Immunomodulation by intravenous immunoglobulin.

In 1980, it was observed in a child with idiopathic thrombocytopenic purpura (ITP) that intravenous administration of pooled human immunoglobulin-G (IVIG) was followed by a rapid increase of the platelet count. Prompted by this finding, a pilot study and two prospective multicenter studies on children with ITP were organized. Efficacy of this new treatment for ITP was soon confirmed worldwide. In addition to the immediate effect, long-term observations following administration of IVIG suggested the occurrence of modulation of the immune response. Also, concomitant with studies on the mechanism of action of IVIG, the use of IVIG in the treatment of patients with other immune-related disorders was explored.

Prophylactic and therapeutic use of immunoglobulin for intravenous administration in patients with secondary immunodeficiencies associated with malignancies.

Failure of host defense systems associated with malignancies may be attributable to the tumor, to cytoreductive therapy or to combined endogenous and iatrogenic influences. Management of the resulting increased susceptibility to infections may require supplementation of antibiotic therapy with additional forms of treatment, including passive immunization with antibodies. This review discusses the use of immunoglobulin preparations for intravenous administration (IVIG) in patients with secondary immunodeficiencies associated with neoplasia. A suitable model for evaluating the prophylactic effect of IVIG is chronic lymphocytic leukemia. Many observations suggest that IVIG reduces the frequency of acute respiratory infections. Another malignant condition with decreased serum levels of polyclonal immunoglobulins and high frequency of infections is multiple myeloma. A crossover study recently demonstrated that IVIG significantly (P less than 0.01) reduced the frequency of respiratory tract infections in these patients. Furthermore the prophylactic effect of IVIG was evaluated in patients with small cell carcinoma of the lung. In a randomized prospective trial it was noticed that IVIG applied during intensive chemotherapy and irradiation courses significantly (P = 0.04) reduced the frequency of infections. Evidence for a therapeutic effect of IVIG was obtained in adult tumor patients and in children with leukemia or non-Hodgkin's lymphoma who developed severe varicella-zoster virus infections. The treatment effectively controlled fever, skin lesions and neuralgia and prevented progression of the infection. Therapeutic usefulness of IVIG in bacterial infections is still based on anecdotal evidence. Experimental data suggest that in addition to effects mediated by specific antibodies, nonspecific interactions of IgG molecules with Fc-receptors on macrophages may be clinically important.

The capacity of various types of immunoglobulin for intravenous use to interact with Fc receptors of human monocytes and macrophages.

The capacity of immunoglobulin for intravenous application (IgG-IV) to interact with Fc receptors of human monocytes and macrophages was tested by quantifying the inhibition of phagocytosis of IgG-sensitized erythrocytes. To this end a spectrometric phagocytosis test has been used. When compared with IgG for i.m. use (IgG-IM), all IgG-IV had reduced activity. This reduction was related, in part, to the reduced amount of IgG dimers and polymers in IgG-IV. On a weight basis dimeric IgG and polymeric IgG exerted 6-fold and 14-fold higher activity, respectively, than monomeric IgG. When this difference was corrected for, chemically modified IgG-IV still had significantly reduced inhibitory activity; DEAE-Sephadex-treated IgG and acid-treated IgG had an activity similar to IgG-IM, and PEG-treated IgG showed a slightly reduced activity. Pepsin-treated IgG was greater than 100-fold less active than IgG-IM. The reactivity of IgG-IV with monocyte and macrophage Fc receptors was closely correlated. The most conspicuous differences found were related to the concentration at which IgG was used. Thus, beta-propiolactone-treated IgG and plasmin-treated IgG were found to have significantly reduced activity at concentrations greater than 20 micrograms/ml, but almost normal activity when used at lower concentrations.

Transplacental passage of intravenous immunoglobulin in the last trimester of pregnancy.

Immunoglobulin G was given intravenously (IVIgG) to pregnant women (27 to 36 weeks gestation) with signs of chorioamnionitis who were at risk for preterm delivery. Twenty-four patients received antibiotics alone (control group). Twenty-seven patients received the same antibiotics in combination with IVIgG, either 12 gm in 12 hours (low IVIgG dosage) or 24 gm on each of 5 consecutive days (high IVIgG dosage). Transplacental passage of IVIgG was shown to be a function of gestational age and of dose. Up to the thirty-second week of gestation, IgG infusions had no effect on IgG concentrations in cord sera. After that time, cord serum IgG levels were significantly higher in the high-dose group compared with the low-dose and control groups. All four subclasses of IgG, and two different antibodies present in the IVIgG preparation passed from the mother to the fetus. Thus the infused IgG mimicked the transplacental passage of endogenous IgG.

