Antiaggregatory and proangiogenic effects of a novel recombinant human dual specificity anti-integrin antibody.

BACKGROUND: beta(3)-Integrins are involved in platelet aggregation via alpha(IIb)beta(3) [glycoprotein (GP)IIb-GPIIIa], and in angiogenesis via endothelial alpha(V)beta(3). Cross-reactive ligands with antiaggregatory and proangiogenic effects, both desirable in peripheral vasculopathies, have not yet been described. OBJECTIVES: In vitro and in vivo characterization of antiaggregatory and proangiogenic effects of two recombinant human Fab fragments, with emphasis on beta(3)-integrins. METHODS: Recombinant Fab fragments were obtained by phage display technology. Specificity, affinity and IC(50) were determined by immunodot assays, enzyme-linked immunosorbent assay (ELISA), and Scatchard plot analysis, and by means of human umbilical vein endothelial cells (HUVECs). Functional analyses included ELISA for interaction with fibrinogen binding to GPIIb-GPIIIa, flow cytometry for measurement of activation parameters and competitive inhibition experiments, human platelet aggregometry, and proliferation, tube formation and the chorioallantoic membrane (CAM) assay for measurement of angiogenic effects. RESULTS: We observed specific and high-affinity binding to an intact GPIIb-GPIIIa receptor complex of two human Fab autoantibody fragments, with no platelet activation. Dose-dependent fibrinogen binding to GPIIb-GPIIIa and platelet aggregation were completely inhibited. One Fab fragment was competitively inhibited by abciximab and its murine analog monoclonal antibody (mAb) 7E3, whereas the other Fab fragment bound to cultured HUVECs, suggesting cross-reactivity with alpha(V)beta(3), and also demonstrated proangiogenic effects in tube formation and CAM assays. CONCLUSIONS: These Fab fragments are the first entirely human anti-GPIIb-GPIIIa Fab fragments with full antiaggregatory properties; furthermore, they do not activate platelets. The unique dual-specificity anti-beta(3)-integrin Fab fragment may represent a new tool for the study and management of peripheral arterial vasculopathies.

Recombinant anti-idiotypic antibodies inhibit human natural anti-glycoprotein (GP)IIb/IIIa autoantibodies.

Anti-idiotypic antibodies (anti-Id) have been described against idiotypes expressed on various autoantibodies. Since an immunoregulatory effect has been postulated for anti-Id, modulation of the anti-Id response in autoimmune disease may be of interest. In chronic immune thrombocytopenic purpura (AITP), autoantibodies directed mainly against platelet membrane glycoprotein (GP) IIb/IIIa cause platelet destruction by Fc-mediated phagocytosis or by complement lysis. We have previously reported on the generation of two recombinant anti-GPIIb/IIIa autoantibody fragments (PDG-X, PDG-B), that are specific for conformationally intact GPIIb/IIIa and inhibit binding of autoantibodies from patients with AITP. In the present study, we show that anti-GPIIb/IIIa specificities are not limited to a single individual by isolating five additional anti-GPIIb/IIIa autoantibody fragments from a second phagemid Fab library of an unrelated healthy donor. Using soluble Fab of PDG-X and PDG-B as antigens for panning Fab phagemid libraries from healthy human individuals, we isolated anti-Id phage clones specific for PDG-X or PDG-B. In addition they inhibited the binding of PDG-X or PDG-B to GPIIb/IIIa. Amino acid sequence comparison between these specific antiId and GPIIb/IIIa was performed. Generation of these anti-Id directed against pathologically relevant anti-GPIIb/IIIa autoantibodies may represent a new suitable and specific therapeutic option for the treatment of antibody-mediated AITP.

Plasma autoantibodies against platelet glycoprotein IIb/IIIa from patients with autoimmune thrombocytopenic purpura may recognize different antigenic determinants.

