Effect Of Intravenous Immunoglobulin Research Articles

Will sialylation change intravenous immunoglobulin therapy in the future?

Will sialylation change intravenous immunoglobulin therapy in the future?

7thInternational Immunoglobulin Conference: Mechanisms of Action

Although intravenous immunoglobulin (IVIg) is widely used for replacement therapy in immunodeficiencies and to treat autoimmune and inflammatory diseases, its mechanisms of action are not fully understood. Examination of immunoglobulin (Ig) receptors, including the Fc-gamma receptors (FCγRs) and the neonatal Fc receptor, have revealed genetic variations that are linked to autoimmune diseases and to the efficacy of IVIg treatment. However, the beneficial effect of IVIg encompasses multiple mechanisms of action. One of these is scavenging of activated complement fragments, such as C3a, C5a, C3b and C4b, by infused Ig molecules. This interaction prevents binding of complement fragments to their receptors on target cells, thus attenuating the immune damage. Additionally, anti-inflammatory effects may be facilitated by IgA via specific receptors and/or complement scavenging. Glycosylation of both the Fc- and Fab-fragments has also been implicated in the anti-inflammatory action of IVIg. Although there is evidence to support a role for sialylated IgG glycovariants in mediating the effect of IVIg, evidence from animal models of inflammatory disease suggest that sialylation may not be a critical factor. However, an increase in IgG glycosylation has been observed following IVIg treatment in Guillain-Barré syndrome patients, and this has been associated with improved clinical outcomes.

Intravenous immunoglobulin G in the treatment of autoimmune bullous disease.

Intravenous immunoglobulin G in the treatment of autoimmune bullous disease.

Fc-dependent mechanisms of action: roles of FcγR and FcRn.

Fc-dependent mechanisms of action: roles of FcγR and FcRn.

Aβ anti-idiotypic antibodies are present in intravenous immunoglobulin and are produced in mice following its administration

The effects of intravenous immunoglobulin (IVIG) products were recently examined in patients with Alzheimer’s disease (AD). Although encouraging results were obtained in pilot studies, later trials produced negative results. The rationale for these studies was that IVIG contains antibodies to amyloid-beta (Aβ). However, if Aβ anti-idiotypic antibodies (antibodies which bind to anti-Aβ antibodies) are present in IVIG or induced by its administration, these antibodies could potentially reduce its neuroprotective effects in AD. The objective of this study was to determine if IVIG contained such antibodies. Enzyme-linked immunosorbent assays (ELISAs) measured specific binding of IVIG Gamunex to purified human anti-Aβ IgG. The mean concentration of its Aβ anti-idiotypic antibodies in four experiments was 1.85 μg/mL (18.5 μg/g IgG; range = 1.82–1.89 μg/mL [18.2–18.9 μg/g IgG]), and their mean percentage of specific binding was 72.2% (range = 68.3–75.3%). We then performed ELISAs to determine if antibodies to purified human anti-Aβ were produced in C57BL/6 mice injected with the IVIG product Gammagard in an earlier study. After subtracting the expected immune response to normal human immunoglobulins, the median concentrations of these antibodies were 15.6 ng/mL (range = 1.2–108.2 ng/mL) in pre-treatment sera and 2419.4 ng/mL (range = 327.4–8478.4 ng/mL) in post-treatment sera. These results indicate that specific Aβ anti-idiotypic antibodies are detectable in IVIG and may be induced in mice by its administration. The presence of Aβ anti-idiotypic antibodies in IVIG products might decrease neuroprotective effects of their anti-Aβ antibodies in AD.

Mycoplasma-associated Stevens-Johnson syndrome in children: retrospective review of patients managed with or without intravenous immunoglobulin, systemic corticosteroids, or a combination of therapies.

