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Clinical and Histological Features in Wegener Granulomatosis
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Anne Lanham, Lillian Mwanri

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The Use of Intravenous Immunoglobulins (IVIG) in Immunological Mediated Diseases and Possible Mechanisms of Actions

Angel Alberto Justiz Vaillant*, Sehlule Vuma, Wayne Mohammed

Pathology and Microbiology Unit, Department of Para-Clinical Sciences, The University of the West Indies, St. Augustine, Trinidad and Tobago, WI

Abstract: Intravenous immunoglobulin (IVIG) is a product prepared from fractionation of pools of thousands of plasma donations collected at blood transfusion services. IVIG has been used in the treatment of neurological disorders, primary and secondary immunodeficiency, skin disorders, autoimmune disorders, immunologic abortion, and as anti-cancer and anti-inflammatory therapy. In this paper we listed a number of diseases for which the use of IVIG has been successful and the most mentioned mechanisms of actions of this immunotherapy. IVIG has different modes of actions involving interference with activation of complement components and the cytokine network; effects on regulatory T cells (Tregs) subset; expression of Fc receptors; modulation of idiotype network; and activation, proliferation and effector functions of B and T lymphocytes and of antigen-presenting cells such as dendritic cells and macrophages. We concluded that IVIG has proven to be efficacious in the treatment of immunodeficiency, autoimmunity, infections and inflammatory disorders over the last three decades. To date IVIG has been used to treat more than 80 diseases. Although some of the mechanisms of actions of IVIG are obscure in nature, the fact that many patients improved with it when all other options of treatment were exhausted, make the use of IVIG an important alternative. On the other hand, treatment with IVIG is expensive. We are hopeful that in near future new horizons will be open for the acquisition and use of a cheaper IVIG to treat weak immune system or as immunosuppressive drug in the treatment of autoimmune and inflammatory disorders.

Keywords: intravenous immunoglobulins (IVIG), immunological diseases, immunotherapy, autoimmunity, immunodeficiency

Received March 20, 2015; Revised April 03, 2015; Accepted April 08, 2015

Citation: Angel Alberto Justiz Vaillant, Sehlule Vuma, Wayne Mohammed, The Use of Intravenous Immunoglobulins (IVIG) in Immunological Mediated Diseases and Possible Mechanisms of Actions. American Journal of Pharmacological Sciences, 3 (2). 33-37. January 2015. doi:10.12691/ajps-3-2-1

1. Introduction

IVIG is a product prepared from fractionation of pools of thousands of plasma donations collected in blood transfusion services [1-4]. Along with purified IgG, other proteins are present in the IVIG in small amounts, for example: traces of IgM and IgA [5], immunomodulating peptides, and various cytokines [6]. IVIG demand worldwide is coupled with shortages and concerns about potentially infected blood from which it may be prepared [7]. This has obligated National Health Authorities to produce guidelines for the better use of IVIG, for example England and Wales regulations [8] and the Canadian guidelines [9]. In this paper we listed a number of diseases for which the use of IVIG has been successful and the most mentioned mechanisms of actions of this immunotherapy.

2. Use of IVIG in Immunological-Mediated Diseases

As shown in Table 1, IVIG has been used in the treatment of neurological disorders, primary and secondary immunodeficiency, skin disorders, autoimmune disorders, immunologic abortion, and as anti-cancer and anti-inflammatory therapy.

The worldwide consumption of IVIG in 1980 was 300 kg per year and it increased to 100 tonnes per year in 2010 [24]. The mechanisms of action of IVIG reflect the importance of natural antibodies in the maintenance of immune homeostasis [25]. Side effects from IVIG are mild and transient and mostly rare. Adverse effects can be minimized by administration of slow infusion rate of 0.4 g/Kg body weight IVIG for 5 consecutive days, and given in monthly cycles. The high price is the only downside of IVIG treatment [27]. The risk of transmission of microorganisms appears only theoretical [31].