Autoantibodies against platelet glycoprotein (GP) GPIIb/IIIa have been demonstrated in patients with autoimmune thrombocytopenic purpura. Recently, it has been shown that plasma autoantibodies from some patients bind to the cytoplasmic domain of GPIIIa. Our aim was to evaluate further the binding specificity of these plasma autoantibodies. From 7 patients with detectable plasma antibodies against intact GPIIb/IIIa, 1 showed strong antibody binding to a synthetic C-terminal peptide of GPIIIa. Ig class analysis of affinity purified anti-GPIIb/IIIa autoantibodies from this patient revealed an IgM antibody that reacted with intact GPIIb/IIIa as well as with recombinant GPIIb/IIIa lacking the C-terminal domains, and an IgG antibody that bound to intact GPIIb/IIIa but not to GPIIb/IIIa lacking the C-terminal region. These data indicate that this patient has at least 2 autoantibodies, an IgG directed against the cytoplasmic domain of GPIIIa and an IgM reacting with the extracellular part of GPIIIa. This may support the hypothesis that plasma IgG antibodies directed against the C-terminal domain of GPIIIa may be due to the exposition of cytoplasmic epitopes of GPIIIa as a result of increased cell lysis by IgM autoantibodies.

Recombinant human natural autoantibodies against GPIIb/IIIa inhibit binding of autoantibodies from patients with AITP.

Autoimmune thrombocytopenic purpura (AITP) is caused by autoantibodies predominantly against platelet membrane glycoproteins (GP) IIb/IIIa and GPIb/IX. Naturally occurring autoantibodies have been described against a variety of autoantigens; it has been suggested that perturbation of their regulation may be associated with autoimmune diseases. Using a combinatorial Fab phagemid library from an individual immunized with human RhD+ red blood cells, we evaluated the presence of natural anti-GPIIb/IIIa autoantibodies as well as their relation to AITP-associated anti-GPIIb/IIIa autoantibodies. Selection on native GPIIb/IIIa and characterization of positive clones by inhibition studies against murine monoclonal anti-GPIIb/IIIa antibodies and by DNA analysis revealed the presence of two distinct recombinant anti-GPIIb/IIIa autoantibodies, which partially inhibited binding of affinity-purified platelet-associated autoantibodies from 8/12 AITP patients. Our results demonstrated that GPIIb/IIIa-specific Fab directed against conformational epitopes within the GPIIb/IIIa complex may be cloned from the genome of an individual immunized with RhD+ red blood cells, who was not affected by AITP. The partial inhibition of binding of platelet-associated autoantibodies from AITP patients to GPIIb/IIIa by the recombinant anti-GPIIb/IIIa phage clones suggests recognition of closely related antigenic epitopes. These phage clones may represent down-regulated, potentially pathological autoantibodies and could be used as new tools for investigation of AITP.

Antibodies against platelet glycoproteins and antiphospholipid antibodies in autoimmune thrombocytopenia.

Autoantibodies against platelet glycoproteins (anti-GP) are found in the majority of patients with autoimmune thrombocytopenia (AITP) as well as in thrombocytopenia associated with systemic lupus erythematosus (SLE). Some of these patients may have anti-phospholipid antibodies (anti-PL). To evaluate the pathogenetic significance of anti-PL and anti-GP antibodies in AITP and SLE patients, we investigated anti-cardiolipin (anti-CL), anti-phosphatidylserine (anti-PS) and anti-GP antibodies (anti-GPIIb-IIIa and anti-GPIb-IX) in 71 patients with AITP and 3 thrombocytopenic patients with SLE. Anti-GP antibodies were detected in 52 (70%) patients. Fifty-six (73%) patients showed anti-PL antibodies. Seven patients (6 AITP, 1 SLE) with both anti-GPIIb-IIIa and IgG anti-PL antibodies were followed during treatment with corticosteroids. Antibodies were measured before treatment and at the time of platelet-peak. Anti-GPIIb-IIIa antibodies decreased in all or became undetectable in five. In contrast, IgG anti-PS and IgG anti-CL antibodies decreased only moderately or remained positive. Adsorption experiments, using gelfiltered platelets, erythrocyte (Ec)-inside-out-vesicles and purified GPIIb-IIIa, showed that anti-GP and anti-PL antibodies have distinct specificities and do not crossreact. We conclude that anti-PL and anti-GP antibodies may be present simultaneously in some patients with immune mediated thrombocytopenia. Although anti-PS as well as anti-CL antibodies may be responsible for thrombocytopenia, we speculate that anti-GPIIb-IIIa antibodies are more related to the severity of thrombocytopenia.