Administration of intravenous immunoglobulin (IVIG) to patients with Stevens-Johnson syndrome (SJS) has been controversial. The objective of this study was to evaluate the effectiveness of IVIG, systemic corticosteroids, or both in treating Mycoplasma pneumoniae-associated SJS (mpSJS). Retrospective series of 10 pediatric mpSJS cases were stratified into four treatment groups: IVIG alone, IVIG and systemic corticosteroids together, systemic corticosteroids alone, and supportive care. The efficacy of therapy was evaluated on the basis of several proxies of disease severity, including hospital length of stay (LOSt ) and number of febrile days (Febt ) after initiation of therapy. Patients treated with IVIG alone had a longer LOSt and more Febt , despite different baseline characteristics, than patients treated with supportive therapy. Of patients who received IVIG, 50% were treated with corticosteroids concurrently and had similar characteristics of disease severity but showed a non-statistically significant trend toward shorter LOSt and fewer Febt than those who received IVIG alone. A patient treated with corticosteroids alone had the shortest LOSt in this series. Therefore treatment with IVIG alone was associated with a more severe disease course than supportive therapy, although causality cannot be inferred given possible confounding by indication. When systemic corticosteroids were used alone or in conjunction with IVIG, hospital LOSt and Febt trended lower than with the use of IVIG alone, although disease severity at baseline was similar between those treated with IVIG and corticosteroids concurrently and those treated with IVIG alone. It was thus concluded that treatment with systemic corticosteroids as monotherapy or in combination with IVIG may be preferable to IVIG alone. Further large-scale studies are warranted to evaluate this hypothesis.

Is intravenous immunoglobulin effective in toxic epidermal necrolysis and Stevens-Johnson syndrome?

Toxic epidermal necrolysis and Stevens-Johnson syndrome are severe cutaneous adverse drug reactions. Intravenous immunoglobulin is described as a therapeutic option, however its use is still controversial. Using Epistemonikos database, which is maintained by screening over 20 databases, we identified six systematic reviews, including 39 primary studies. We combined the evidence using tables for summary of findings, following the GRADE approach, and concluded there is uncertainty about the effects of intravenous immunoglobulin because the certainty of the evidence is very low; it probably leads to important adverse effects; and has high cost. Intravenous immunoglobulin should not be used outside the context of a clinical trial, or only in cases where other treatments have failed and there are no resource constraints.

Nimesulide induced Stevens Johnson syndrome (SJS); managed successfully with combined approach of steroids, intravenous immunoglobulin and placentrex gel: A case report

There is a high mortality rate in Stevens Johnson Syndrome (SJS) and it ranges between 5%-15%. At present, there is no definite consensus regarding treatment in SJS although the effectiveness of intravenous immunoglobulin’s (IVIg) and immunosuppressive like cyclosporine have generated new hopes in the lives of these patients. But the options of combination therapy of steroids, IVIg and Placentrex gel have not been fully exercised in SJS. Henceforth, we report a case of Nimesulide induced SJS; managed successfully with a combined approach without any recurrence during a 12 months follow-up.

Effect of intravenous immunoglobulins on natural killer cells

Effect of intravenous immunoglobulins on natural killer cells

Intravenous Immunoglobulin in the Therapeutic Armamentarium of Systemic Lupus Erythematosus

Prepared from the plasma of thousands of blood donors, therapeutic intravenous immunoglobulin (IVIg) mostly consists of human polyspecific immunoglobulin G (IgG). The use of IVIg in systemic lupus erythematosus (SLE) is still considered experimental without any clear indications.The purpose of this systematic review is, therefore, to evaluate the available evidence to determine the therapeutic role of IVIg in SLE.A comprehensive, computerised search was performed in the MEDLINE (Pubmed), Scopus, EMBASE, and Cochrane controlled trials.The study eligibility criteria were randomized controlled trials, and prospective and retrospective observational studies that examined the efficacy of IVIg in adult patients with SLE who were considered the participants.IVIg therapy was the mode of intervention in these patients.Data abstracted included the study design, study population, changes in the disease activity scores (Systemic Lupus Erythematosus Disease Activity Index, Systemic Lupus Activity Measure, and Lupus Activity Index-Pregnancy), steroid dose, complement levels, autoantibodies, and renal function. Thereafter, data analysis established statistical procedures for meta-analysis.Thirteen studies (including 3 controlled and 10 observational) were eligible for inclusion. There was significant reduction in the SLE disease activity scores with IVIg therapy with a standard mean difference of 0.584 (P = 0.002, 95% confidence interval [CI] 0.221–0.947). In terms of rise in complement levels, the response rate was 30.9% (P = 0.001, 95 CI 22.1–41.3). The effects of IVIg on other clinical outcome measures including anti-double-stranded DNA, antinuclear antibody, average steroid dose, and renal function could not be determined because of the limited numbers of trials.The limitations of this review were lack of well-designed controlled trials with adequate sample size on the use of IVIg in SLE.In conclusion, the use of IVIg is associated with significant reduction in SLE disease activity and improvement in complement levels.