IVIG was not recommended for 8 conditions including amyotropic lateral sclerosis, autism, adrenoleukodystrophy, critical illness polyneuropathy, intractable childhood epilepsy, inclusion body myositis, paraproteinemic neuropathy (IgM variant), and POEMS syndrome (this name is an acronym deriving from some of the main features of this syndrome: Polyneuropathy, Organomegaly, Endocrinopathy or Edema, M-protein and Skin abnormalities). Dissemination and development of evidence-based clinical practice guidelines may facilitate appropriate IVIG use [9]. The immunomodulatory mechanisms of action of IVIG are not well-understood and unclear because of the diversity and often contradictory Fc, F(ab')(2), and non-IgG-related mechanisms. Results obtained in various in vitro and in vivo experimental models have been contradictory [3].

Table 1. Use of IVIG in a number of immunological mediated-diseases

3. Mechanisms of Actions of IVIG

The gamma globulin therapy began in 1930 when, in Finland, Cohn, Bruton and Imbach carried out the treatment of pneumococcal pneumonia in patients with equine serum. This improved notably the survival rate of this type of pneumonia. Originally IVIG was used to treat immunodeficiencies. Later, the IVIG use was extended for the treatment of autoimmune disorders and inflammatory diseases [27]. IVIG has been used successfully to treat SLE patients with a broad spectrum of clinical manifestations, such as pancytopenia, refractory thrombocytopenia, secondary antiphospholipid syndrome, central nervous system (CNS) involvement and lupus nephritis [29]. The different mechanisms of actions of IVIG are listed in Table 2.

IVIG has different modes of action that involve interference with activation of complement components and the cytokine network; effects on Tregs, expression of Fc receptors, modulation of idiotype network, among others mechanisms as shown in Table 2. The IVIG therapeutic effects most likely reflect the functions of natural antibodies, which play an important role in the maintenance of the immune homeostasis in healthy individuals.

Table 2. Mechanisms of actions of IVIG in immunological mediated disorders

The use of IVIG as a therapeutic option in arthritis is significant. In the United States of America the prevalence of this disorder is quite high and varies according to ethnicity. Helmick and colleagues reported in 2008 that 21% of USA adults (46.4 million persons) were found to have self-reported doctor diagnosed arthritis. They estimated that rheumatoid arthritis affects 1.3 million adults, juvenile arthritis affects 294,000 children, spondyloarthropathy affect from 0.6 million to 2.4 million adults, systemic lupus erythematosus affects from 161,000 to 322,000 adults, systemic sclerosis affects 49,000 adults, and primary Sjögren's syndrome affects from 0.4 million to 3.1 million adults [56]. All of these conditions may benefit from the use of IVIG, in addition to many other autoimmune disorders, immunodeficiency and inflammatory disorders. The IVIG worldwide shortage is an issue of concern in specialized areas of medicine that has to be overcome in the near future.

4. Conclusions

We concluded that IVIG has proven to be efficacious in the treatment of immunodeficiency, autoimmunity, infections and inflammatory disorders. To date more than 80 diseases have benefited from the use of IVIG. Its modes of action must be clarified for a wider and better use in immunological mediated diseases.