Antibody studies in a patient with acute thrombocytopenia following infusion of plasma containing anti-PI(A1).

Immune thrombocytopenia due to passive transfer of anti-PI(A1) alloantibody has been noted as a rare but potentially dangerous complication of plasma transfusions. We report a patient with a preoperative platelet count of 241 x 10(9)/l who developed severe thrombocytopenia within 2 hr following transfusion of 2 U of fresh frozen plasma. The plasma donor was found to be a PI(A1)-negative woman. The platelet count of the PI(A1)-positive patient recovered within 7 days to normal values. In the frozen plasma, excessive antibody binding to GPIIb-IIIa on the recipient's platelets was detected. The antibody was shown to have anti-PI(A1)-specificity. Only 40 min after transfusion of the frozen plasma, no antibody was detected in the plasma of the recipient. This case suggests that passively administered anti-PI(A1) alloantibody is immediately adsorbed onto the recipient's platelets and thus removed from circulation.

International study to compare antigen-specific methods used for the measurement of antiplatelet autoantibodies.

Platelet-associated and plasma autoantibodies against platelet glycoproteins (GP) have been demonstrated in patients with autoimmune thrombocytopenia (AITP) using various methods. Eight laboratories in seven countries participated in this international study to evaluate the interlaboratory agreement using glycoprotein-specific immunoassays for these autoantibodies. The participating laboratories received blind samples of frozen washed platelets and plasma from 22 normal donors and 22 AITP patients. Platelet-associated and plasma autoantibodies against GPIIb-IIIa and GPIb-IX were measured by MAIPA, immunobead assay or modified antigen capture assay. Of the control samples, 96.0% and 97.2% of all results for platelet-associated and plasma autoantibodies to GPIIb-IIIa/ GPIb-IX, respectively, were negative. The mean variation coefficient of the control samples of platelet-associated and plasma autoantibodies was 89.5% (range 11.1-272.9%) and 46.5% (range 21.0-78.0%), respectively. In 20/22 patient samples, platelet-associated autoantibodies to either glycoprotein were noted by at least two laboratories. The mean degree of agreement in these samples was 74.0%. There was a significant correlation in the individual antibody measurements between all laboratories (Kendall coefficient of concordance 0.60 and 0.38, P < 0.001; Spearman rank order test, range of correlation coefficient 52.3-94.0% and 42.2-85.0%, P < 0.05, for anti-GPIIb-IIIa and anti-GPIb-IX, respectively). In contrast, plasma autoantibodies to either glycoprotein were noted by at least two laboratories in only 13/22 patient samples. Moreover, the degree of agreement was poor (50.1%) and a significant correlation was noted between only six pairs of laboratories. We conclude that methods used in this study yield good interlaboratory agreement in measuring platelet-associated autoantibodies against GPIIb-IIIa and GPIb-IX. In contrast, poor agreement was found in detecting plasma autoantibodies to the same glycoproteins.

[Immunosuppression--a tightrope walk between iatrogenic harm and therapy]. / Immunsuppression--Gratwanderung zwischen latrogenie und Therapie.

The therapeutic effect of most immunosuppressive agents is unspecific and therefore often limited by an increased risk of infection by viral, bacterial or fungal organisms as well as by an increased incidence of malignant neoplasms. This short review includes the most commonly used immunosuppressants such as corticosteroids, azathioprine, methotrexate, cyclophosphamide and cyclosporine. The most common risks of long-term corticosteroid treatment are Cushing-like changes, decreased glucose tolerance and the usually benign steroid diabetes. Also clinically important is osteoporosis, since it can be prevented by physical training, calcium supplementation and treatment with vitamin D if necessary. Although there is still no proof of a significantly increased risk of peptic ulcer during steroid therapy, patients may develop gastrointestinal hemorrhage and even perforation without producing pain while being treated with corticosteroids. Mineralocorticoid effects, such as salt and water retention, are seen only with hydrocortisone and prednisone, whereas with synthetic steroids such as dexamethasone, sodium retention is absent despite their strong antiphlogistic activity. The most important side effect of the cytotoxic agents azathioprine, methotrexate and cyclophosphamide is marrow suppression. Due to the high turnover of neutrophils, patients most frequently suffer neutropenia rather than thrombocytopenia or anemia. Neutropenia, as well as impaired humoral and cellular immune mechanisms, are responsible for increased susceptibility to bacterial, viral or parasitic diseases during immunosuppressive therapy. Hepatotoxicity has been reported among patients receiving azathioprine (cholestatic hepatitis) and methotrexate (elevated AST levels and, rarely, liver fibrosis or cirrhosis). Cyclophosphamide causes hemorrhagic cystitis in a substantial proportion of patients, as well as an increased incidence of urothelial neoplasms. Both these side effects may be prevented by Mesna. The most important side effects of cyclosporine are acute and chronic nephrotoxicity usually associated with significantly elevated plasma levels of the drug. It must be borne in mind that severe nephrotoxicity may occur in patients receiving cyclosporine and ketoconazole together, since the latter may inappropriately increase the plasma cyclosporine level.