Intravenous immunoglobulins for Alzheimer's disease.

Alzheimer's disease (AD) is a chronic neurodegenerative disease associated with intracerebral accumulation of aggregated amyloid-beta (Aβ) and tau proteins, as well as neuroinflammation. Human intravenous immunoglobulin (IVIG) is a mixture of polyclonal IgG antibodies isolated and pooled from thousands of healthy human donors. The scientific rationale for testing IVIG as a potential AD treatment include its natural anti-Aβ antibody activity, its favorable safety profile and inherent anti-inflammatory/immunomodulatory properties. Over the past decade, several clinical and pre-clinical experimental findings, advanced our knowledge about biological and therapeutic properties of IVIG that are relevant to AD therapy. Anti-amyloid antibodies in IVIG show significantly higher binding avidity for amyloid oligomers and fibrils than for Aβ monomers. In a double transgenic murine model of AD, intracerebral injection of IVIG causes suppression of Aβ fibril pathology whereas long term peripheral IVIG treatments causes elevation of total brain Aβ levels with no measurable impact on Aβ deposits or tendency for inducing cerebral microhemmorhage. Furthermore, chronic IVIG treatment suppressed neuroinflammation and fostered adult hippocampal neurogenesis. In clinical studies with AD patients, IVIG showed an acceptable safety profile and has not been reported to increase the incidence of amyloid related imaging abnormalities. Preliminary studies on small number of patients reported clinical benefits in mild to moderate stage AD patients. However, double blind, placebo controlled studies later did not replicate those initial findings. Interestingly though, in APOE4 carriers and in moderate disease stage subgroups, positive cognitive signals were reported. Nevertheless, both clinical and experimental (mouse) studies show that antibodies in IVIG can accumulate in CNS and its biological activities include neutralization of Aβ oligomers, suppression of neuroinflammation and immunomodulation. Identifying mediators of IVIG's effects at the cellular and molecular level is warranted. In light of its favourable safety profile and aforementioned biological properties, IVIG is still an enigmatic experimental candidate with enormous potential for being an AD therapeutic.

Intravenous immunoglobulin treatment preserves and protects primary rat hippocampal neurons and primary human brain cultures against oxidative insults.

Alzheimer's disease (AD) is characterized by deleterious accumulation of amyloid-β (Aβ) peptide into senile plaque, neurofibrillary tangles formed from hyperphosphorylated tau protein, and loss of cholinergic synapses in the cerebral cortex. The deposition of Aβ-loaded plaques results in microglial activation and subsequent production of reactive oxygen species (ROS), including free radicals. Neurons in aging and AD brains are particularly vulnerable to ROS and other toxic stimuli. Therefore, agents that decrease the vulnerability of neurons against ROS may provide therapeutic values for the treatment or prevention of AD. In the present study, our goal was to test whether intravenous immunoglobulin (IVIG) treatment could preserve as well as protect neurons from oxidative damage. We report that treatment with IVIG protects neuronal viability and synaptic proteins in primary rat hippocampal neurons. Further, we demonstrate the tolerability of IVIG treatment in the primary human fetal mixed brain cultures. Indeed, a high dose (20 mg/ml) of IVIG treatment was well-tolerated by primary human brain cultures that exhibit a normal neuronal phenotype. We also observed a potent neuropreservatory effect of IVIG against ROS-mediated oxidative insults in these human fetal brain cultures. These results indicate that IVIG treatment has great potential to preserve and protect primary human neuronal-enriched cultures and to potentially rescue dying neurons from oxidative insults. Therefore, our findings suggest that IVIG treatment may represent an important therapeutic agent for clinical trials designed to prevent and delay the onset of neurodegeneration as well as AD pathology.

