Action Of Intravenous Immune Globulin Research Articles

Intravenous Immune Globulin Uses in the Fetus and Neonate: A Review.

Intravenous immune globulin (IVIG) is made after processing plasma from healthy donors. It is composed mainly of pooled immunoglobulin and has clinical evidence-based applications in adult and pediatric populations. Recently, several clinical applications have been proposed for managing conditions in the neonatal population, such as hemolytic disease of the newborn, treatment, and prophylaxis for sepsis in high-risk neonates, enterovirus parvovirus and COVID-19 related neonatal infections, fetal and neonatal immune-induced thrombocytopenia, neonatal hemochromatosis, neonatal Kawasaki disease, and some types of immunodeficiency. The dosing, mechanism of action, effectiveness, side effects, and adverse reactions of IVIG have been relatively well studied in adults but are not well described in the neonatal population. This review aims to provide the most recent evidence and consensus guidelines about the use of IVIG in the fetus and neonate.

Mechanisms of action of intravenous immune globulin in immune-mediated diseases

Intravenous immune globulin (IVIG) exhibits a number of immunomodulatory properties that are mediated by the Fe portion of IgG and by the spectrum of variable (V) regions contained in the immune globulin preparations. Five predominant and non-exclusive mechanisms of action have been proposed to account for the immunomodulatory effects of IVIG in immune-mediated diseases: (i) functional blockade of Fc receptors on splenic macrophages; (ii) inhibition of complement-mediated damage, an effect that is dependent on the ability of IgG to bind C3b and C4b and thus reduce the number of activated complement fragments that may deposit on target surfaces of complement activation; (iii) modulation of the production of cytokines and cytokine antagonists; (iv) neutralization of circulating autoantibodies by complementary (e.g. anti-idiotypic) antibodies in IVIG, a mechanism that accounts for the rapid decrease in titre of circulating autoantibodies that is often observed within hours following the infusion of IVIG; (v) selection of immune repertoires, a complex set of effects that may be observed in individuals receiving IVIG far beyond the half-life of the infused immunoglobulin and that is directly relevant to the ability of IVIG to, for example, suppress autoantibody-producing clones in patients with antibody-mediated autoimmune disease and modulate graft versus host disease (GVHD). IVIG has been shown to downregulate or activate B-cell clones expressing surface IgG that is complementary (anti-idiotypic) to V regions of antibodies present in IVIG. IVIG has been shown also to interact with surface molecules of T cells that are essential to immune regulation, such as the alpha beta TCR, CD5, CD4, non-polymorphic determinants of MHC class I molecules and adhesion molecules of T and B cells. The complex interactions of IVIG with functional molecules of cells of the immune system are relevant to its therapeutic effects in T cell- as well as B cell-mediated diseases and indeed, to our understanding of the physiological role of normal IgG and antibody networks in controlling autoreactivity in healthy individuals.

Editorial introductions

Editorial introductions

CD44 antibody-mediated amelioration of murine immune thrombocytopenia (ITP): mouse background determines the effect of FcγRIIb genetic disruption.

Several monoclonal antibodies to CD44 can successfully ameliorate murine immune thrombocytopenia (ITP). As these antibodies may be a potential replacement for intravenous immune globulin (IVIG) in the treatment of ITP and other autoimmune diseases, an understanding of their mechanisms of action is important. The role of the inhibitory Fc receptor (FcγRIIb) in the mechanism of action of IVIG and therapeutic CD44 antibodies remains uncertain. To assess if FcγRIIb in splenic macrophages plays a critical role in the action of these two therapeutics, splenectomized mice and mice genetically deficient in FcγRIIb on different backgrounds were evaluated. Thrombocytopenia was induced in FcγRIIb-deficient mice on B6;129S, C57BL/6, and BALB/C backgrounds, as well as splenectomized mice and control mice by platelet (PLT) antibody. PLT counts were enumerated before and after treatment with anti-CD44, red blood cell antibodies, or IVIG. Anti-CD44 is ineffective at inhibiting thrombocytopenia in B6;129S FcγRIIb-deficient mice but, like IVIG, is effective in splenectomized mice and FcγRIIb-deficient mice on the BALB/C and C57BL/6 background. These data suggest that 1) the B6;129S background itself is unlikely to be the sole reason for anti-CD44's inability to function in B6;129S FcγRIIb-deficient mice, 2) the simple loss of macrophage FcγRIIb expression alone is insufficient to explain anti-CD44 ameliorative function, and 3) a combination of mouse background genes in addition to FcγRIIb genetic disruption may affect the ability of anti-CD44 to function therapeutically. Similarities between IVIG and anti-CD44 mechanisms suggest that patients responsive to IVIG may also potentially respond to anti-CD44 treatment.