[Vomiting, upper abdominal pain and sepsis]. / Erbrechen, Oberbauchschmerzen und Sepsis.

A 78-year-old man was admitted to a surgical emergency room because of an acute abdomen. He had vomited violently four times shortly after a meal. This episode was followed by severe upper abdominal and thoracic pain, radiating to the back. Clinical evaluation revealed epigastric peritoneal signs and a soft lower abdomen. Emergency laparotomy disclosed peritoneal adhesions, a distended stomach and numerous diverticula of the small intestine. Neither a perforation nor inflammatory signs were noted. A dramatic accentuation of the pain occurred, followed by the clinical picture of septic-toxic shock. On a chest X-ray, liquid was noted in the left pleural cavity. On occasion of a puncture, this liquid was found to be malodorous and bloody. Cultures yielded Vibrio vulmificus, streptococcus viridans as well as proteus and klebsiella species. The patient succumbed to multiorgan failure on the third day of hospitalization. The autopsy disclosed a recent rupture of the esophagus (Boerhaave syndrome) with purulent peri-esophagitis and mediastinitis as well as fibrinopurulent left-sided pleuritis.

Acromegaly. Clinical and biochemical features in 500 patients.

This prospective study defines the clinical and biochemical features of acromegaly in a large cohort of patients. There was no difference in sex distribution, and for men and women the mean ages at diagnosis (40 +/- 12 and 40 +/- 14 yr, respectively) were similar. Nearly three-quarters of patients were overweight and some 12% severely overweight; the frequency and severity of obesity also was not different between the sexes. Half of patients were hypertensive or were taking anti-hypertensive drugs. Neither GH nor insulin levels were significantly different between normotensive and hypertensive patients. Acral growth and facial coarsening, soft tissue swelling, and excessive perspiration were present in the majority (98%) of patients. Mean serum GH, Sm-C, and PRL levels did not differ between the sexes. Sm-C levels correlated with mean GH concentration (r = 0.31, p < 0.001), both variables inversely related to age. With each decade of life, mean GH and Sm-C levels declined by 7.6 +/- 0.2 ng/mL and 0.5 +/- 0.2 U/mL, respectively. Impaired glucose tolerance was diagnosed in 36% and frank diabetes mellitus in 30% of patients. Hyperprolactinemia was noted in 18% of patients. Galactorrhea was noted in 43 (9%) patients, most of whom were female; the mean GH levels of patients with galactorrhea (60.1 +/- 13 ng/mL) were higher than those of patients without (35.4 +/- 2.6 ng/mL, p = 0.02). Acromegaly appears to afflict men and women equally with a preponderance of presentation in the fourth decade of life.(ABSTRACT TRUNCATED AT 250 WORDS)

Autoantibodies against the platelet glycoproteins (GP) IIb/IIIa, Ia/IIa, and IV and partial deficiency in GPIV in a patient with a bleeding disorder and a defective platelet collagen interaction.

