Intravenous Gamma Globulin Preparations Research Articles

The history and evolution of immunoglobulin products and their clinical indications

The history of providing antibodies to treat diseases began in the 19th century with the discovery of tetanus and diphtheria toxins and the demonstration that immunity to tetanus and diphtheria infections could be transferred by immune sera. Characterization of the mediators of this immunity resulted in the discovery that antibodies are proteins that can be isolated and used to protect against infectious diseases. Development of a method to isolate antibodies from human plasma that could be safely injected into people initiated the development of human gamma globulin preparations to provide antibodies to patients with inherited antibody deficiencies. To overcome the limitations imposed by intramuscular injection of gamma globulin, intravenous gamma globulin preparations were developed that began to be used in a wide variety of clinical conditions. Thus the original clinical indication for infection prevention was expanded to several other indications that employ large doses to suppress inflammatory and autoimmune disorders. The most recent development in immunoglobulin therapy is the production of concentrated immune globulins for subcutaneous injection. Home infusions of subcutaneous immunoglobulin are increasingly used to treat immunodeficient patients and are being studied for other clinical applications.

Receptor-Mediated Maternofetal Transfer of ImmunoglobulinsInhibition of Transport of Anti-HIV-1 Immunoglobulin by Generic Immunoglobulins in the in vitro Perfused Placenta

Objectives: The passage of immunoglobulin G (IgG) across the placenta is thought to involve Fc’ receptors on the syncytiotrophoblast. To confirm the receptor dependency of this process we have studied the changes in the tissue content and transfer kinetics of immunoglobulins and hyperimmune serum to HIV (HIVIG) during in vitro dual placental perfusion. Methods: Isolated lobules of term placentae from normal pregnancies were perfused in a model of maternal and fetal circulation. The perfused tissue was compared to fresh tissue samples from the same placenta for the content of IgG, IgG subclasses, IgM, cytokeratin, human placental lactogen and SP1 antigen by immunohistochemistry and by protein elution. Results: The immunoglobulin staining faded by an average of 40% during the 1st hour of perfusion. In contrast, staining for cytokeratin, human placental lactogen and SP1 remained unchanged. During a 4-hour recycling of endogenous immunoglobulins in the maternal circulation, IgG and HIVIG crossed to the fetal side in a steady rate. The transport of HIVIG could be inhibited by preperfusion with an intravenous gammaglobulin preparation (IVIG). Discussion: The transfer of IgG across the placenta occurs in a steady state rate consistent with a receptor-mediated mechanism. Furthermore, inhibition of HIVIG maternofetal transfer by IVIG further establishes the receptor-mediated transfer of immunoglobulins through the placenta.

Comparison of different intravenous gammaglobulin preparations in the treatment of Kawasaki disease

Comparison of different intravenous gammaglobulin preparations in the treatment of Kawasaki disease

Procedure for evaluation of neutralizing antibody to cytomegalovirus in commercial intravenous gamma globulin preparations.

Cytomegalovirus (CMV) is a common pathogen complicating the course of renal transplant recipients, as well as the course of bone marrow, cardiac and liver transplant recipients (1–4). In organ transplant patients, CMV is the single most important infection manifesting as either a subclinical infection or a potentially life-threatening disease. The incidence of symptomatic CMV infection in the transplant population is high, 60–90%, compared to immunosuppressed non-transplant patients, 42–66% (2).KeywordsCytomegalovirus InfectionGamma GlobulinIdiopathic Interstitial PneumoniaELISA TiterPatient Undergo Bone Marrow TransplantationThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

IgG subclass deficiency

The different biological properties of human IgG subclasses make each subclass unique in its functional role in either resistance to infection, autoimmune diseases or allergy. Not only are there marked differences in the relative concentrations of IgG subclasses in serum (IgG1 > IgG2 > IgG3/IgG4) but the distribution of the antibody responses in the 4 subclasses of IgG can vary markedly depending on the nature of the antigen, the type of infection, the degree of antigen exposure, the immunization regimens, the age of individual, the immune disorder and the allotype of the individual. Measurement of the IgG subclass distribution of antibodies can be informative in identifying an immunological deficiency, evaluating the production of host protective antibodies, and assessing pathophysiology. Determination of IgG subclass concentrations is essential in the diagnosis of immunodeficiencies. However, there is still uncertainty about the accuracy of measurements in relation to standards, monoclonal antibodies and assay types. For the paediatric population, a sensitive assay, such as an enzyme linked immunoabsorbent assay, is essential. A standardised definition of IgG subclass deficiency is yet to be accepted; however, values substantially below the 5th percentile for a normal healthy population of appropriate age measured by a defined assay system may be indicative of significant abnormality. There is emerging evidence that some subclass deficiencies are associated with increased susceptibility to infection. Such IgG subclass deficiencies may be amenable to treatment with intravenous gammaglobulin preparations, but further carefully designed and controlled studies are needed to ascertain treatment efficacy.