Platelet-leukocyte interaction: selective binding of thrombin-stimulated platelets to human monocytes, polymorphonuclear leukocytes, and related cell lines.

The association of platelets with leukocytes was investigated, using gel-filtered platelets stimulated with thrombin and then fixed with formaldehyde. Evidence is presented that stimulation of gel-filtered platelets with low concentrations of thrombin (0.01 to 0.1 U/mL) induces the expression of surface determinants interacting strongly with monocytes and polymorphonuclear leukocytes (PMNs) but only weakly with lymphocytes. Both monocyte-platelet binding and PMN-platelet binding occurred at 37 degrees C and more intensively at 0 degrees C; it was Ca2+-dependent and was unaffected by the addition of sodium azide. The binding also occurred with the monocytoid cell lines HL 60 and U 937 in exponential growth and was much less two days after induction of terminal differentiation by phorbol myristate acetate (PMA). No other tested cell lines (B cells, T cells, and myeloid cells) bound thrombin-stimulated platelets. Monocyte-derived macrophages kept in culture for one week also exhibited reduced binding of thrombin-stimulated platelets. IgG and fibronectin could be ruled out as ligands that mediate binding.

Effect of various treatments of gamma-globulin (IgG) for achieving intravenous tolerance on the capacity to interact with human monocyte Fc receptors. A comparative study.

Gamma-globulins for intravenous application (IgG-IV), processed by various methods, were tested for their ability to interact with human monocyte Fc receptors by determining the dose required to inhibit monocyte Fc receptor-mediated rosette formation and phagocytosis by half (ID50). Since dimeric and oligomeric IgG were found to be 2-3 times and 5-15 times more potent, respectively, than monomeric IgG, the varying proportions of polymeric IgG in intact IgG-IV were corrected for by calculation. The results of the rosette formation and phagocytosis tests were closely correlated, and insignificant differences between preparations processed by the same procedure were noted, while considerable differences were found between different procedures. The decreasing order of inhibitory activity was DEAE-Sephadex-treated IgG, acid-treated IgG, plasmin-digested IgG, polyethylene glycol(PEG)-precipitated IgG, IgG subjected to reduction/alkylation, IgG that underwent sulfitolysis, IgG treated with beta-propiolactone, and finally pepsin-treated IgG. Thus, while mild procedures preserve the capacity of IgG to interact with monocyte Fc receptors, chemical modification severely interferes with this important effector function.

Correlation of in vitro antibody synthesis with the outcome of intravenous gamma-globulin treatment of chronic idiopathic thrombocytopenic purpura.

Intravenous gamma-globulin (IVGG) effectively elevates the platelet count of most patients with chronic idiopathic thrombocytopenic purpura (ITP). This study examined whether this effect was related to changes in in vitro immunoglobulin secretion and suppression in coculture. Before treatment, patient in vitro immunoglobulin secretion was less than 50% of the concurrent control in all eight cases and the patients suppressed antibody synthesis in coculture an average of 39%. After treatment, increases in in vitro immunoglobulin secretion and decreases in suppression were closely related to a good response to IVGG therapy as measured both by acute increases in the platelet count (P less than 0.05) and by the long-term outcome from therapy (P less than 0.05). Decreases in platelet-associated IgG correlated with increases in in vitro immunoglobulin secretion (P less than 0.05). Data consistent with the lack of inhibition of in vitro immunoglobulin secretion following IVGG included long-term increases in both serum IgM and IgG (independent of transfused IgG) and maintenance of the percentage of total IgG that was IgG3. T-cell numbers and subsets and lymphocyte proliferation were unaffected by IVGG. IVGG tends to normalize in vitro immunoglobulin secretion and its suppression in those ITP patients with good clinical responses in conjunction with decreased levels of autoantibody. This evidence suggests that good responders to IVGG may have inhibition of antiplatelet antibody production. IVGG does not appear to interfere with normal antibody production.

Intravenous immunoglobulin versus oral corticosteroids in acute immune thrombocytopenic purpura in childhood.

