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Concept: Intravenous immunoglobulin


An available supply of intravenous immunoglobulin (IVIG) is essential for individuals with primary humoral immunodeficiency. A shortage in 1997 prompted the Food and Drug Administration (FDA) to revise guidelines for the licensure, production, and distribution of new IVIG products, including the standardization of United States clinical trials regarding endpoints for safety, efficacy, and pharmacokinetics. The following review is intended to present current information and results of clinical trials in patients with primary immunodeficiency treated with IVIG products currently licensed or awaiting licensure in the United States. The data presented are compiled from published clinical trials and prescribing information generated by manufacturers.

Concepts: Pharmaceutical industry, Food and Drug Administration, Pharmacology, X-linked agammaglobulinemia, United States, Antibody, Intravenous immunoglobulin, Immune system


Immune globulins for IgG supplementation have been produced for over 35 years with essentially no differentiating features regarding their specific antibody composition. Furthermore, the compositions of plasma donor pools used for IG manufacturing are not standardized. While all immune globulin products meet the specifications set by the US FDA for antibodies to pathogens like measles and polio, they have variable levels of antibodies to other important viruses and infectious pathogens, particularly respiratory syncytial virus (RSV).

Concepts: Gamma globulin, Infectious disease, Immunology, Intravenous immunoglobulin, Bacteria, Human respiratory syncytial virus, Antibody, Immune system


Amyloid-reactive IgGs isolated from pooled blood of normal individuals (pAbs) have demonstrated clinical utility for amyloid diseases by in vivo targeting and clearing amyloidogenic proteins and peptides. We now report the following three novel findings on pAb conformer’s binding to amyloidogenic aggregates: 1) pAb aggregates have greater activity than monomers (HMW species > dimers > monomers), 2) pAbs interactions with amyloidogenic aggregates at least partially involves unconventional (non-CDR) interactions of F(ab) regions, and 3) pAb’s activity can be easily modulated by trace aggregates generated during sample processing. Specifically, we show that HMW aggregates and dimeric pAbs present in commercial preparations of pAbs, intravenous immunoglobulin (IVIg), had up to ~200- and ~7-fold stronger binding to aggregates of Aβ and transthyretin (TTR) than the monomeric antibody. Notably, HMW aggregates were primarily responsible for the enhanced anti-amyloid activities of Aβ- and Cibacron blue-isolated IVIg IgGs. Human pAb conformer’s binding to amyloidogenic aggregates was retained in normal human sera, and mimicked by murine pAbs isolated from normal pooled plasmas. An unconventional (non-CDR) component to pAb’s activity was indicated from control human mAbs, generated against non-amyloid targets, binding to aggregated Aβ and TTR. Similar to pAbs, HMW and dimeric mAb conformers bound stronger than their monomeric forms to amyloidogenic aggregates. However, mAbs had lower maximum binding signals, indicating that pAbs were required to saturate a diverse collection of binding sites. Taken together, our findings strongly support further investigations on the physiological function and clinical utility of the inherent anti-amyloid activities of monomeric but not aggregated IgGs.

Concepts: Glycoproteins, Intravenous immunoglobulin, Protein, Amyloid, Monomer, Dimer, Immune system, Antibody


Kawasaki disease (KD) is the most common pediatric vasculitis. The study aimed to identify the risk factors of intravenous immunoglobulin (IVIG) unresponsiveness from the initial clinical parameters of the Taiwanese KD patients.

Concepts: Vasculitis, X-linked agammaglobulinemia, Wegener's granulomatosis, Immune system, Antibody, Intravenous immunoglobulin, Kawasaki disease


Glossopharyngeal and/or vagus nerve involvement is infrequent in patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). We herein report the case of a 69-year-old Japanese woman who presented with muscle weakness and numbness of the extremities with dysphagia. The serum anti-ganglioside GM1 immunoglobulin IgM antibody levels were elevated, and treatment with intravenous immunoglobulin (IVIg) resulted in a dramatic improvement; the weakness, numbness and dysphagia all resolved. However, relapse comprising dysphagia alone occurred on hospital day 26, and treatment with IVIg again proved extremely effective. IVIg therapy can be effective against cranial nerve involvement in cases of CIDP.

Concepts: Accessory nerve, Nucleus ambiguus, Myelin, Antibody, Chronic inflammatory demyelinating polyneuropathy, Immune system, Intravenous immunoglobulin, Cranial nerves


Severe influenza remains unusual in its virulence for humans. Complications or ultimately death arising from these infections are often associated with hyperinduction of proinflammatory cytokine production, which is also known as ‘cytokine storm’. For this disease, it has been proposed that immunomodulatory therapy may improve the outcome, with or without the combination of antiviral agents. Here, we review the current literature on how various effectors of the immune system initiate the cytokine storm and exacerbate pathological damage in hosts. We also review some of the current immunomodulatory strategies for the treatment of cytokine storms in severe influenza, including corticosteroids, peroxisome proliferator-activated receptor agonists, sphingosine-1-phosphate receptor 1 agonists, cyclooxygenase-2 inhibitors, antioxidants, anti-tumour-necrosis factor therapy, intravenous immunoglobulin therapy, statins, arbidol, herbs, and other potential therapeutic strategies.Cellular & Molecular Immunology advance online publication, 20 July 2015; doi:10.1038/cmi.2015.74.