To evaluate the physiologic importance of the different collagen receptors on platelets, we screened 806 patients admitted to the hospital because of hemorrhagic diathesis for eventual laboratory evidence of a pathologic platelet collagen interaction, and found 5 patients with an isolated deficiency in collagen-induced platelet aggregation. Four of these five patients had a partial defect, one had a complete defect. The structural and functional analysis of the platelets from the patient with a complete defect showed a deficiency in glycoprotein (GP) IV and autoantibodies against GPIIb/IIIa, GPIa/IIa, and GPIV. Patient plasma had only a minimal effect on normal control platelets and Naka-negative platelets. The analyses of the defect in the patient and of the data in the literature suggest that a single defect may not result in clinical bleeding (GPIV-deficient patients do not bleed), but may become symptomatic in combination with another defect such as the autoantibodies against GPIa/IIa, GPIV, and/or GPIIb/IIIa, all of which are involved in platelet collagen interactions (three of four of our immune thrombocytopenic purpura patients with anti-GPIV and anti-GPIIb/IIIa autoantibodies had a bleeding disorder). We hypothesize that it is the synergism of two abnormalities that results in the defective function, a mechanism that is in agreement with earlier studies on platelet collagen interaction that suggests that a double defect in platelet collagen interactions is required to become clinically apparent.

[Acute poisoning--a brief review]. / Akute Vergiftungen--eine kurze Ubersicht.

Poisonings are frequently encountered in hospital emergency departments. Approximately 80% of poisonings occur by ingestion of toxic substances. The basic approach to the poisoned patient includes initial stabilization to correct immediate life-threatening problems, treatment to reduce absorption, measures to improve elimination of the toxin and the use of specific antidotes. Traditional gastric lavage is indicated today in severely intoxicated patients if they present within the first few hours of ingestion. Administration of activated charcoal is recommended in most cases of poisoning. It should be administered early, in an adequate dose and repeatedly if necessary.

Autoantibodies against platelet glycoproteins in autoimmune thrombocytopenic purpura: their clinical significance and response to treatment.

Autoantibodies against platelet glycoproteins (GP) have been demonstrated in patients with autoimmune thrombocytopenic purpura (ATP). However, their clinical and pathogenetic significance as well as their response to immunosuppressive treatment is unknown. Using an immunobead assay capable of measuring autoantibodies against GPIIb-IIIa and GPIb-IX, we studied 58 adult patients with active ATP (platelet count < 150 x 10(9)/L) and 26 patients with ATP in remission (platelet count > 150 x 10(9)/L and without any therapy at time of investigation). Platelet-associated autoantibodies were detected in 39 of 53 patients with active ATP (73.6%) and in 2 of 26 patients in remission (7.7%). Circulating plasma autoantibodies were noted in 17 of 58 patients in the group with active disease (29.3%) and in none of the patients in remission. Twelve patients with active ATP and autoantibodies against GPIIb-IIIa were studied prospectively during treatment with corticosteroids. Of eight patients whose platelet count normalized during treatment, platelet-associated and plasma antibodies decreased significantly in two or became undetectable in six. In contrast, of four patients whose platelet counts were unchanged or increased moderately, we noted no significant change in antibodies. Moreover, autoantibodies reappeared in two responding patients at the time of relapse. The effect of high-dose intravenous immunoglobulin was studied in six active ATP patients with antiglycoprotein autoantibodies and refractoriness to prednisone. In one patient who developed a sustained remission after IvIgG, platelet-associated and plasma antibodies to GPIIb-IIIa decreased and became undetectable. In contrast, two patients who had only a transient rise of the platelet count after IvIgG showed no significant change in autoantibody. In three unresponsive patients, autoantibodies were without change in two and decreased transiently in one patient. We conclude that in ATP the presence of autoantibodies to GPIIb-IIIa and GPIb-IX is related to the activity of the disease. Corticosteroids may inhibit autoantibody formation in some ATP patients, whereas during the early response to IvIgG, autoantibody production may not be affected.

[Cost-conscious procedure in treatment of autoimmune thrombocytopenic purpura]. / Kostenbewusstes Vorgehen bei der Behandlung der autoimmunthrombozytopenischen Purpura.

Autoimmune thrombocytopenic purpura is a common hematologic autoimmune disease. Approximately three fourth of the patients respond to corticosteroids or splenectomy and need no further treatment. Patients refractory to these two therapeutic approaches are relatively resistant to other forms of treatment and are at much greater risk for morbidity and mortality. The therapeutic choice for the refractory patient depends on the age of the patient, the degree of thrombocytopenia, on compliance, toxicity, costs of the treatment and expected duration of the response. Since there is no universal option for all patients, physicians and patients must be prepared to try several approaches over a long period of time.

