Intravenous Immune Serum Globulin Research Articles

Primary immunodeficiency disorders: Antibody deficiency

As a group, antibody deficiencies represent the most common types of primary immune deficiencies in human subjects. Often symptoms do not appear until the latter part of the first year of life, as passively acquired IgG from the mother decreases to below protective levels. As with the T-cell immune deficiencies, the spectrum of antibody deficiencies is broad, ranging from the most severe type of antibody deficiency with totally absent B cells and serum Igs to patients who have a selective antibody deficiency with normal serum Ig. In addition to the increased susceptibility to infections, a number of other disease processes (eg, autoimmunity and malignancies) can be involved in the clinical presentation. Fortunately, the availability of intravenous immune serum globulin has made the management of these patients more complete. Recently, molecular immunology has led to identification of the gene or genes involved in many of these antibody deficiencies. As discussed in this review, this has led to a better elucidation of the B-cell development and differentiation pathways and a more complete understanding of the pathogenesis of many of these antibody deficiencies. (J Allergy Clin Immunol 2002;109:581-91.)

Mechanisms of action of intravenous immune serum globulin therapy.

Department of Pediatrics, Division of Allergy, Immunology and Pediatric Rheumatology, Children's Hospital of Buffalo, State University of New York at Buffalo, School of Medicine and Biomedical Sciences, Buffalo, NY.

Intravenous immune serum globulin therapy in the primary antiphospholipid antibody syndrome: Ann Parke and Mark Ballow, University of Connecticut School of Medicine and Buffalo Children's Hospital

Intravenous immune serum globulin therapy in the primary antiphospholipid antibody syndrome: Ann Parke and Mark Ballow, University of Connecticut School of Medicine and Buffalo Children's Hospital

The uses of intravenous immune globulin in collagen vascular disorders

Studies in our laboratory demonstrated that the long-term administration of intravenous immune serum globulin in patients with common variable hypogammaglobulinemia produced increased suppressor activity, which resulted in diminished in vitro B cell immunoglobulin synthesis. These studies suggested that intravenous immune globulin therapy might be a useful modality in altering immunoregulation in patients with collagen vascular autoimmune disease. In the present preliminary study, two groups of patients with collagen vascular disease were chosen: systemic lupus erythematosus and primary Sjögren's syndrome. Patients with systemic lupus erythematosus with mild clinical disease were chosen to minimize the risk of adverse effects on the disease process, particularly specific organ involvement (e.g., lupus nephritis). Each patient was used as his or her own clinical and laboratory control. Patients received 300 mg/kg of intravenous immune globulin every 4 weeks. As a whole the patient group did not experience any adverse effects from the intravenous immune globulin therapy. No clinical or laboratory changes were observed in one patient with systemic lupus erythematosus and one patient with Sjögren's syndrome. In the other patient with Sjögren's syndrome, there were subjective changes of improved well-being and increased energy levels without any objective changes in the sicca syndrome. There was a slight steroid-sparing effect (10 to 3 mg/day) but no effects on the sedimentation rate, the antinuclear antibody, or rheumatoid factor serologic studies. In a patient with steroid-dependent systemic lupus erythematosus, there was marked clinical improvement of the cutaneous vasculitis after the third infusion, with reduction in her oral steroid requirements from 25 to 7.5 mg/day. The fifth patient, with a lupus anticoagulant and multiple miscarriages, was treated with an induction regimen of 0.4 gm/kg of intravenous immune globulin for 4 days after she became pregnant. Shortly thereafter for the first time, the lupus anticoagulant became negative with a decrease in anticardiolipin serologies. However, despite maintenance infusions given every 3 weeks at 500 mg/kg, the anticardiolipin antibody titers increased, and her lupus anticoagulant levels returned to previous ranges. This patient was treated concomitantly with low-dose anticoagulants (aspirin) and low-dose heparin. She delivered a normal, healthy child at 36 weeks' gestation. The placenta was grossly and microscopically normal, with no evidence of thrombosis. These preliminary studies indicate that select patients with collagen vascular disorders may benefit, although in some cases transiently, from intravenous immune globulin therapy. Further studies are needed to identify better those patients with collagen vascular disorders that might respond to intravenous immune globulin as adjunct therapy and select an optimal dosage regimen.