Prospective Study on the Hepatitis Safety of Intravenous Immunoglobulin, pH 4.25

Recent reports of transmission by intravenous gamma-globulin preparations of non-A non-B hepatitis (NANBH), including several cases that progressed to severe liver damage and death, have raised concerns about the safety of intravenous gamma-globulin. However, the problem does not seem to be widespread. To assess this issue, we previously reported the results of liver function tests monitored in 41 patients with primary immunodeficiency treated with intravenous immunoglobulin (IGIV), pH 4.25 over periods ranging from 6 to 15 months. Eighteen of these patients at two of the three centers have now had serial serum glutamic pyruvic transaminase (SGPT) levels performed regularly at intervals of 1-5 weeks while continuing monthly intravenous infusions of nonmodified IGIV, pH 4.25 for an additional 14-26 months. The standard dosage was 400 mg per kg body weight IGIV, pH 4.25. Six lots of IGIV, pH 4.25 were used. Transient minor SGPT elevations were observed in 5 of the patients on a total of 8 occasions. None of the elevations was considered indicative of NANBH or of any chronic hepatic disease. All patients remained negative for hepatitis B surface antigen throughout the study.

Common Variable Immunodeficiency: The Disorder and Treatment

A case of common variable immunodeficiency, a relatively rare disorder, is presented. This case was complicated by the presence of an anti-IgA antibody in the patient's serum and a history of a possible anaphylactic reaction to a prior intravenous infusion of gamma-globulin. Common variable immunodeficiency is actually a heterogeneous group of demonstrable immunoglobulin deficiencies that have in common low levels of most immunoglobulin isotypes, the inability to form antibodies to antigen, an absence of gross defects in cell-mediated immunity, and the presence of recurrent bacterial infections. The history of immunoglobulin deficiency and its treatment is reviewed. Although the primary therapy for common variable immunodeficiency is gamma-globulin replacement, ancillary measures such as early treatment of infections with antibiotics are also important. Intravenous gamma-globulin replacement therapy is preferred to intramuscular replacement therapy in these patients because intramuscular doses must be limited in volume to minimize local pain and take 2 to 14 days to achieve maximal blood levels, during which time in situ degradation of up to 50% of the administered dose can occur. Five intravenous gamma-globulin preparations are currently available in the United States. The potential adverse effects of intravenous gamma-globulin infusion and the precautions currently taken to ensure safety during administration of this product are discussed.

Intravenous immunoglobulin (IVIG) for the therapy of autoimmune disorders

The weight of evidence from numerous clinical studies supports the use of IVIG, particularly at higher doses, in the treatment of a wide range of autoimmune disorders. Extensive experience has documented the safety of IVIG therapy but its present relatively high cost necessitates firmly establishing its efficacy. There is an acute need to define those disease states where IVIG is indicated and effective. Large-scale, possibly multicentered, clinical trials employing rigorous controls will resolve these questions. Concurrent fundamental immunologic studies will elucidate the mechanisms underlying the clinical effects. We are experiencing an exciting new era of effective immunotherapies and intravenous gamma-globulin preparations have already secured an important place in the therapeutic armamentarium. While one must guard against unsubstantiated applications, critical exploration of new uses for this unique product is warranted.

