Administration Of IgG Research Articles

From immune substitution to immunomodulation

Intravenous immunoglobulins (IVIGs) are currently used in many fields of medicine for replacement and immunomodulation. This review focuses on the milestones in the history of human immunoglobulins since the initial observation by Ogden C. Bruton who described replacement therapy in a boy with agammaglobulinemia. Since then, the preparations used for treatment have been markedly improved with respect to tolerability, clinical efficacy, and pathogen safety. Preparations and appropriate pumps for subcutaneous administration of IgG have been developed and offer an alternative mode of treatment for immunodeficient patients. Appropriate replacement today allows patients with humoral immunodeficiencies to reach adulthood and normal or near-normal quality of life. In 1981 a second fundamental discovery was made. Paul Imbach and coauthors in children with idiopathic thrombocytopenic purpura (ITP) showed that IVIG has immunomodulatory potential, offering a chance for affected children to receive effective treatment with little or no side effects compared to systemic corticosteroids. This new principle of treatment encouraged many researchers worldwide to exploit the potential of IVIG in many other immunopathological situations. As an example, Rhesus hemolytic disease in newborn babies is discussed.

Clinical and Serologic Response to the 23-valent Polysaccharide Pneumococcal Vaccine in Children and Teens with Recurrent Upper Respiratory Tract Infections and Selective Antibody Deficiency.

We report the clinical and serological response of 72 children and adolescents after immunization with the 23-valent polysaccharide pneumococcal vaccine (PPV23). All had been diagnosed with recurrent upper respiratory tract infections and low antipneumococcal immunity. Forty-five (62%) of these patients had received PCV7, the 7-serotype pneumococcal conjugated vaccine (Prevnar7). After immunization with the polysaccharide vaccine, 69 (96%) patients, including 42 of the 45 who had previously been immunized with the conjugate vaccine, had a positive clinical response including 12 patients (17%) whose serological response to the polysaccharide vaccine was inadequate. Clinical and serological response to PPV23 was assessed at approximately 1, 3 and 6 months after immunization. Our study also confirmed that a small group of patients with recurrent upper respiratory tract infections are unable to develop a normal response to pneumococcal and other bacterial polysaccharides despite vaccination with the newer conjugated vaccines. This immunodeficiency has been named selective antibody deficiency with normal immunoglobulins or impaired polysaccharide responsiveness. These patients did well after administration of intravenous IgG.

Quantitative Investigation on Correlation Between IgG and FcRn During Gestation and Lactating Periods in Rat.

IgG is transformed from maternal serum into the offspring as passive immunization by FcRn expressed in placenta and/or infant intestine. This study aimed to investigate the quantitative correlation between IgG and FcRn during gestation and lactating periods in rat. ELISA was performed to determine the variation of maternal and offspring IgG. Western blot and RT-qPCR were carried out to characterize FcRn expression in placenta and infant intestine. Maternal serum IgG appeared higher in first 2 weeks of lactation. The embryo IgG was in accordance with the FcRn expression in placenta. During the post-natal, the serum IgG concentration in feta was obviously lower than maternal IgG on day 0 before uptaking colostrums and rapidly increased on day 1. These findings would provide clues for the endogenous transportation and exogenous administration of IgG for a better IgG intervention in offspring.

Influence of the serum levels of immunoglobulins on clinical outcomes in medical intensive-care patients

Endogenous immunoglobulins (Igs) are of fundamental importance in the host defense after microbial infections. However, the therapeutic administration of intravenous IgG (IVIgG) has not yet been shown to improve clinical outcomes in patients suffering from sepsis, and in the case of IgM-containing preparations (IVIgGMA) the positive evidence is only weak. Recently published studies implicate that Ig levels on admission could have an impact on the patient's response to IVIg treatment and on outcomes of critically ill patients. In this noninterventional study, the serum levels of IgG, IgM, and IgA were determined in 340 medical patients on ICU admission, and clinical outcomes were prospectively recorded (ICU mortality, need for renal replacement therapy (RRT), need for mechanical ventilation, substitution of coagulation factors, and amount of red cell transfusions). Patients were prospectively grouped according to their main reason for ICU admission (sepsis, respiratory failure, cardiovascular diseases, acute renal failure, postoperative condition, state after cardiopulmonal resuscitation, gastrointestinal diseases, and others). There was no correlation between the Ig levels on admission and ICU mortality neither in the total cohort of medical ICU patients nor in any prespecified subgroup. However, in a logistic regression model that was adjusted for APACHE II score on admission, an increase in serum IgG was associated with a reduced need for mechanical ventilation in patients suffering from cardiovascular disease. On the other hand, in patients suffering from sepsis, an increased level of IgM was linked to an increased administration of coagulation factors. Our data do not support the hypothesis that serum levels of immunoglobulins are linked to mortality in medical ICU patients.