Concepts: Humoral immunity, Inflammation, Immunity, Infectious disease, Intravenous immunoglobulin, Immunology, Antibody, Immune system


Intravenous immunoglobulin (IVIG) preparations comprise pooled IgG antibodies from the serum of thousands of donors and were initially used as an IgG replacement therapy in immunocompromised patients. Since the discovery, more than 30 years ago, that IVIG therapy can ameliorate immune thrombocytopenia, the use of IVIG preparations has been extended to a wide range of autoimmune and inflammatory diseases. Despite the broad efficacy of IVIG therapy, its modes of action remain unclear. In this Review, we cover the recent insights into the molecular and cellular pathways that are involved in IVIG-mediated immunosuppression, with a particular focus on IVIG as a therapy for IgG-dependent autoimmune diseases.

Concepts: Antigen, Immunosuppressive drug, Immunity, Humoral immunity, Antibody, Immunology, Intravenous immunoglobulin, Immune system


BACKGROUND: Rituximab has altered the treatment approach to B-cell malignancies and other diseases. Reports consider that rituximab had limited impact on serum immunoglobulins. However, anecdotes suggest that rituximab can cause symptomatic hypogammaglobulinemia. This retrospective study examined the relationship among rituximab, hypogammaglobulinemia, and treatment of symptomatic hypogammaglobulinemia with intravenous immune globulin (IVIG). METHODS: Patients with serial quantitative serum immunoglobulin (SIgG) concentrations before and subsequent to rituximab administration at Memorial Sloan-Kettering Cancer Center were identified. Information regarding rituximab administration, SIgG concentrations, frequency of infection, and administration of IVIG were recorded. RESULTS: Between December 1998 and April 2009, 211 patients with B-cell lymphoma treated with rituximab and with serial SIgG concentrations were identified. One hundred seventy-nine (85%) patients had normal SIgG before rituximab, 32 (15%) had low SIgG. After rituximab use, hypogammaglobulinemia was identified in 38.54% of patients with initially normal SIgG. The risk was greater in patients who received maintenance rituximab. Symptomatic hypogammaglobulinemia that prompted IVIG administration developed in 6.6% of patients. CONCLUSIONS: In this data set, rituximab administration was associated with a high frequency of hypogammaglobulinemia, particularly symptomatic hypogammaglobulinemia, among patients who received multiple courses of rituximab. Baseline and periodic monitoring of SIgGs is appropriate in patients who receive rituximab.

Concepts: Immunity, Lymphoma, Humoral immunity, Gamma globulin, X-linked agammaglobulinemia, Antibody, Immune system, Intravenous immunoglobulin


OBJECTIVE: To investigate changes in the T-cell repertoire in patients with chronic inflammatory demyelinating polyneuropathy (CIDP) without and with treatment of IV immunoglobulins (IVIg). METHODS: The T-cell receptor (TCR) repertoire of CD4+ and CD8+ T cells in the peripheral blood was analyzed using CDR3 spectratyping. Patients with CIDP were included without (n = 14) and with IVIg treatment (n = 11) cross-sectionally and longitudinally (n = 2). RESULTS: While the TCR length distribution of patients with CIDP was only moderately altered for most of the Vβ elements of CD4+ T cells, the CD8+ population displayed extensive oligoclonal expansions in all analyzed 24 Vβ elements. A public expansion of a distinct TCR length in one Vβ element within a majority of affected patients was not detectable. Treatment with IVIg reduced the oligoclonal expansions within both the CD4+ and CD8+ population. CONCLUSIONS: Our data demonstrate that cytotoxic CD8+ T cells exhibit a much broader activation than CD4+ T cells, indicating a potentially crucial role of CD8+ T cells in the immunopathogenesis of CIDP. The profound oligoclonal response in T-cell activation suggests that multiple peptides may induce and propagate this autoimmune-driven disease. The observed reduction of highly activated T cells may contribute to the therapeutic effects of IVIg.

Concepts: Immune system, Myelin, Intravenous immunoglobulin, Protein, Natural killer cell, T cell, T cell receptor, Chronic inflammatory demyelinating polyneuropathy


A recognized paradigm for the therapeutic action of intravenous immunoglobulin (IVIG) in immune thrombocytopenia (ITP) involves up-regulation of the inhibitory Fcγ receptor (FcγRIIB) in splenic macrophages. However, published data have indicated that opposing results are obtained when using FcγRIIB-deficient mice on different strain backgrounds. Herein we show BALB/c FcγRIIB(-/-) and wild-type, with or without spleens, all recover ITP with similar dynamics after IVIG (1 g/kg) treatment; however, this was not the case for C57BL/6 (B6) FcγRIIB(-/-). In investigating this conundrum, we found that wild-type B6 mice are much less sensitive than BALB/c to IVIG-mediated amelioration of ITP, requiring approximately 2- to 2.5-fold more IVIG than BALB/c. When using 2.5 g/kg IVIG in FcγRIIB(-/-) B6 mice, amelioration of ITP was as in wild-type in all animals. Our findings led us to the conclusion that different strains of mice respond differently to IVIG and that FcγRIIB plays no role in the mechanism of effect of IVIG in experimental ITP.

Concepts: X-linked agammaglobulinemia, Platelet, White blood cell, Spleen, Antibody, Intravenous immunoglobulin, Idiopathic thrombocytopenic purpura, Immune system