Use of Intravenous immune globulin in Critically Ill Patients

Intravenous immune globulin (IVIG) preparations have been suggested for many years for the treatment of various conditions. It is apparent, through in vitro and in vivo studies, that IVIG exerts potent anti-inflammatory and immunomodulatory effects. However, the mechanism of action remains mostly unknown. The following article reviews the current literature and summarizes what is known about the mechanism of action of IVIG and the use of IVIG to treat certain conditions. Specifically, the use of IVIG for treatment of critically ill patients is outlined.

Editorial introductions

Editorial introductions

The IgG molecule as a biological immune response modifier: Mechanisms of action of intravenous immune globulin in autoimmune and inflammatory disorders

The IgG molecule as a biological immune response modifier: Mechanisms of action of intravenous immune globulin in autoimmune and inflammatory disorders

Intravenous Immune Globulin: Clinical Applications in the Newborn

Intravenous immune globulin (IVIG) is manufactured from plasma isolated from healthy blood donors and includes mostly immunoglobulin G (IgG). IVIG is approved by the United States Food and Drug Administration (FDA) for use in a variety of diseases in adults and children, although there are no FDA-approved uses of IVIG in newborns. Off-label use of IVIG in newborns includes prophylaxis against infections in low-birthweight infants and treatment of neonatal alloimmune diseases such as hemolytic disease of the newborn (HDN) and neonatal alloimmune thrombocytopenia (NAIT). More recently, IVIG has been used in parvovirus B19 infection, hemochromatosis, and neonatal Kawasaki disease. The mechanism of action of IVIG includes antibody-specific immunity as well as mechanisms triggered via IgG binding to fragment crystallizable (Fc) receptors on phagocytes, natural killer (NK) cells, and reticuloendothelial cells located throughout the body. Adverse effects of IVIG in adults and children are well recognized and include anaphylaxis, thromboembolism, renal failure, and aseptic meningitis. The adverse effects of IVIG in the newborn are less well described but include severe diseases such as necrotizing enterocolitis (NEC). Hence, although IVIG may be indicated as an adjunct for the prevention and treatment of infectious and certain alloimmune-mediated diseases in infants, it should be used with caution in the newborn period.

Improved mouse models for the study of treatment modalities for immune‐mediated platelet destruction

We found when using a mouse model of immune thrombocytopenia (ITP) that platelet (PLT) nadir could not be maintained in the face of daily PLT antibody, making interpretation of treatment modalities difficult. This finding was documented to be at least in part due to increased thrombopoiesis as a result of a compensated thrombocytolytic state. Thus, it was important to develop an improved mouse model of human ITP so as to maintain PLT nadir over time. To maintain PLT nadir, we have developed two mouse models. One model uses single-dose sublethal total body gamma irradiation (TBI) in combination with daily low-dose PLT antibody administration while the second model uses escalation of the dose of PLT antibody over time. Both models maintain PLT nadir and allow for the study of treatment modalities without interference by marrow compensation. Surprisingly, intravenous immune globulin (IVIG) shows no efficacy when using the TBI combination model but works well using the dose-escalation mouse model. In contrast, anti-TER-119 shows efficacy using either mouse model. Our results indicate that the mechanism of action of IVIG requires a functional marrow and/or involves a radiosensitive regulatory cell. However, IVIG works using the dose-escalation model without TBI and the increase in PLT counts correlates directly with reticulated PLTs suggesting that the IVIG mechanism involves effects on megakaryopoiesis/thrombopoiesis. These mouse models should be useful for investigators wishing to maintain PLT nadir over prolonged periods of time for the study of mechanism and efficacy of various treatments for ITP.