Optimal attenuation of experimental autoimmune encephalomyelitis by intravenous immunoglobulin requires an intact interleukin-11 receptor.

BackgroundIntravenous immunoglobulin (IVIg) has been used to treat a variety of autoimmune disorders including multiple sclerosis (MS); however its mechanism of action remains elusive. Recent work has shown that interleukin-11 (IL-11) mRNAs are upregulated by IVIg in MS patient T cells. Both IVIg and IL-11 have been shown to ameliorate experimental autoimmune encephalomyelitis (EAE), an animal model of MS. The objective of this study was to determine whether the protective effects of IVIg in EAE occur through an IL-11 and IL-11 receptor (IL-11R)-dependent mechanism.MethodsWe measured IL-11 in the circulation of mice and IL-11 mRNA expression in various organs after IVIg treatment. We then followed with EAE studies to test the efficacy of IVIg in wild-type (WT) mice and in mice deficient for the IL-11 receptor (IL-11Rα−/−). Furthermore, we evaluated myelin-specific Th1 and Th17 responses and assessed spinal cord inflammation and demyelination in WT and IL-11Rα−/− mice, with and without IVIg treatment. We also examined the direct effects of mouse recombinant IL-11 on the production of IL-17 by lymph node mononuclear cells.ResultsIVIg treatment induced a dramatic surge (>1000-fold increase) in the levels of IL-11 in the circulation and a prominent increase of IL-11 mRNA expression in the liver. Furthermore, we found that IL-11Rα−/− mice, unlike WT mice, although initially protected, were resistant to full protection by IVIg during EAE and developed disease with a similar incidence and severity as control-treated IL-11Rα−/− mice, despite initially showing protection. We observed that Th17 cytokine production by myelin-reactive T cells in the draining lymph nodes was unaffected by IVIg in IL-11Rα−/− mice, yet was downregulated in WT mice. Finally, IL-11 was shown to directly inhibit IL-17 production of lymph node cells in culture.ConclusionThese results implicate IL-11 as an important immune effector of IVIg in the prevention of Th17-mediated autoimmune inflammation during EAE.

Intravenous immunoglobulin-induced IL-33 is insufficient to mediate basophil expansion in autoimmune patients.

Intravenous immunoglobulin (IVIg) is used in the therapy of various autoimmune and inflammatory diseases. Recent studies in experimental models propose that anti-inflammatory effects of IVIg are mainly mediated by α2,6-sialylated Fc fragments. These reports further suggest that α2,6-sialylated Fc fragments interact with DC-SIGN+ cells to release IL-33 that subsequently expands IL-4-producing basophils. However, translational insights on these observations are lacking. Here we show that IVIg therapy in rheumatic patients leads to significant raise in plasma IL-33. However, IL-33 was not contributed by human DC-SIGN+ dendritic cells and splenocytes. As IL-33 has been shown to expand basophils, we analyzed the proportion of circulating basophils in these patients following IVIg therapy. In contrast to mice data, IVIg therapy led to basophil expansion only in two patients who also showed increased plasma levels of IL-33. Importantly, the fold-changes in IL-33 and basophils were not correlated and we could hardly detect IL-4 in the plasma following IVIg therapy. Thus, our results indicate that IVIg-induced IL-33 is insufficient to mediate basophil expansion in autoimmune patients. Hence, IL-33 and basophil-mediated anti-inflammatory mechanism proposed for IVIg might not be pertinent in humans.

