous immunoglobulin treatment in chronic inflammatory demyelinating polyneuropathy: a double-blind, placebo-controlled, cross-over study. Brain. 1996;1191067- 1077Article
3.
Nobile-Orazio  E Multifocal motor neuropathy. J Neurol Neurosurg Psychiatry. 1996;60599- 603Article
4.
Fazekas  FDeisenhammer  FStrasser-Fuchs  SNahler  GMamoli  Bfor the Austrian Immunoglobulin in Multiple Sclerosis Study Group, Randomised placebo-controlled trial of monthly intravenous immunoglobulin therapy in relapsing-remitting multiple sclerosis. Lancet. 1997;349589- 593Article
5.
Rodriguez  MLennon  VA Immunoglobulins promote remyelination in the central nervous system. Ann Neurol. 1990;2712- 17Article
6.
Basta  MDalakas  MC High-dose intravenous immunoglobulin exerts its beneficial effect in patients with dermatomyositis by blocking endomysial deposition of activated complement fragments. J Clin Invest. 1994;941729- 1735Article
7.
Hartung  H-PToyka  KVGriffin  JW Guillain-Barré syndrome and chronic inflammatory demyelinating polyradiculoneuropathy. Antel  JBirnbaum  GHartung  H-Peds.Clinical Neuroimmunology. Blackwell Science Malden, Mass1998;294- 306
8.
Lutz  HUStammler  PJelezarova  ENater  MSpath  PJ High doses of immunoglobulin G attenuate immune aggregate-mediated complement activation by enhancing physiologic cleavage of C3b in C3bn-IgG complexes. Blood. 1996;88184- 193
9.
Kaveri  SVassilev  THurez  V  et al.  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. 1996;97865- 869Article
10.
Kondo  NKasahara  KKameyama  T  et al.  Intravenous immunoglobulins suppress immunoglobulin productions by suppressing Ca2+-dependent signal transduction through Fcg receptors in B lymphocytes. Scand J Immunol. 1994;4037- 42Article
11.
Kazatchkine  MDDietrich  GHurez  V  et al.  V region-mediated selection of autoreactive repertoires by intravenous immunoglobulin (i.v.Ig). Immunol Rev. 1994;13979- 107Article
12.
Debré  MBonnet  M-CFridman  W-H  et al.  Infusion of Fc-gamma fragments for treatment of children with acute immune thrombocytopenic purpura. Lancet. 1993;342945- 949Article
13.
Yu  ZLennon  VA Mechanism of intravenous immune globulin therapy in antibody-mediated autoimmune diseases. N Engl J Med. 1999;340227- 228Article
14.
Miyagi  FHoriuchi  HNagata  I  et al.  Fc portion of intravenous immunoglobulins suppresses the induction of experimental allergic neuritis. J Neuroimmunol. 1997;78127- 131Article
15.
Silvestris  FD'Amore  OCafforio  PSavino  LDammacco  F Intravenous immune globulin therapy of lupus nephritis: use of pathogenic anti-DNA-reactive IgG. Clin Exp Immunol. 1996;104(suppl 1)91- 97
16.
van Doorn  PABrand  AVermeulen  M Anti-neuroblastoma cell line antibodies in inflammatory demyelinating polyneuropathy: inhibition in vitro and in vivo by IV immunoglobulin. Neurology. 1988;381592- 1595Article
17.
Andersson  JSkansén-Saphir  USparrelid  EAndersson  U Intravenous immune globulin affects cytokine production in T lymphocytes and monocytes/macrophages. Clin Exp Immunol. 1996;104(suppl 1)10- 20
18.
Ross  CSvenson  MHansen  MBVejlsgaard  GLBendtzen  K High avidity IFN-neutralizing antibodies in pharmaceutically prepared human IgG. J Clin Invest. 1995;951974- 1978Article
19.
Stangel  MSchumacher  HCRuprecht  KBoegner  FMarx  P Immunoglobulins for intravenous use inhibit TNF α cytotoxicity in vitro. Immunol Invest. 1997;26569- 578Article
20.
Pavelko  KDvan Engelen  BGMRodriguez  M Acceleration in the rate of CNS remyelination in lysolecithin-induced demyelination. J Neurosci. 1998;182498- 2505
21.
Dalakas  MCQuarles  RHFarrer  RG  et al.  A controlled study of intravenous immunoglobulin in demyelinating neuropathy with IgM gammopathy. Ann Neurol. 1996;40792- 795Article
×