Association of systemic lupus erythematosus with decreased immunosuppressive potential of the IgG glycome.

ObjectiveGlycans attached to the Fc portion of IgG are important modulators of IgG effector functions. Interindividual differences in IgG glycome composition are large and they associate strongly with different inflammatory and autoimmune diseases. IKZF1, HLA–DQ2A/B, and BACH2 genetic loci that affect IgG glycome composition show pleiotropy with systemic lupus erythematosus (SLE), indicating a potentially causative role of aberrant IgG glycosylation in SLE. We undertook this large multicenter case–control study to determine whether SLE is associated with altered IgG glycosylation.MethodsUsing ultra‐performance liquid chromatography analysis of released glycans, we analyzed the composition of the IgG glycome in 261 SLE patients and 247 matched controls of Latin American Mestizo origin (the discovery cohort) and in 2 independent replication cohorts of different ethnicity (108 SLE patients and 193 controls from Trinidad, and 106 SLE patients and 105 controls from China).ResultsMultiple statistically significant differences in IgG glycome composition were observed between patients and controls. The most significant changes included decreased galactosylation and sialylation of IgG (which regulate proinflammatory and antiinflammatory actions of IgG) as well as decreased core fucose and increased bisecting N‐acetylglucosamine (which affect antibody‐dependent cell‐mediated cytotoxicity).ConclusionThe IgG glycome in SLE patients is significantly altered in a way that decreases immunosuppressive action of circulating immunoglobulins. The magnitude of observed changes is associated with the intensity of the disease, indicating that aberrant IgG glycome composition or changes in IgG glycosylation may be an important molecular mechanism in SLE.

Efficacy of Intravenous Immunoglobulin in Neurological Diseases.

Owing to its anti-inflammatory efficacy in various autoimmune disease conditions, intravenous immunoglobulin (IVIG)-pooled IgG obtained from the plasma of several thousands individuals-has been used for nearly three decades and is proving to be efficient in a growing number of neurological diseases. IVIG therapy has been firmly established for the treatment of Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, and multifocal motor neuropathy, either as first-line therapy or adjunctive treatment. IVIG is also recommended as rescue therapy in patients with worsening myasthenia gravis and is beneficial as a second-line therapy for dermatomyositis and stiff-person syndrome. Subcutaneous rather than intravenous administration of IgG is gaining momentum because of its effectiveness in patients with primary immunodeficiency and the ease with which it can be administered independently from hospital-based infusions. The demand for IVIG therapy is growing, resulting in rising costs and supply shortages. Strategies to replace IVIG with recombinant products have been developed based on proposed mechanisms that confer the anti-inflammatory activity of IVIG, but their efficacy has not been tested in clinical trials. This review covers new developments in the immunobiology and clinical applications of IVIG in neurological diseases.

Intravenous immunoglobulin replacement induces an in vivo reduction of inflammatory monocytes and retains the monocyte ability to respond to bacterial stimulation in patients with common variable immunodeficiencies

Intravenous IgG administration induces significant modifications in the innate and adaptive compartment of the immune system including the monocyte/macrophage system. We analyzed the in vivo effect of IgG administered at replacement dosages on the frequency of monocytes subsets, on the modulation of CD11b and sialic acid-binding immunoglobulin-like lectin receptor (Siglec 9) expression and on monocytes production of reactive oxygen species. We showed that patients with Common Variable Immune Deficiency have an increased frequency pro-inflammatory intermediate CD14++CD16+ monocytes and an increased expression of CD11b and Siglec 9 on monocytes. IgG administered at replacement dosages exerted an in vivo anti-inflammatory effect as shown by a reduction of circulating monocytes, of intermediate pro-inflammatory monocytes, of CD11b and Siglec 9 expression and of ex vivo monocytes oxidative burst. Nevertheless, intravenous IgG administration did not affect the monocyte functional ability to respond to a bacterial stimulation in terms of CD11b and Siglec 9 expression and reactive oxygen species production.