References

[1]   | Bayry J, Negi VS, Kaveri SV. Intravenous immunoglobulin therapy in rheumatic diseases. Nat Rev Rheumatol 2011 Jun; 7(6): 349-59.
[2]   | Timmerman PR. Intravenous immunoglobulin in oncology nursing practice. Oncol Nurs Forum. 1993 Jan-Feb; 20(1): 69-75.
[3]   | Lemieux R, Bazin R, Néron S. Therapeutic intravenous immunoglobulins. Mol Immunol. 2005 May; 42 (7): 839-48.
[4]   | Larroche C, Chanseaud Y, Garcia de la Pena-Lefebvre P, Mouthon L. Mechanisms of intravenous immunoglobulin action in the treatment of autoimmune disorders. BioDrugs. 2002; 16(1): 47-55.
[5]   | Hartung HP. Advances in the understanding of the mechanism of action of IVIg. J Neurol. 2008 Jul; 255 Suppl 3:3-6.
[6]   | Sapir T, Shoenfeld Y. Facing the enigma of immunomodulatory effects of intravenous immunoglobulin. Clin Rev Allergy Immunol. 2005 Dec; 29(3):185-99.
[7]   | Mouthon L, Bussone G, Kaveri S. Indications and mechanisms of action of the intravenous immunoglobulines in the systemic autoimmune and inflammatory pathologies. Rev Med Interne. 2009 Dec; 30(12 Suppl):H14-20.
[8]   | Mulhearn B, Bruce IN. Indications for IVIG in rheumatic diseases. Rheumatology (Oxford). 2015 Mar; 54 (3): 383-391.
[9]   | Feasby T, Banwell B, Benstead T, Bril V, Brouwers M, Freedman M, Hahn A, Hume H, Freedman J, Pi D, Wadsworth L. Guidelines on the use of intravenous immune globulin for neurologic conditions. Transfus Med Rev. 2007 Apr; 21(2 Suppl 1):S57-107.
[10]   | Hara M. Intravenous immunoglobulin (IVIG). Nihon Rinsho. 2009 Mar; 67(3):599-605.
[11]   | Duff K. You can make a difference in the administration of intravenous immunoglobulin therapy. J Infus Nurs. 2006 May-Jun; 29(3 Suppl): S5-14.
[12]   | Hurez V, Kaveri SV, Kazatchkine MD. Normal polyspecific immunoglobulin G (IVIg) in the treatment of autoimmune diseases. J Autoimmun. 1993 Dec; 6(6):675-81.
[13]   | Mastaglia FL, Garlepp MJ, Phillips BA, Zilko PJ. Inflammatory myopathies: clinical, diagnostic and therapeutic aspects. Muscle Nerve. 2003 Apr; 27(4):407-25.
[14]   | Dalakas MC. Therapeutic approaches in patients with inflammatory myopathies. Semin Neurol. 2003 Jun; 23(2):199-206.
[15]   | Mastaglia FL. Inflammatory muscle diseases. Neurol India. 2008 Jul-Sep; 56(3):263-70.
[16]   | Kazatchkine M, Mouthon L, Kaveri SV. Immunomodulatory effects of intravenous immunoglobulins. Ann Med Interne (Paris). 2000 May;151 Suppl 1:1S13-8.
[17]   | Sapir T, Shoenfeld Y. Facing the enigma of immunomodulatory effects of intravenous immunoglobulin. Clin Rev Allergy Immunol. 2005 Dec;29(3):185-99.
[18]   | Sapir T, Shoenfeld Y. Uncovering the hidden potential of intravenous immunoglobulin as an anticancer therapy. Clin Rev Allergy Immunol. 2005 Dec;29(3):307-10.
[19]   | Sapir T, Carp H, Shoenfeld Y. Intravenous immunoglobulin (IVIG) as treatment for recurrent pregnancy loss (RPL). Harefuah. 2005 Jun;144(6):415-20.
