1. Introduction

IVIG is a product prepared from fractionation of pools of thousands of plasma donations collected in blood transfusion services [1-4]^[1]. 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

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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

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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.

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