Diet-induced obesity causes peripheral and central ghrelin resistance by promoting inflammation.

Ghrelin, a stomach-derived orexigenic peptide, transmits starvation signals to the hypothalamus via the vagus afferent nerve. Peripheral administration of ghrelin does not induce food intake in high fat diet (HFD)-induced obese mice. We investigated whether this ghrelin resistance was caused by dysfunction of the vagus afferent pathway. Administration (s.c.) of ghrelin did not induce food intake, suppression of oxygen consumption, electrical activity of the vagal afferent nerve, phosphorylation of ERK2 and AMP-activated protein kinase alpha in the nodose ganglion, or Fos expression in hypothalamic arcuate nucleus of mice fed a HFD for 12 weeks. Administration of anti-ghrelin IgG did not induce suppression of food intake in HFD-fed mice. Expression levels of ghrelin receptor mRNA in the nodose ganglion and hypothalamus of HFD-fed mice were reduced. Inflammatory responses, including upregulation of macrophage/microglia markers and inflammatory cytokines, occurred in the nodose ganglion and hypothalamus of HFD-fed mice. A HFD blunted ghrelin signaling in the nodose ganglion via a mechanism involving in situ activation of inflammation. These results indicate that ghrelin resistance in the obese state may be caused by dysregulation of ghrelin signaling via the vagal afferent.

The 5XFAD Mouse Model of Alzheimer's Disease Exhibits an Age-Dependent Increase in Anti-Ceramide IgG and Exogenous Administration of Ceramide Further Increases Anti-Ceramide Titers and Amyloid Plaque Burden.

We present evidence that 5XFAD Alzheimer's disease model mice develop an age-dependent increase in antibodies against ceramide, suggesting involvement of autoimmunity against ceramide in Alzheimer's disease pathology. To test this, we increased serum anti-ceramide IgG (2-fold) by ceramide administration and analyzed amyloid plaque formation in 5XFAD mice. There were no differences in soluble or total amyloid-β levels. However, females receiving ceramide had increased plaque burden (number, area, and size) compared to controls. Ceramide-treated mice showed an increase of serum exosomes (up to 3-fold using Alix as marker), suggesting that systemic anti-ceramide IgG and exosome levels are correlated with enhanced plaque formation.

Host protein C inhibitor inhibits tumor growth, but promotes tumor metastasis, which is closely correlated with hypercoagulability

IntroductionProtein C inhibitor (PCI), a member of the serine protease inhibitor family, is expressed in various human tissues, including liver and kidneys. In the plasma, PCI physiologically inhibits an anticoagulant serine protease, activated protein C (APC). PCI expressed by cancer cells suppresses tumor invasion by inhibiting urokinase-type plasminogen activator, and inhibits tumor growth and metastasis, which are independent of its protease-inhibitory activity. In the present study, we clarified the effects of host PCI on growth and metastasis of B16 melanoma (B16) cells by comparing between wild-type mice and mice transgenic for human PCI gene (hPCI-TG), which have a tissue distribution of PCI similar to that observed in humans. Materials and MethodsGrowth of intracutaneously-injected B16 cells was evaluated by measuring the tumor volume, and metastatic behavior of intravenously-injected B16 cells by counting the number of metastatic lung nodules. ResultsGrowth of intracutaneously injected B16 cells was significantly faster in wild-type mice than in hPCI-TG mice; however, hPCI-TG mice developed more metastatic nodules of B16 cells in the lungs. Immunohistochemical analysis using anti-mouse fibrinogen antibody revealed more fibrin deposition in the lung in hPCI-TG mice than in wild-type mice. Furthermore, the more invasive behavior observed in hPCI-TG mice was reduced by rabbit anti-human PCI IgG, APC, or soluble TM administration for 3 consecutive days including the day that B16 cells were injected. ConclusionsOur results suggest that like PCI expressed in tumor cells, host PCI also inhibits tumor growth, but host PCI promotes tumor metastasis via its procoagulant properties.