In a randomised, multicentre study intravenous IgG was compared with oral corticosteroids in 108 children with untreated acute immune thrombocytopenic purpura. IgG was an efficient treatment with no severe untoward reactions. The effects of corticosteroids and IgG were identical for rapid responders, who accounted for 62% of all patients. In contrast, patients requiring more than initial treatment responded better if randomised to IgG. The serum IgG level increased two-fold after IgG. A significant rise in IgM levels was observed after both IgG and corticosteroids. The platelet-associated IgG index was high in 75% of all patients. No significant differences between the two treatment groups were found, but rapid responders had a smaller mean initial platelet-associated IgG index which returned more rapidly and more permanently to normal than that of slow responders.

Elevation of platelet associated antibody levels in patients with chronic idiopathic thrombocytopenic purpura expressing the B8 and/or DR3 allotypes.

The HLA type DR3 was present in 11 of 26 patients with Chronic Idiopathic Thrombocytopenic Purpura (ITP), a significantly increased frequency (p less than 0.05). Levels of platelet associated immunoglobulin M(PAIgM) were significantly higher in the B8 and/or DR3 positive group of chronic ITP patients than in the B8 DR3 negative patients despite similar clinical outcomes. Other immunologic parameters assessed, including serum immunoglobulin levels, rate of catabolism of transfused IgG, and antibody coated autologous red cell clearances were similar for both groups. These results suggest that there is an immunobiologic abnormality associated with the B8 DR3 allotypes which may result in a predisposition not only to chronic ITP, but also to a significant increase in PAIgM. These results are in accord with studies linking autoantibody with B8 DR3.

Surface markers, 5'-nucleotidase activity, and in vitro functions of lymphocytes from patients with primary humoral immunodeficiency.

Immunologic surface markers, 5'-nucleotidase activity, and in vitro cell functions were determined on peripheral blood mononuclear cells from 20 patients with primary humoral immunodeficiencies. Imbalances of T-cell subsets were a frequent finding and often associated with a deficiency of helper T lymphocytes, predominantly in common variable immunodeficiency. The magnitude of the blastogenic response to mitogens was subnormal in the majority of the samples and showed no correlations to the proportions of helper, suppressor T cells or monocytes in the cultures. Moderate to marked suppression of the pokeweed mitogen-driven allogenic B-cell maturation was mostly mediated by T lymphocytes but modified by monocytes in some patients. In identical twins, T lymphocytes selectively suppressed IgA production. Both in sex-linked agammaglobulinemia and common variable immunodeficiency the activity of 5'-nucleotidase was significantly lower than in controls. This deficiency was mediated by T lymphocytes and showed no correlations to imbalances of T-cell subpopulations or to alterations of lymphocyte functions.

Estimation of the degree of opsonization of homologous erythrocytes by IgG for intravenous and intramuscular use.

In an effort to evaluate the capacity of polyspecific IgG preparations to sensitize homologous erythrocytes, immunoglobulin G for intramuscular use and an IgG preparation for intravenous use were tested for their tendency to associate with and to opsonize homologous erythrocytes. It was found that the amount of IgG associated with erythrocytes by far exceeded the opsonic moiety. Erythrocytes incubated in IgG in amounts higher than that achieved in vivo after 5 infusions of 0.4 g/kg body weight each, were sometimes lightly opsonized when tested on rosette formation with and phagocytosis by adherent monocytes. IgG for intravenous use was lower than IgG for intramuscular use in its opsonic activity and did often not reach the level of significance. Comparison with rosette formation and phagocytosis of erythrocytes with known amounts of antibodies allowed the prediction that following high-dose infusion of IgG, less than 25 opsonic molecules per red blood cell are achieved in recipients of blood groups A, B, and AB (and probably even less in those of blood group (O). Erythrocytes preincubated in polyspecific IgG failed to inhibit phagocytosis of optimally sensitized erythrocytes by cultured macrophages.

Efficacy of intravenous immunoglobulin in primary humoral immunodeficiency disease.

Twenty-one patients with primary humoral immunodeficiency were treated for 1 year with a chemically intact immunoglobulin, 300 mg/kg body weight given intravenously every 3 weeks, to compare immunoglobulin levels and clinical status with results achieved after standard treatment with intramuscular immunoglobulin given previously for 1 year. A substantial reduction of specific acute illnesses and antibiotic use was found for 18 of the 21 patients, particularly during the second 6 months of treatment. Average IgG levels before intravenous infusion were increased 243 mg/dL over previous intramuscular pre-injection levels. Adverse effects were recorded for 2.5% of infusions.