Effect of an Intravenous Gammaglobulin Preparation on the Opsonophagocytic Activity of Preterm Serum against Coagulase‐Negative Staphylococci

Recent reports have described cases of septicaemia caused by coagulase-negative staphylococci in preterm neonates, mainly due to the use of artificial intravenous devices. It was of interest to examine if intravenous immunoglobulin therapy, known to be effective in group B streptococcal infections of neonates, had a similar beneficial effect in coagulase-negative staphylococcal infections. Opsonophagocytosis of coagulase-negative staphylococci by normal polymorphonuclear leukocytes in the presence of cord blood serum supplemented with the commercial IgG preparation 'Sandoglobulin' was investigated, using luminol-dependent chemiluminescence. It was found that with two different coagulase-negative staphylococcal strains, Sandoglobulin had a concentration-dependent enhancing effect on the chemiluminescent response. This effect was demonstrated in the presence of native as well as inactivated cord blood serum and in the presence of sera from preterm infants (28-33 weeks). It is concluded that intravenous Sandoglobulin therapy may be effective in the treatment of preterm infants with severe coagulase-negative staphylococcal infections.

Modulation of functional activity of human polymorphonuclear and mononuclear phagocytes by intravenous gamma globulin

Intravenous gamma-globulin was tested in a range of concentrations compatible with the increments obtained after therapeutic infusions for modulation of phagocytic functions of human polymorphonuclears (PMNs) and monocytes. Intravenous gammaglobulin in concentrations of 3.0 mg/ml or more increased adhesiveness and suppressed chemotaxis of PMNs. There was marked dose-dependent enhancement of opsonization of gram-positive and gram-negative microorganisms. Preincubation of PMNs with intravenous gamma-globulin caused enhancement of the total bacteria ingested, total bacteria killed, phagocytosis, and phagocytic index, when gram-positive and gram-negative bacteria were tested. During phagocytosis, there was no release of LDH or lysozyme; however, there was release of beta-glucuronidase. No significant difference in phagocytic enhancement was found when filtered and native intravenous gamma-globulin preparations were compared. There was marked enhancement of the superoxide anion generation by intravenous gamma-globulin above the concentration of 0.01 mg/ml. Intravenous gamma-globulin also markedly enhanced phagocytic activity of monocytes. Therefore, intravenous gamma-globulin modulates not only opsonization-related phenomena, but also exerts a complex influence on other aspects of phagocytic activity.

Antibody Against the Human Immunodeficiency Virus in Commercial Intravenous Gammaglobulin Preparations

In a 6-month study, antibody levels against the human immunodeficiency virus (HIV) were determined in intravenous gammaglobulin preparations and 45 serum samples from 20 patients on gammaglobulin therapy. All 10 lots of a reduced and alkylated preparation and 4 of 8 lots of a pH4/pepsin-treated preparation were seropositive by enzyme-linked immunosorbent assay (ELISA). By Western blot analysis, 8 of 10 lots of the reduced and alkylated preparation and 3 of 8 lots of the pH4/pepsin-treated preparation were positive. Before gammaglobulin infusion, 2 of 45 preinfusion samples were seropositive by ELISA but seronegative by Western blot. After infusion, 15 of 45 samples were seropositive by ELISA, and 8 had antibody against p24 by Western blot. Seropositivity persisted for less than 1 month. Cultures of HIV-positive intravenous gammaglobulin lots were negative for reverse transcriptase activity or viral antigen expression. These results suggest that current methods of preparation either exclude or inactivate HIV.

In vivo Reduction of Circulating C1q Binding Immune Complexes by Intravenous Gammaglobulin Administration

Six patients with systemic lupus erythematosus were treated with high-dose intravenous gammaglobulin. Immunological parameters were studied and included solid-phase immune complex determinations, quantitative immunoglobulins G, A, and M, as well as C3 and C4 concentrations. Pretreatment values of circulating immune complex concentrations as measured by either C1q binding or anti-C3 binding assays were elevated in all patients. Posttreatment values showed reductions in all C1q binding immune complexes (p less than 0.01) and anti-C3 binding immune complexes also decreased in 5 out of 6 patients. These assays are described in detail and were also used to define in vitro interactions between the intravenous gammaglobulin preparation and heat-aggregated IgG or sera containing elevated circulating immune complexes. No reduction of immune complex levels were observed when IgG was incubated in vitro with either heat-aggregated IgG or sera with elevated immune complex concentrations. The duration of the in vivo effect and the patients' clinical responses are described. These findings show that high-dose intravenous gammaglobulin administration can reduce certain types of immune complexes in patients with elevated levels of these substances.