Adverse effects of immunoglobulin G therapy: thromboembolism and haemolysis.

Adverse effects of immunoglobulin G therapy: thromboembolism and haemolysis.

Subcutaneous immunoglobulin loading regimens for previously untreated patients with primary antibody deficiency.

Subcutaneous immunoglobulin loading regimens for previously untreated patients with primary antibody deficiency.

Efficiency of immunoglobulin G replacement therapy in common variable immunodeficiency: correlations with clinical phenotype and polymorphism of the neonatal Fc receptor.

Efficiency of immunoglobulin G replacement therapy in common variable immunodeficiency: correlations with clinical phenotype and polymorphism of the neonatal Fc receptor.

Complement C5-inhibitor rEV576 (coversin) ameliorates in-vivo effects of antiphospholipid antibodies.

Activation of the complement cascade is an important mechanism for antiphospholipid antibody-mediated thrombosis. We examined the effects of rEV576 (coversin), a recombinant protein inhibitor of complement factor 5 activation, on antiphospholipid antibody-mediated tissue factor up-regulation and thrombosis. Groups of C57BL/6J mice (n=5) received either IgG from a patient with antiphospholipid syndrome (APS) or control IgG from normal human serum (NHS). Each of these groups of mice had IgG administration preceded by either rEV576, or phosphate buffer control. For each of the four treatment groups, the size of induced thrombus, tissue factor activity in carotid homogenates, anticardiolipin and anti-β2glycoprotein I (anti-β2GPI) levels were measured 72 h after the first injection. Mice treated with IgG-APS had significantly higher titers of anticardiolipin antibodies and anti-β2GPI at thrombus induction compared with those treated with IgG-NHS. The IgG-APS/phosphate buffer treatment induced significantly larger thrombi and tissue factor activity compared with other groups. Mice treated with IgG-APS/rEV576 had significantly smaller thrombi and reduced tissue factor activity than those treated with IgG-APS/phosphate buffer. The data confirm involvement of complement activation in antiphospholipid antibody-mediated thrombogenesis and suggest that complement inhibition might ameliorate this effect.

Injection of celiac disease patient sera or immunoglobulins to mice reproduces a condition mimicking early developing celiac disease.

Typical features of celiac disease are small-bowel villus atrophy, crypt hyperplasia, and inflammation which develop gradually concomitant with ingestion of gluten. In addition, patients have anti-transglutaminase 2 (TG2) autoantibodies in their serum and tissues. The aim of this study was to establish whether celiac disease can be passively transferred to mice by serum or immunoglobulins. Serum aliquots or purified immunoglobulins (Ig) were intraperitoneally injected into Hsd:Athymic Nude-Foxn1nu mice for 8 or 27 days. As mice do not have proper IgA transport from peritoneum to blood, sera with a high content of IgG class anti-TG2 antibodies from untreated IgA-deficient celiac patients were used. Mouse sera were tested for celiac disease-specific autoantibodies, and several tissues were analyzed for autoantibody deposits targeted to TG2. Morphological assessment was made of the murine small intestinal mucosa. Injection of celiac disease patient sera or total IgG led to a significant delay in weight gain and mild diarrhea in a subset of mice. The mice injected with celiac patient sera or IgG had significantly decreased villus height crypt depth (Vh/CrD) ratios and celiac disease-specific autoantibody deposits targeted to TG2 in several tissues, including the small intestine. None of these features were observed in control mice. We conclude that administration of IgA-deficient celiac disease patient serum or total IgG induces both deterioration of the intestinal mucosa and clinical features of celiac disease in mice. The experimentally induced condition in the mice injected with patient serum or IgG resembles early developing celiac disease in humans. Celiac disease patient sera or total IgG was injected into athymic mice. A significant delay in weight gain and mild diarrhea was observed. Mice evinced significantly decreased villus height crypt depth ratios. Celiac disease-specific autoantibody deposits were present in several tissues. The condition in mice resembles early stage celiac disease in humans.

Near-term anti-CD25 monoclonal antibody administration protects murine liver from ischemia-reperfusion injury due to reduced numbers of CD4+ T cells.