Specific and nonspecific mechanisms of action of immunoglobulin G in therapy of idiopathic thrombocytopenic purpura (ITP).

The efficacy of IgG infusion therapy in ITP is now established even in cases resistant to other forms of therapy. However, the mechanism of action is still speculative. We assume that a correction of the elevated thrombocyte clearance is brought about at several levels. First, antibodies specific for an inciting antigen (and for which the patient is deficient) may remove free antigen and/or immune complexes which adhere to platelet surfaces, thereby rendering platelets less susceptible to clearance. Second, IgG may act nonspecifically by protecting the platelet surface from becoming covered with immune complexes. Third, monomeric IgG may display a nonspecific inhibitory effect at the level of the interaction of immunologically altered platelets with Fc receptors of mononuclear phagocytes. For the latter effect, good in vivo evidence exists. However, it must be born in mind that interaction of antibodies with Fc receptors is but one mechanisms for triggering adherence and endocytosis. A variety of other receptors and binding sites exists which may interact with immunologically altered thrombocytes. These may either trigger phagocytes on their own or facilitate the interaction of antibodies and Fc receptors. How IgG infusion influences such interactions remains to be determined.

Intravenous immunoglobulin therapy: new aspects and outlook.

Experiences gathered while exploring the usefulness of intravenous immunoglobulin for children with idiopathic (immune) thrombocytopenic purpura (ITP) are reviewed in view of further investigations characterizing the effects of IgG i.v. in other immune diseases without detectable antibody deficiency. The most pertinent factors to be considered are i) the heterogeneity of an immune disease investigated; ii) the criteria used to evaluate the effects of the IgG therapy; iii) the IgG preparations used and i.v. dose-fractionation. Controlled, prospective clinical trials will be required to further explore the practical usefulness of IgG i.v.

Correlation of natural killer cell function with Leu 7 reactivity in patients with humoral immunodeficiency.

We studied the surface markers Leu 7, Leu 1, Leu 2a and Leu 3a on lymphocytes of 54 healthy blood donors and 19 patients with humoral immunodeficiencies and compared the relative numbers of positive cells with the natural killer cell (NK) activity. In controls, and in 12 out of 19 patients (group A) the percentage of the Leu 7+ cells was positively correlated with NK activity. Seven of 19 patients had increased relative numbers of Leu 7+ cells and low NK activity (group B). In controls and group A patients about 40% of the Leu 7+ cells simultaneously expressed the cell markers Leu 1 and Leu 2a. In group B patients approximately 70% of the Leu 7+ cells carried T cell antigens. Furthermore, a distinct suppressor T cell predominance was noticed and the large granular lymphocytes of these patients showed morphological abnormalities.

[Immunotherapy of chronic bronchitis: importance of humoral antibodies]. / Immuntherapie der chronischen Bronchitis: Bedeutung der humoralen Antikörper.

Properties and potentialities of passive and active immunization are discussed in relation to antibody deficiency syndromes (ADS) and in situations with increased risk of infections. Passive immunization with immunoglobulins is indicated whenever the specific antibodies needed for defence against an infectious agent are lacking. The protective effect provided by passive immunization is polyvalent and of immediate onset, but fades rapidly with a halflife of 2-3 weeks. Adequate protection can only be expected with a high dosage. Active immunization with specific vaccines provides longlasting protection against certain infectious diseases with high morbidity and lethality. Using the example of pneumococcal polysaccharide vaccine, the authors offer evidence that a single subcutaneous injection provides a high level of protection in immunologically normal young individuals, but not in old and immunocompromised subjects.

Varicella and herpes zoster in immunosuppressed children: preliminary results of treatment with intravenous immunoglobulin.

Seven immunosuppressed children with varicella and two with herpes zoster were treated with large intravenous doses of polyvalent, intact immunoglobulin (IgG i.v.). In all patients the treatment was effective for controlling fever and skin lesions and for preventing progression and complications, even if this therapy was started late and/or if the patient was severely lymphopenic . More IgG was needed to control disseminated than less advanced varicella. No untoward effects of IgG therapy were observed. The preliminary results suggest that in future trials i.v. IgG should be used for comparison with antiviral agents.