Adverse reactions in selected patients following intravenous infusions of gamma globulin

Fifteen patients with hypogammaglobulinemia or agammaglobulinemia were treated with intravenous gamma globulin preparation over a 17-month period. The patients were selected for treatment if they had chronic antibody deficiency syndromes associated with increased susceptibility to infections. Levels of circulating immune complexes, C1q, C3, and C3d were determined in serum samples obtained before treatment and immediately following treatment with the gamma globulin. In every patient studied, circulating immune complexes were detectable in the postinfusion samples. Two patients had adverse reactions to the intravenous gamma globulin therapy. Analysis of the serum samples of both of these patients showed that one patient had an autoantibody to IgA and the other had an autoantibody to β-lipoprotein. Both IgA and β-lipoprotein were present in the intravenous gamma globulin preparations. Therefore, reaction with each of the autoantibodies by the antigens activated the complement system in vivo with production of split products of C3.

Intravenous gamma globulin in the treatment of chronic idiopathic thrombocytopenic purpura in adults

Eight adult patients with chronic idiopathic thrombocytopenic purpura have been treated with an intravenous gamma globulin preparation. All patients received at least one “induction” course of intravenous gamma globulin for five consecutive days at a dose of 400 mg/kg per day. There were a total of 12 induction treatments. In five instances, patients also received single “maintenance” infusions of intravenous gamma globulin at the same dose. The mean peak increment in platelet count (×10 3/μl) after induction was 87.3 ±42.37; after maintenance therapy it was 62.2 ± 12.99. In only one instance was the platelet count increment less than 50 × 10 3/μl. In 13 of 17 intravenous gamma globulin treatments (both induction and maintenance), the platelet count returned to baseline or near-baseline levels within one to two weeks. In four instances, more prolonged remissions were observed. Measurements of platelet-associated IgG demonstrated the following: when platelet-associated IgG was greater than 100 ng/10 6 platelets, platelet-associated IgG usually decreased markedly after intravenous gamma globulin therapy. When platelet-associated IgG was less than 20 ng/10 6 platelets, platelet-associated IgG usually increased with therapy. There was no correlation between starting platelet-associated IgG levels or changes in platelet-associated IgG levels with therapy and the increment in the patient's platelet count.

A preparation of modified immune serum globulin (human) suitable for intravenous administration: Further characterization and comparison with pepsin-treated intravenous gamma globulin

Numerous methods have been used in previous attempts to prepare a human gamma globulin solution suitable for intravenous administration. These include fractionation schemes, enzyme digestion, manipulations of pH, and various combinations of these methods. The selective reduction and alkylation process that we have developed for Gamimune causes a controlled and reproducible modification of a limited number of disulfide bonds in the hinge region of IgG, resulting in a functional antibody molecule of undiminished molecular weight and possessing complement-binding properties suitable for intravenous administration. Subtle changes in molecular structure or properties that may be caused by trace enzyme hydrolysis or extremes of pH and temperature are avoided. The biochemical characterization of immune globulin intravenous (Gamimune) is described herein, and the attributes of this chemically modified IgG are compared with some of the other intravenous gamma globulin preparations.

Comparative opsonic activity of intravenous gamma globulin preparations for common bacterial pathogens

Immune globulin intravenous is a reduced and alkylated preparation of gamma globulin that is stabilized in 10 percent maltose and 0.1 M glycine at pH 6.8. Recently, a modified immune globulin intravenous preparation was developed that is identical to the standard preparation except that it does not contain glycine and the pH has been lowered to 5.25. The effect of these modifications has resulted in a higher IgG monomer content in the preparation. In the present studies the opsonic activity against several common bacterial pathogens was assessed in the standard (pH 6.8) versus the more acidic immune globulin intravenous (pH 5.25). Opsonic activity was detected in each preparation for Staphylococcus aureus, group B streptococci, Pseudomonas aeruginosa, Escherichia coli, and Serratia marcescens. With all of the organisms except S. marcescens, an intact complement system was required for optimal uptake and killing with each preparation. In general, the opsonic activity of the pH 5.25 immune globulin intravenous was equivalent to the standard pH 6.8 preparation. With several organisms, however, the more acidic preparation had greater activity than the standard one. An immune globulin intravenous preparation with increased antibody titers to P. aeruginosa was also prepared from selected donors and tested for opsonic activity against six of the seven Pseudomonas immunotypes. This preparation was found to have strikingly increased opsonic titers for most of the Pseudomonas immunotypes when compared with the standard immune globulin intravenous. These studies indicate that changes in donor selection or minor modifications in production techniques may markedly affect the biologic activity of intravenous gamma globulin.