BackgroundCD4+ T cell is acknowledged as a key factor in the initiation phase of liver ischemia reperfusion injury. The purpose of current study is to demonstrate the effect of antecedent near-term anti-CD25 monoclonal antibody treatment on IR-induced liver injury by modulation of CD4+ T cells.Methods70% liver warm IR was induced in male C57BL/6 mice after anti-CD25 mAb or non-specific IgG administration. Liver function, histological damage, in vitro Proliferation, FACS, cytokine production, and immunofluorescence were assessed to evaluate the impact of antecedent near-term PC61 treatment on IR-induced liver injury.ResultsAfter 70% liver ischemia, mice preconditioned with PC61 displayed significantly preserved liver function as characterized by less histological damage and reduced serum enzymes level. Mechanistic studies revealed that the protection effect of anti-CD25 mAb was associated with ameliorated intrahepatic inflammatory milieu and reduced CD4+ T lymphocytes as manifested by the decrease of proinflammatory cytokine production (less expression of TNF-α, IFN-γ, IL-2, and IL-6) and the lower CD4/CD8 proportion.ConclusionsOur results provide first line of evidence indicating that near-term treatment with anti-CD25 monoclonal antibody might provide protection for livers against IR-induced injury by reducing CD4+ T cells, but not influencing functional Treg population. Therefore, our results demonstrate a potential function of anti-CD25 monoclonal antibody which was neglected in the past, and may be helpful in various clinical conditions, particularly in liver and kidney transplantations.

Citrullinated histone H3: A novel target for the treatment of sepsis

We have recently demonstrated that in a rodent model of lipopolysaccharide (LPS)-induced shock, an increase in circulating citrullinated histone H3 (Cit H3) is associated with lethality of sepsis, and treatment with suberoylanilide hydroxamic acid (SAHA), a histone deacetylase (HDAC) inhibitor (HDACI), significantly improves survival. However, the role of Cit H3 in pathogenesis and therapeutics of sepsis are largely unknown. The present study was designed to test whether treatment with HDACI could inhibit cellular Cit H3 production, and inhibition of peptidylarginine deiminase (PAD, an enzyme producing Cit H3) with Cl-amidine (PAD inhibitor) or neutralization of blood Cit H3 with anti-Cit H3 antibody could improve survival in a clinically relevant mouse model of cecal ligation and puncture (CLP)-induced septic shock. Three experiments were carried out. In experiment I, HL-60 neutrophilic cells grown on a coverslip were treated with LPS (100 ng/mL) in the presence or absence of SAHA (5 μmol) for 3 hours, and subjected to immunostaining with anti-Cit H3 antibody to assess effect of SAHA on Cit H3 production under a fluorescence microscope. The ratio of Cit H3 positive cells was calculated as mean values ± SD (n = 3). In experiment II, male C57BL/6J mice were subjected to CLP, and 1 hour later randomly divided into 2 groups for intraperitoneal injection as follows: (1) Dimethyl sulfoxide (DMSO), (2) SAHA (50 mg/kg) in DMSO, and (3) Cl-amidine (80 mg/kg) in DMSO (n = 10/group). In experiment III, male C57BL/6J mice were divided into control and treatment groups, and subjected to CLP. Two hours later, immunoglobulin (Ig)G and Cit H3 antibody (20 mg/kg IV; n = 5/group) were injected into the control and treatment groups, respectively. Survival was monitored for ≤10 days. In experiment I, LPS induced Cit H3 production in the HL-60 cells, and SAHA treatment inhibited H3 citrullination significantly (P < .05). In experiment II, all vehicle-injected mice died within 3 days with increased circulating Cit H3 levels, whereas treatment with HDACI or Cl-amidine notably improved long-term survival (P < .01). In experiment III, administration of IgG did not improve survival, but a single treatment with Cit H3 specific antibody significantly improved survival (P < .014). Inhibition of HDAC or PAD significantly suppresses Cit H3 production in vitro and improves survival in vivo. Neutralization of Cit H3 significantly improves survival in septic mice. Collectively, our findings indicate for the first time that Cit H3 could not only serve as a potential biomarker, but also a novel therapeutic target in sepsis.