Immunoregulatory effects of intravenous immune serum globulin therapy in common variable hypogammaglobulinemia

Because of evidence of immunoregulatory effects of short-term administration of pooled donor gamma globulins, the effects of intravenous immune serum globulin were studied in nine adult patients with common variable hypogammaglobulinemia over a two-year period. Baseline assessment prior to immune serum globulin replacement included evaluation of B cell function, suppressor cell activity, and T cell subsets. These analyses were subsequently performed during the course of a first-year treatment period of intravenous immune serum globulin at doses of 100 to 200 mg/kg per month and a second-year trial at doses of 300 to 400 mg/kg per month. Five patients were re-evaluated following discontinuation of the intravenous immune serum globulin therapy for four months between the first and second treatment periods. During both treatment periods with intravenous immune serum globulin, suppressor cell activity increased markedly compared with baseline, and declined following discontinuation of drug therapy in the five patients. Suppressor cell activity was reversed by either irradiation of the T cell fraction or removal of the T8-positive cell fraction by flow cytometry. There was a reduction in the absolute number of total lymphocytes, the T3-positive cells (total T cells), and the T4-positive cells (helper cells) following intravenous immune serum globulin therapy; however, the percentages of the T cell subsets did not change significantly. Following immune serum globulin therapy, the number of T8-positive cells was not significantly changed but the T4:T8 ratio decreased from 2.1 at baseline to 1.5 after therapy (p >0.05). These data demonstrate that long-term intravenous immune serum globulin administration modulates the immune system by increasing suppressor T cell functional activity but is not accompanied by changes in the number of T8-positive cells in the peripheral blood.

Corticosteroids for prevention of adverse reactions to intravenous immune serum globulin infusions in hypogammaglobulinemic patients

Severe adverse reactions to intravenous immune serum globulin occurred repeatedly in four of 10 hypogammaglobulinemic patients. Treatment-limiting symptoms included fever, chills, headache, hypertension, and chest pain. Pretreatment of patients with hydrocortisone immediately prior to infusion prevented subsequent adverse reactions and permitted these patients to receive immune serum globulin intravenously.

Intravenous Immune Serum Globulin in Immune Thrombocytopenia: Clinical Results and Biochemical Evaluation

Intravenous gamma-globulin of the pH 4-treated Swiss Red Cross (SRC) preparation is an effective therapy for acute and chronic immune thrombocytopenia (ITP) of childhood and chronic ITP in adults. Patients who may respond satisfactorily to treatment include those without detectable immune complexes and those with poor response to pretreatment. Results are especially good in children, half of whom with chronic conditions are able to discontinue therapy.

Evaluation of Intravenous Immune Serum Globulin in Immune Thrombocytopenia: Preliminary Results

Due to difficult clinical problems caused or aggravated by the presence of severe thrombocytopenia, 4 patients with immune thrombocytopenia (ITP) refractory to conventional regimens were treated with intravenous gamma-globulin. One patient had a lasting remission, 2 others had a partial or brief response, and 1 patient had no improvement in platelet count.

Individualizing the Dose of Intravenous Immune Serum Globulin for Therapy of Patients with Primary Humoral Immunodeficiency

The availability of safe and effective IgG preparations for replacement therapy for patients with primary disorders of humoral immunity allows almost unlimited doses of IgG to be used. Thus, knowledge of the optimal dose and serum concentration of IgG to be achieved is of practical importance. In a multicenter study of a reduced and alkylated IgG preparation (MISG), it was shown that the MISG was well tolerated and as effective as the intramuscular immune serum globulin (ISG) used for more than 30 years. During the course of this study, we observed that the standard dose of 100 mg/kg/month resulted in a wide range of IgG levels. We began a study using another intravenous IgG preparation to determine whether the variable IgG levels were due to variability in the half-life of IgG in these patients and whether an individualized dose of IgG could be calculated based on the half-life for each patient. The half-life was greatly prolonged, ranging from 26 to 86 days compared with 21 days in normal individuals. However, there was no correlation between the half-life and the serum IgG concentration over the range of concentrations measured. When patients were treated with higher doses of IgG, based on the amount calculated to raise the serum IgG concentration to 200 mg/dl, only 1 patient actually achieved that level and only 3 had a significant increase in the serum concentration despite the higher dose. Failure to achieve the predicted levels could not be explained by a shortened half-life and seemed to be related to increased losses in the early, redistribution, phase. The half-life was not reduced in patients who did achieve higher serum IgG concentrations, suggesting that the half-life is characteristic for each patient and not directly dependent on the serum IgG concentration. However, only modest increases were observed and additional studies using much higher doses of IgG will be necessary before this issue can be settled. Similarly, we did not see an additional benefit in those patients receiving higher doses of IgG, and further studies will be necessary before it can be determined whether higher levels of IgG can reduce the incidence of chronic infections and justify the increased time and expense. The results of the completed study have been published elsewhere [7].