Intravenous Immunoglobulin Attenuates Experimental Autoimmune Arthritis by Inducing Reciprocal Regulation of Th17 and Treg Cells in an Interleukin‐10–Dependent Manner

Intravenous immunoglobulin (IVIG) is used as a therapeutic agent in various autoimmune diseases. The aims of this study were to investigate the therapeutic effects of IVIG on collagen-induced arthritis (CIA) and identify the mechanism responsible for any therapeutic effects. IVIG was administered to mice with CIA, and the in vivo effects were determined. Th17 and Treg cell frequencies were analyzed by flow cytometry, and cytokine levels in the supernatant were measured by enzyme-linked immunosorbent assay. Subpopulations of T cells and B cells in the spleen were assessed by confocal microscopy. The arthritis severity score and incidence of arthritis were lower in mice treated with IVIG compared with untreated mice. Histopathologic analysis showed less joint damage in mice treated with IVIG. The expression of proinflammatory cytokines, specific type II collagen antibodies, and osteoclast markers was significantly reduced in mice treated with IVIG. Administration of IVIG induced increased FoxP3 expression and inhibited Th17 cell development. The number of FoxP3+ Treg cells was increased, and the number of Th17 cells was decreased in the spleens of mice treated with IVIG. The number of FoxP3+ follicular helper T cells was increased, and subsequent maturation of germinal center B cells was inhibited by IVIG. In addition, IVIG up-regulated interleukin-10 (IL-10) and Fcγ receptor IIB expression. The treatment effects of IVIG on arthritis were lost in IL-10-knockout mice. These results showed that IVIG has therapeutic effects by modulating CD4+ T cell differentiation. The therapeutic effects of IVIG are dependent on IL-10.

Intravenous immunoglobulin (IVIg) provides protection against endothelial cell dysfunction and death in ischemic stroke.

BackgroundThe brain endothelium is a key component of the blood brain barrier which is compromised following ischemia, allowing infiltration of damaging immune cells and other inflammatory molecules into the brain. Intravenous immunoglobulin (IVIg) is known to reduce infarct size in a mouse model of experimental stroke.FindingsFlow cytometry analysis showed that the protective effect of IVIg in ischemia and reperfusion injury in vivo is associated with reduced leukocyte infiltration, suggesting an involvement of the endothelium. In an in vitro model of ischemia, permeability analysis of the mouse brain endothelial cell line bEnd.3 revealed that IVIg prevented the loss of permeability caused by oxygen and glucose deprivation (OGD). In addition, western blot analysis of these brain endothelial cells showed that IVIg prevented the down-regulation of tight junction proteins claudin 5 and occludin and the decline in anti-apoptotic proteins Bcl-2 and Bcl-XL caused by OGD.ConclusionIVIg protects endothelial cells from ischemic insult. These studies support the use of IVIg as a pharmacological intervention for stroke therapy.

Specific binding of intravenous immunoglobulin products to tau peptide fragments.

The effects of intravenous immunoglobulin (IVIG) products are being evaluated in Alzheimer's disease (AD) patients. IVIG contains antibodies to tau protein, the main constituent of neurofibrillary tangles (NFTs). Tau has microtubule binding domain (MBD) repeats which are thought to be necessary for its aggregation, a key process in NFT formation. Tau's N-terminal region may also contribute to its aggregation and to the neurotoxicity of its soluble oligomers. This study examined the specific binding of IVIG products Gammagard, Gamunex, and Flebogamma to a tau N-terminal fragment (tau 45-73), tau's four MBD repeat sequences (tau 244-274, 275-305, 306-336, and 337-368), and a tau C-terminal fragment (tau 422-441). Mean antibody levels to tau 45-73 and tau 422-441 were significantly higher in Gamunex than in Gammagard and Flebogamma, while there were no significant differences between IVIG products for antibody concentrations to the MBD repeat sequences. Patterns of binding to tau fragments differed between IVIG products. Gammagard's highest binding was to tau 275-305 and tau 306-336 while Gamunex bound preferentially to tau 45-73 and tau 422-441. Flebogamma's binding to tau 275-305 and tau 306-336 was greater than to tau 337-368, and its binding to tau 306-336 was also higher than to tau 422-441. These findings indicate that IVIG products vary with respect to their binding to different regions of tau. This could result in differences with regard to their ability to prevent tau's aggregation and/or tau soluble oligomer neurotoxicity.