TRANSFUSION PRACTICE: sHLA‐I contaminating molecules as novel mechanism of ex vivo/in vitro transcriptional and posttranscriptional modulation of transforming growth factor‐β1 in CD8+ T lymphocytes and neutrophils after intravenous immunoglobulin treatment

BACKGROUND: Numerous mechanisms have been proposed to explain the beneficial action of intravenous immune globulin (IVIG) in autoimmune and systemic inflammatory disorders. Among others' data, an in vitro increase of intracellular TGF‐β expression when culturing CD4+ T lymphocytes in the presence of IVIG has been reported. As IVIG infusion involves administration of soluble contaminants likewise all hemoderivative preparations, we hypothesized that, besides several other immunomodulatory proposed mechanisms, the clinical effects of IVIG therapy might be, at least partly, due to contaminating soluble HLA Class I (sHLA‐I) molecules capable to exert pleiotropic immunomodulatory effects among which TGF‐β1 modulation.STUDY DESIGN AND METHODS: Ex vivo and in vitro transcriptional and posttranscriptional modulation of TGF‐β1 in CD8+ T lymphocytes and neutrophils after IVIG infusion was analyzed.RESULTS: Ex vivo analysis of cells drawn from 10 enrolled IVIG recipients pointed out a significant increase of TGF‐β1 mRNA and intracellular TGF‐β1 molecules in both leukotypes. In vitro comparable results were obtained incubating CD8+ T lymphocytes and neutrophils from healthy donors with IVIG. The immunodepletion of sHLA‐I and/or soluble Fas ligand (sFasL) abolished TGF‐β1 modulation in both leukotypes. Coculture with human immunoglobulin (Ig)M monoclonal antibody or chimeric IgG (MabThera, Roche), whose manufacturing excludes “contamination,” did not exert any mRNA modulation. Finally, IgM or MabThera plus purified sHLA‐I molecules enhanced TGF‐β1 mRNA in both white blood cells to levels comparable to those obtained with IVIG incubation.CONCLUSION: On the whole, these data lead us to speculate that the ability of IVIG administration to modulate TGF‐β1 might be related to the immunomodulatory activities of sHLA‐I and sFasL molecules on activated CD8+ T lymphocytes and neutrophils.

SHLA-I Contamination, A Novel Mechanism to Explain Ex Vivo/In Vitro Modulation of IL-10 Synthesis and Release in CD8+ T Lymphocytes and in Neutrophils Following Intravenous Immunoglobulin Infusion

Numerous mechanisms have been proposed to explain the beneficial action of intravenous immune globulin (IVIG) in autoimmune and systemic inflammatory disorders; among others, they could decrease pro-inflammatory cytokine levels and also induce anti-inflammatory cytokines. Ex vivo analysis of cells from ten IVIG recipients showed significant increase of IL-10 mRNA and intra-cellular IL-10 molecules in both leukotypes. In vitro comparable results were obtained incubating CD8(+) T lymphocytes and neutrophils from healthy donors with IVIG. sHLA-I and/or sFasL immunodepletion abolished IL-10 modulation. Co-culture with contaminant-free IgM or MabThera did not exert any mRNA modulation. Finally, IgM or MabThera plus purified sHLA-I molecules enhanced IL-10-mRNA in both leukotypes to levels comparable to those obtained with IVIG incubation. As IVIG infusion involves administration of soluble contaminants, these data consent to speculate that IVIG might modulate IL-10 via the immunomodulatory activities of sHLA-I contaminant molecules inducing transcriptional and post-transcriptional modulation of IL-10 in CD8(+) T lymphocytes and neutrophils.

IVIG Therapy: Interfering with Interferon-γ

The immunosuppressive mechanism of action of intravenous immune globulin (IVIG) has remained enigmatic despite the many years of clinical experience in the treatment of autoimmunity. In this issue of Immunity, Park-Min et al. demonstrate that IVIG engagement of Fcgamma RIII receptor on monocytes inhibits the cellular response to interferon-gamma.

Intravenous immune globulin therapy for neurologic diseases.