[20]   | Stricker RB, Winger EE. Update on treatment of immunologic abortion with low-dose intravenous immunoglobulin. Am J Reprod Immunol. 2005 Dec;54(6):390-6.
[21]   | Emmi L, Chiarini F. The role of intravenous immunoglobulin therapy in autoimmune and inflammatory disorders. Neurol Sci. 2002 Apr;23 Suppl 1:S1-8.
[22]   | 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 Feb;127(2):315-23; quiz 324-5.
[23]   | Imbach P, Lazarus AH, Kühne T. Intravenous immunoglobulins induce potentially synergistic immunomodulations in autoimmune disorders. Vox Sang. 2010 Apr;98 (3 Pt 2):385-94.
[24]   | Imbach P. Treatment of immune thrombocytopenia with intravenous immunoglobulin and insights for other diseases. A historical review. Swiss Med Wkly. 2012 May 31;142:w13593.
[25]   | Sibéril S, Elluru S, Negi VS, Ephrem A, Misra N, Delignat S, Bayary J, Lacroix-Desmazes S, Kazatchkine MD, Kaveri SV. Intravenous immunoglobulin in autoimmune and inflammatory diseases: more than mere transfer of antibodies. Transfus Apher Sci. 2007 Aug;37(1):103-7.
[26]   | Kasztalska K, Ciebiada M, Górski P. Mechanism of action of immunoglobulin applied intravenously. Pol Merkur Lekarski. 2010 Oct;29(172):263-8.
[27]   | Sapir T, Blank M, Shoenfeld Y. Immunomodulatory effects of intravenous immunoglobulins as a treatment for autoimmune diseases, cancer, and recurrent pregnancy loss. Ann N Y Acad Sci. 2005 Jun;1051:743-78.
[28]   | Ephrem A, Misra N, Hassan G, Dasgupta S, Delignat S, Duong Van Huyen JP, Chamat S, Prost F, Lacroix-Desmazes S, Kavery SV, Kazatchkine MD. Immunomodulation of autoimmune and inflammatory diseases with intravenous immunoglobulin. Clin Exp Med. 2005 Dec;5(4):135-40.
[29]   | Toubi E, Kessel A, Shoenfeld Y. High-dose intravenous immunoglobulins: an option in the treatment of systemic lupus erythematosus. Hum Immunol. 2005 Apr;66(4):395-402.
[30]   | Vani J, Elluru S, Negi VS, Lacroix-Desmazes S, Kazatchkine MD, Bayry J, Kaveri SV. Role of natural antibodies in immune homeostasis: IVIg perspective. Autoimmun Rev. 2008 Jun;7(6):440-4.
[31]   | Mouthon L, Berezné A, Le Guern V, Guillevin L. Intravenous immunoglobulins: therapeutic indications. Presse Med. 2005 Sep 24; 34(16 Pt 1):1166-75.
[32]   | Misra N, Bayry J, Ephrem A, Dasgupta S, Delignat S, Duong Van Huyen JP, Prost F, Lacroix-Desmazes S, Nicoletti A, Kazatchkine MD, Kaveri SV. Intravenous immunoglobulin in neurological disorders: a mechanistic perspective. J Neurol. 2005 May;252 Suppl 1:I1-6.
[33]   | Michael D, Grando SA. Novel mechanism for therapeutic action of IVIg in autoimmune blistering dermatoses. Curr Dir Autoimmun. 2008;10:333-43.
[34]   | Mittmann N, Chan BC, Knowles S, Shear NH. IVIG for the treatment of toxic epidermal necrolysis. Skin Therapy Lett. 2007 Feb;12(1):7-9.
[35]   | Teo L, Tay YK, Liu TT, Kwok C. Stevens-Johnson syndrome and toxic epidermal necrolysis: efficacy of intravenous immunoglobulin and a review of treatment options. Singapore Med J. 2009 Jan;50(1):29-33.