Pathological activation of canonical nuclear-factor κB by synergy of tumor necrosis factor α and TNF-like weak inducer of apoptosis in mouse acute colitis

Tumor necrosis factor (TNF)-α is a major effector in various inflammatory conditions. TNF-like weak inducer of apoptosis (TWEAK) is a member of the TNF superfamily that promotes inflammatory tissue damage through its receptor, FGF-inducible molecule 14 (Fn14). Since both TWEAK and TNF-α have been shown to mediate pathological responses through inter-dependent or independent pathways by in vitro, the potential interplay of these pathways was investigated in a mouse colitis model. Acute colitis was induced by rectal injection of trinitrobenzene sulfonic acid (TNBS), with administration of control IgG, TNF receptor (TNFR)-Ig chimeric protein, anti-TWEAK monoclonal antibody, or the combination of TNFR-Ig and anti-TWEAK antibody. On day 4, disease severity was evaluated and gene expression profiling was analyzed using whole colon tissue. NF-κB activation was investigated with Western blot. Levels of transcript of TWEAK, Fn14 and NF-κB-related molecules were measured in purified colon epithelial cells (ECs). As a result, activation of the canonical (p50/RelA), but not noncanonical (p100/RelB)-mediated pathway was the hallmark of inflammatory responses in this model. Inflammation induced upregulation of Fn14 only in ECs but not in other cell types. Combination treatment of TNFR-Ig and anti-TWEAK antibody synergistically reduced disease severity in comparison with the control antibody or single agent treatment. Gene expression profile of the colon indicated downregulation of canonical NF-κB pathway with combination treatment. In conclusion, synergistic activation of canonical NF-κB by TWEAK and TNF-α is critical for the induction of inflammatory tissue damage in acute inflammation.

Open-label study on treatment with 20 % subcutaneous IgG administration in polymyositis and dermatomyositis

The objective of this study is to describe the benefit of 20 % subcutaneous infusions of immunoglobulin (SCIg) in patients with dermatomyositis (DM) or polymyositis (PM) after a switch from previous 16 % SCIg treatment. Eight patients with DM or PM, who met the Bohan and Peter's criteria, previously treated with 16 % SCIg, were switched to weekly 20 % SCIg infusions (Hizentra®; CSL Behring) at doses equivalent to their previous subcutaneous treatment. A standardised protocol was used to evaluate patients, disease activity and treatment response. The disease remained stable in three and improved in four other patients, as documented by increased Medical Research Council scores and normal serum CK levels. No relapse of disease occurred. Local reactions were mild and self-limiting. No serious adverse events were reported. The mean duration of infusion per week was significantly lower compared to the mean duration of the 16 % SCIg preparation. A specifically designed questionnaire documented the patients' satisfaction with treatment. The weekly administration of 20 % SCIg is effective in maintaining a quiescent disease in patients with DM or PM with no increased safety concerns. SCIg therapy is particularly attractive for patients because it does not require venous access and hospitalisation and requires less assistance from healthcare provider services. The administration of 20 % SCIg was beneficial and safe in maintaining a quiescent disease and in inducing a complete remission in moderately active disease in patients with DM or PM. The treatment with 20 % SCIg led to the possibility to discontinue and to reduce the use of glucocorticoids and/or the immunosuppressants. Patients reported their satisfaction in terms of contact with health professionals, quality of treatment-related information and administration convenience, with an improved quality of life.

Subcutaneous IgG in neurologic diseases

Subcutaneous administration of IgG (SCIG) has become widely used in primary immune deficiency diseases but it has only recently been studied for maintenance therapy in autoimmune peripheral neuropathies, such as chronic idiopathic demyelinating polyneuropathy and multifocal motor neuropathy. Weekly self-administration of SCIG is safe and well-tolerated, and results in steady-state serum IgG levels, as contrasted with the peaks and troughs of monthly immune globulin (human) for intravenous use. Freedom from the need for venous access or medical personnel for infusions, flexibility in scheduling, convenience of home therapy, and improved clinical stability due to the steady-state IgG levels, lead many patients to prefer SCIG to immune globulin (human) for intravenous use. Long-term studies are needed to determine if the constant IgG levels and clinical stability translate into better long-term outcomes.