High-dose intravenous immune globulin (IVIg) has emerged as an important therapy for various neurologic diseases. Different interpretations of clinical trial results; the expected benefit of IVIg compared with that of alternate therapies; and issues about IVIg's safety, cost, and mechanisms of action have raised concern and uncertainty among practitioners. To clarify these areas, this paper examines the clinical, serologic, and immunologic data on more than 110 patients with various autoimmune neurologic diseases who received IVIg during the past 6 years at the National Institute of Neurological Disorders and Stroke. It also reviews work by other investigators on the efficacy, risks, benefits, and mechanisms of the action of IVIg in these diseases. In controlled clinical trials, IVIg has been effective in treating the Guillain-Barré syndrome, multifocal motor neuropathy, chronic inflammatory demyelinating polyneuropathy, and dermatomyositis. In other controlled or open-label trials and case reports, IVIg produced improvement in several patients with the Lambert-Eaton myasthenic syndrome and myasthenia gravis but had a variable, mild, or unsubstantiated benefit in some patients with inclusion-body myositis, paraproteinemic IgM demyelinating polyneuropathy, certain intractable childhood epilepsies, polymyositis, multiple sclerosis, optic neuritis, and the stiff-man syndrome. The primary adverse reaction was headache; aseptic meningitis, skin reactions, thromboembolic events, and renal tubular necrosis occurred rarely. The most relevant immunomodulatory actions of IVIg, operating alone or in combination, are inhibition of complement deposition, neutralization of cytokines, modulation of Fc-receptor-mediated phagocytosis, and down-regulation of autoantibody production. Therapy with IVIg is effective for certain autoimmune neurologic diseases, but its spectrum of efficacy has not been fully established. Additional controlled clinical trials are needed.

Treatment of systemic and renal-limited vasculitic disorders with pooled human intravenous immune globulin.

Idiopathic crescentic glomerulonephritis is characterized by an absence of immunohistological evidence of immune deposits, often with evidence of segmental glomerular necrosis. Such pauciimmune crescentic glomerulonephritis is the most common renal manifestation seen in patients with Wegener's granulomatosis, polyarteritis nodosa, and glomerulonephritis associated with other systemic vasculitic disorders (i.e., Churg-Strauss syndrome). Recently, the idiopathic crescentic glomerulonephritides, either in renal-limited form or in association with other systemic vasculitic disorders, were found to have in common a serologic marker, antineutrophil cytoplasmic autoantibodies. These cytoplasmic and perinuclear antineutrophil cytoplasmic autoantibodies are specific for constituents of neutrophil primary granules and monocyte lysosomes. As serologic markers for vasculitic disorders, they are also felt to be directly involved in the pathogenesis of necrotizing vascular injury. In vitro, both perinuclear and cytoplasmic antineutrophil cytoplasmic autoantibodies are capable of causing cytokine-primed neutrophils to undergo degranulation and respiratory burst, releasing toxic oxygen species and lytic enzymes. Anti-idiotype antibodies which inhibit antineutrophil cytoplasmic autoantibodies in vitro, in a V region-dependent manner, are found in pooled human gamma-globulin preparation. Intravenous immune globulin infusions in vivo have produced dramatic improvements in the necrotizing vascular injury produced by antineutrophil cytoplasmic autoantibodies, and a rapid reduction in these autoantibody levels is seen post-intravenous immune globulin infusion in most patients. The proposed mechanisms of action of intravenous immune globulin in vasculitic disorders include Fc-dependent mechanisms, and F(ab')2-dependent mechanisms are likely important. Intravenous immune globulin infusions appear to have an important place in the management of the necrotizing vascular injury. Blinded, randomized, placebo-controlled trials will be necessary to establish definitely intravenous immune globulin as a therapeutic option in vasculitic disorders.

Dimer formation in immunoglobulin preparations and speculations on the mechanism of action of intravenous immune globulin in autoimmune diseases.