[36]  
Ephrem A, Chamat S, Miquel C, Fisson S, Mouthon L, Caligiuri G, Delignat S, Elluru S, Bayry J, Lacroix-Desmazes S, Cohen JL, Salomon BL, Kazatchkine MD, Kaveri SV, Misra N. Expansion of CD4+CD25+ regulatory T cells by intravenous immunoglobulin: a critical factor in controlling experimental autoimmune encephalomyelitis. Blood. 2008 Jan 15;111(2):715-22.

[37]   | Tjon AS, Tha-In T, Metselaar HJ, van Gent R, van der Laan LJ, Groothuismink ZM, te Boekhorst PA, van Hagen PM, Kwekkeboom J. Patients treated with high-dose intravenous immunoglobulin show selective activation of regulatory T cells. Clin Exp Immunol. 2013 Aug;173(2):259-67.

[38]  
Hirabayashi Y, Takahashi Y, Xu Y, Akane K, Villalobos IB, Okuno Y, Hasegawa S, Muramatsu H, Hama A, Kato T, Kojima S. 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 Jun;172(6):833-7.

[39]   | Rossi F, Dietrich G, Kazatchkine MD. Anti-idiotypes against autoantibodies in normal immunoglobulins: evidence for network regulation of human autoimmune responses. Immunol Rev. 1989 Aug;110:135-49.
[40]   | Dietrich G, Kaveri SV, Kazatchkine MD. Modulation of autoimmunity by intravenous immune globulin through interaction with the function of the immune/idiotypic network. Clin Immunol Immunopathol. 1992 Jan;62(1 Pt 2):S73-81.
[41]   | Lacroix-Desmazes S, Mouthon L, Spalter SH, Kaveri S, Kazatchkine MD. Immunoglobulins and the regulation of autoimmunity through the immune network. Clin Exp Rheumatol. 1996 May-Jun;14 Suppl 15:S9-15.
[42]   | Mouthon L, Kaveri S, Kazatchkine M. Immune modulating effects of intravenous immunoglobulin (IVIg) in autoimmune diseases. Transfus Sci. 1994 Dec;15(4):393-408.
[43]   | Guilpain P, Chanseaud Y, Tamby MC, Larroche C, Guillevin L, Kaveri SV, Kazatchkine MD, Mouthon L. Immunomodulatory effects of intravenous immunoglobulins. Presse Med. 2004 Oct 9;33(17):1183-94.
[44]   | Bayry J, Misra N, Latry V, Prost F, Delignat S, Lacroix-Desmazes S, Kazatchkine MD, Kaveri SV. Mechanisms of action of intravenous immunoglobulin in autoimmune and inflammatory diseases. Transfus Clin Biol. 2003 Jun;10(3):165-9.
[45]   | Mouthon L, Kaveri SV, Spalter SH, Lacroix-Desmazes S, Lefranc C, Desai R, Kazatchkine MD. Mechanisms of action of intravenous immune globulin in immune-mediated diseases. Clin Exp Immunol. 1996 May;104 Suppl 1:3-9.
[46]   | Ibáñez C, Montoro-Ronsano JB. Intravenous immunoglobulin preparations and autoimmune disorders: mechanisms of action. Curr Pharm Biotechnol. 2003 Aug;4(4):239-47.
[47]   | Negi VS, Elluru S, Sibéril S, Graff-Dubois S, Mouthon L, Kazatchkine MD, Lacroix-Desmazes S, Bayry J, Kaveri SV. Intravenous immunoglobulin: an update on the clinical use and mechanisms of action. J Clin Immunol. 2007 May;27(3):233-45.
[48]   | Arnson Y, Shoenfeld Y, Amital H. Intravenous immunoglobulin therapy for autoimmune diseases. Autoimmunity. 2009 Sep;42(6):553-60.
[49]   | Galeotti C, Maddur MS, Kazatchkine MD, Mouthon L, Kaveri SV. Intravenous immunoglobulins in autoimmune and inflammatory disorders: beyond a simple substitution. Transfus Clin Biol. 2009 May;16(2):75-9.
[50]   | Lacroix-Desmazes S, Kaveri S, Kazatchkine MD. Regulation of autoreactivity by the idiotypic network and therapeutic modulation of autoimmunity by polyvalent intravenous immunoglobulins (IgIV). Rev Neurol (Paris). 1996 May;152(5):349-54.
[51]   | Maddur MS, Othy S, Hegde P, Vani J, Lacroix-Desmazes S, Bayry J, Kaveri SV. Immunomodulation by intravenous immunoglobulin: role of regulatory T cells. J Clin Immunol. 2010 May; 30 Suppl 1:S4-8
[52]   | Yen MH, Huang YC², Chen MC³, Liu CC⁴, Chiu NC⁵, Lien R⁶, Chang LY⁷, Chiu CH⁶, Tsao KC⁸, Lin TY⁹. Effect of intravenous immunoglobulin for neonates with severe enteroviral infections with emphasis on the timing of administration. J Clin Virol. 2015 Mar;64:92-6.
[53]   | Capasso L, Borrelli A, Cerullo J, Pisanti R, Figliuolo C, Izzo F, Paccone M, Ferrara T Lama S¹, Raimondi F. Role of immunoglobulins in neonatal sepsis. Transl Med UniSa. 2014 Dec 19;11:28-33.
[54]   | Basta M, Branch DR. 7th International Immunoglobulin Conference: Mechanisms of action. Clin Exp Immunol. 2014 Dec;178 Suppl 1:87-8.
[55]   | Jimenez-Rivera C, Gupta A, Feberova J, de Nanassy JA, Boland MP. Successful treatment of neonatal hemochromatosis as gestational alloimmune liver disease with intravenous immunoglobulin. J Neonatal Perinatal Med. 2014;7(4):301-4.

[56]  
Helmick CG, Felson DT, Lawrence RC, Gabriel S, Hirsch R, Kwoh CK, Liang MH, Kremers HM, Mayes MD, Merkel PA, Pillemer SR, Reveille JD, Stone JH; National Arthritis Data Workgroup. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part I. Arthritis Rheum. 2008 Jan;58(1):15-25.