Induction of PD-L1 on monocytes: A new mechanism by which IVIg inhibits mixed lymphocyte reactions

Allograft rejection and graft-versus-host disease (GvHD) are frequent complications following solid organ or stem cell transplantation in which T cell activation plays a central role. Despite the development of new immunosuppressive drugs that improve the success rate of transplantation, allograft survival continues to be a challenge. Recently, intravenous immunoglobulin (IVIg) has been proposed as prophylaxis and post-transplant treatment to reduce acute rejection episodes. IVIg is a therapeutic agent that is known to down-modulate T cell functions in patients with autoimmune disorders. To test the hypothesis that this immunomodulatory effect could be beneficial in the context of transplantation, we used mixed lymphocyte reactions (MLR) as an in vitro model of allograft rejection and GvHD. Our results show that IVIg strongly inhibits the MLR as evaluated by IL-2 secretion, a well-known marker of T cell activation. IVIg also modulates the secretion of other pro-(IL-6, IFN-γ) and anti-inflammatory (IL-1RA) cytokines. More importantly, we show that IVIg induces monocytes with a CD80low PD-L1high phenotype and that blockade of PD-L1 partially abrogates the inhibitory effect of IVIg. We have thus identified a new mechanism by which IVIg inhibits T cell functions in the context of transplantation, supporting the potential usefulness of IVIg in the prevention or treatment of graft rejection and GvHD.

Sialylation may be dispensable for reciprocal modulation of helper T cells by intravenous immunoglobulin

Several mechanisms account for the beneficial effect of intravenous immunoglobulin (IVIg) in autoimmune and inflammatory diseases. These mechanisms include effects on the cellular compartment and on the humoral compartment. Thus, IVIg impacts on dendritic cells, macrophages, neutrophils, basophils, NK cells, and B and T lymphocytes. Several studies have emphasized that the antiinflammatory effect of IVIg is dependent on α2,6-sialylation of the N-linked glycan on asparagine-297 of the Fc portion of IgG. However, recent reports have questioned the necessity of sialylated Fc and the role of FcγRIIB in IVIg-mediated antiinflammatory effects. In view of the critical role played by Th17 cells in several autoimmune pathologies and the increasing use of IVIg in several of these conditions, by using neuraminidase-treated, desialylated IVIg, we addressed whether the α2,6-sialylation of IgG is essential for the beneficial effect of IVIg in experimental autoimmune encephalomyelitis (EAE), a Th17-driven condition, and for the reciprocal modulation of helper T-cell subsets. We observed no difference in the ability of IVIg to ameliorate EAE irrespective of its sialylation. Our findings thus show that sialylation of IVIg is not necessary for IVIg-mediated amelioration of EAE or for downregulation of Th17 cells and upregulation of regulatory T cells.

Tregitope-mediated antigen-specific tolerance induction in autoimmune and allergic disease in vivo. (THER5P.831)

Abstract Tregitopes are a novel class of therapeutic compounds that harness the activity of regulatory T cells (Tregs) and represent a promising new approach for the treatment of autoimmune and inflammatory diseases. Tregitopes are Treg epitopes found in IgG that provide beneficial immunomodulatory effects, paralleling those attributed to intravenous immunoglobulin (IVIG), in vitro and in vivo. When APCs present Tregitopes to Tregs, APC expression of MHC II, CD80, and CD86 are decreased; expression of the tolerance-associated marker ILT3 is increased. These results are consistent with reported effects of IVIG (Bayry et al. Blood, 2003, 101:758) and the IgG-derived peptide hCDR1 (Sela et al. Immunology, 2009, 128:395). Tregitopes also cause CD4+CD25+FoxP3+ Treg to expand and produce IL-10 in vitro. Evaluation of Tregitope effects in mouse models of MS (EAE), OVA-induced allergic airway disease, and AAV-mediated gene transfer show that effector T cells are modified in the presence of Tregitopes. In OVA-induced allergic airway disease, we observed significant and reproducible expansion of Tregs in conjunction with decreased airway reactivity comparable to, if not greater than, IVIG. We have additional unpublished evidence demonstrating the antigen specificity of tolerance induction using Tregitopes in conjunction with target antigens. Formulated with or without the target antigen, Tregitopes represent a promising new treatment for human immune-mediated disease.