IgG dimers occurring in therapeutic Ig preparations have been characterized as Id-anti-Id, in that the sites of interaction are localized to the distal tips of the Fab arms. The observation that such dimers are prevalent in Ig or Igi.v. prepared from large plasma pools, but absent in preparations from a single individual, supports the notion that the individual immune repertoire is small with respect to the species repertoire. A crude mathematical model that attempts to relate Id-dimer content to the number of donors is presented. This model suggests that Id-pairs may be much more prevalent in Ig than is reflected by the Id-dimer content, inasmuch as the concentrations of the individual Ids and anti-Ids may limit the equilibrium level of dimer. The model further suggests that the antibody diversity in Ig derived from thousands of donors may be representative of the species repertoire; hence, virtually all specificities, including anti-Id specificities, will be included. Because Ig is derived from normal healthy donors, it should be relatively free of pathogenic autoantibodies. However, there is no reason to suspect that anti-Ids to such autoantibodies would not occur, and indeed the presence of such anti-Ids has been demonstrated. Several mechanisms have been proposed by which such anti-Ids might ameliorate autoimmune disease. They may directly inhibit the binding of autoantibody to its target antigen, or they may target for destruction those cells expressing or secreting autoantibody. It may well be that anti-Ids play no role in the mechanism of action of Igi.v. in autoimmune disease. Such appears to have been demonstrated, for example, in the treatment of ITP. There is an obvious need for additional studies in order to elucidate the mechanism of action of Igi.v. in various autoimmune diseases. Experimental animal models of autoimmune disease, such as the mouse model for systemic lupus erythematosus (Mozes et al. 1993), might be very useful in this regard. Finally, it needs to be emphasized that the usefulness of high doses of Igi.v. in many autoimmune diseases remains to be established by controlled clinical trials. Because Igi.v. is a limited resource, and one which cannot be produced through biotechnological advances (at least in the foreseeable future), its widespread use should be restricted to the treatment of diseases for which efficacy has been demonstrated. To do otherwise might deprive appropriate patients of a valuable therapy.

The effects of intravenous immune globulin on complement-dependent immune damage of cells and tissues

The mechanism of action of intravenous immune globulin (IVIG) in the therapy of autoimmune disease has been speculated upon for many years. Previous studies have raised the possibility that IVIG acts via an effect on IgG Fc receptors (FcRs) on phagocytic cells and B lymphocytes, on the production of anti-idiotype antibody, or on the control of the immune response. In the course of our studies of complement function we were struck by the fact that complement activation often leads to the binding of complement components to individual immunoglobulin molecules. For example, C3 has been shown to bind to the Fd fragment of IgG in the form of a C3b/IgG one-to-one complex. The C3b/IgG complex has new properties that differ from those of either IgG or C3b alone in that the complex can interact with two receptors on phagocytes: CR1, which recognizes C3b, and FcR, which recognizes the Fc fragment of IgG. Particles opsonized with IgG/C3b interact with both receptors and are phagocytized rapidly. The complex acts as a superopsonin and superlysin. IgG/C3b resists degradation by factors H and I, which also adds to its inflammatory potential. We and others have noted that bacteria coated with immunoglobulin and then incubated in serum have C3 deposited on their surfaces, which in many instances is bound to the IgG molecules. For example, we found that 30% of the C3 deposited on antibody-coated pneumococci is bound not to the pneumococcal surface but rather to the coating immunoglobulin. We reasoned that IVIG may act as a receptor for activated complement components, preventing their attachment to targets. This was tested directly in a number of animal and human models. The results of these tests and their clinical implications are presented.

Future directions of immunoglobulin therapy: Foreword

This is our second symposium on the future directions of immunoglobulin therapy. While the first symposium explored the mechanisms of action of intravenous immune globulin (IVIG) and its use in various clinical disorders, this symposium has taken a new direction in reviewing the potential therapeutic role of monoclonal antibodies in the treatment of malignancy and autoimmune diseases. It has been 16 years since K6hler and Milstein (1) successfully immortalized antibody-producing cells by fusing them with mouse myeloma cells. The ability to generate hybridoma cell lines producing a specific antibody has provided the tools which have had far-reaching implications in many areas of basic and clinical medicine. Dr. Matthew Scharff reviewed the fascinating history of monoclonal antibodies and the current state of hybridoma technology. For years scientists have been looking for the magic bullet for the treatment of malignant disorders. The concept of a specific immunotoxin, an extremely potent poison conjugated to a monoclonal antibody, has initiated a new era in cancer chemotherapy. Recent advances in monoclonal antibody methodologies, recombinant DNA, and gene transfer technologies have enabled scientists to genetically engineer antibody molecules with highly potent toxins. Drs. Ellen