Intravenous and standard immune serum globulin preparations interfere with uptake of 125I-C3 onto sensitized erythrocytes and inhibit hemolytic complement activity

Antibody-sensitized sheep erythrocytes were used as a model to determine the effects of therapeutic immune serum globulin (ISG) preparations on the ability of this particulate activator to fix C3 and initiate hemolysis. Both standard and intravenous forms of ISG inhibit uptake of 125I-C3, presumably by competing for the deposition of “nascent” C3b molecules onto the erythrocytes. Both forms of ISG also inhibit hemolytic activity of whole serum or purified complement components. The inhibition appears to be a specific property of IgG itself, since similar inhibition was not caused by equivalent concentrations of human serum albumin, and was not affected by the buffer in which the ISG was dissolved. Interference with C3 uptake onto antibody-sensitized platelets and/or inhibition of hemolytic complement activity could contribute to the efficacy of high dose intravenous ISG in idiopathic thrombocytopenic purpura.

Intravenous Immune Serum Globulin in Immune Thrombocytopenia: Clinical Results and Biochemical Evaluation

Intravenous gamma-globulin of the pH 4-treated Swiss Red Cross (SRC) preparation is an effective therapy for acute and chronic immune thrombocytopenia (ITP) of childhood and chronic ITP in adults. Patients who may respond satisfactorily to treatment include those without detectable immune complexes and those with poor response to pretreatment. Results are especially good in children, half of whom with chronic conditions are able to discontinue therapy.

Individualizing the Dose of Intravenous Immune Serum Globulin for Therapy of Patients with Primary Humoral Immunodeficiency

Individualizing the Dose of Intravenous Immune Serum Globulin for Therapy of Patients with Primary Humoral Immunodeficiency

Evaluation of Intravenous Immune Serum Globulin in Immune Thrombocytopenia: Preliminary Results

Due to difficult clinical problems caused or aggravated by the presence of severe thrombocytopenia, 4 patients with immune thrombocytopenia (ITP) refractory to conventional regimens were treated with intravenous gamma-globulin. One patient had a lasting remission, 2 others had a partial or brief response, and 1 patient had no improvement in platelet count.

Efficacy and safety of high-dose intravenous immune globulin therapy for antibody deficiency syndromes

Ten patients with antibody deficiency syndromes were admitted to a treatment protocol in which the dose of intravenous immune serum globulin was increased from 100 mg/kg to a maximum of 250 mg/kg each four weeks. The dose increases were determined by recurrence of infection during treatment and by IgG trough levels of less than 400 mg/dl. Infectious episodes during intravenous immune serum globulin treatment responded well to 10 to 20 day long periods of antibiotic treatment, and prolonged infection-free periods were achieved in all patients. Only one hospital admission was necessary during the entire study period. The increase in intravenous immune serum globulin dose to 200 mg/kg did not significantly reduce the recurrence of infections. Infections also occurred in patients whose IgG trough levels were persistently above 400 mg/dl. High doses of intravenous immune serum globulin were well tolerated, and all patients are still receiving intravenous immune serum globulin treatment. A generalized pruritic rash was observed in two patients. In no patient have clinical or laboratory signs of deficiency in cell-mediated immunity developed.

Use of intravenous immune globulin in pregnant women with common variable hypogammaglobulinemia

Two patients with common variable hypogammaglobulinemia were treated with immune serum globulin during pregnancy. An intravenous immune serum globulin preparation was used in the last trimester of pregnancy. Both patients tolerated this preparation well and had an uneventful pregnancy. The two term newborns were healthy and had cord blood IgG levels likely to be the result of transplacental transfer of the intravenous immune serum globulin preparation. During pregnancy there is an increase in the IgG distribution space due to plasma volume expansion. Therefore, pregnancy is an indication for these immune serum globulin preparations that can be administered at high doses intravenously in order to confer adequate protection to the mother and the newborn.