Effect of high-dose intravenous immunoglobulin therapy on blood rheology.

Stroke has been reported after high-dose intravenous immunoglobulin (IVIG) therapy, so a study was conducted to find out what effect IVIG has on factors influencing blood flow. The influence of IVIG on plasma viscosity, blood viscosity, and erythrocyte aggregation was examined in vitro and in vivo. For the in-vitro experiments different amounts of IVIG were added to whole blood or plasma from healthy subjects. The in-vivo effects were assessed during five courses of treatment with IVIG (24-54 g/day) in 4 patients with chronic immune thrombocytopenia (ITP). Concentration of IgG infused correlated strongly with viscosity of plasma and whole blood, both in vitro and in vivo, and plasma viscosity increased to beyond the normal range after IVIG treatment. The changes in viscosity that occur after IVIG therapy can impair blood flow, and in patients at risk of cardiovascular and thromboembolic events they might be sufficient to produce myocardial infarction or stroke.

[High-dose gamma globulin in autoimmune diseases]. / Hochdosiertes Gammaglobulin bei Autoimmunkrankheiten.

The short-term benefit of high-dose intravenous gammaglobulin (IvIgG) in autoimmune diseases is widely accepted in patients with chronic immune thrombocytopenic purpura (ITP). Recent studies reported remission or stabilization of the disease in some patients receiving long-term IvIgG therapy. It has been suggested that this long-term effect may be due to antiidiotypic antibodies in IvIgG down-regulating the immune response in chronic ITP. Because of the high costs and the transient effect in most instances, this treatment should not be used routinely. IvIgG may be considered in severely thrombocytopenic patients with chronic ITP who develop serious bleeding.

[Antibodies as antigens--idiotypes and idiotypic networks]. / Antikörper als Antigene--Idiotypen und idiotypische Netzwerke.

The variable regions of an antibody are unique and therefore potentially immunogenic. This may result in the formation of antiidiotypic antibodies directed against these antigenic determinants. Based on this observation, JERNE has proposed his theory of idiotypic networks. According to this concept, interactions between idiotypes and antiidiotypic antibodies may play an important role in the regulation of the immune response. Idiotypic networks are thought to be essential for the maintenance of immunological tolerance to self-antigens and there is evidence that autoimmunity may in part be due to perturbation of the idiotypic network. Anti-idiotypes may be of therapeutic importance. Although production of idiotypic vaccines or treatment of hematological malignancies with tailored anti-idiotypes are still hampered by various difficulties, a widespread clinical application may be only a matter of time.

Therapy of chronic idiopathic thrombocytopenic purpura in adults.

Chronic ITP is a common hematologic illness. Approximately three fourths of the patients respond to corticosteroids or splenectomy and need no further treatment. Patients refractory to these two therapeutic approaches are relatively resistant to present forms of treatment and are at much greater risk for morbidity and mortality. Future clinical studies evaluating therapy in this refractory group would be best performed in a cooperative group setting in which large numbers of patients could be treated in a prospective randomized manner.

Inhibition of autoantibody binding to platelet glycoprotein IIb/IIIa by anti-idiotypic antibodies in intravenous gammaglobulin.

Intravenous immunoglobulin (IVIgG) causes an acute rise in the platelet count in the majority of patients with chronic immune thrombocytopenic purpura (ITP) but the mechanism(s) of action is still unknown. We evaluated the ability of three different IVIgG preparations to inhibit the in vitro binding of autoantibody to platelet glycoprotein (GP) IIb/IIIa. ITP plasma, known to contain anti-GPIIb/IIIa antibodies, was incubated overnight with either IVIgG or bovine serum albumin (BSA) followed by measurement of the autoantibody titer. Binding of autoantibody from eight ITP patients was inhibited by IVIgG in proportion to the IVIgG concentration. Using 3.2% IVIgG, compatible with therapeutic concentrations expected in vivo, mean inhibition of autoantibody binding ranged from 20.2% to 41.3%. No inhibition by IVIgG of alloantibody binding to the same or different molecules was detected (five patients with anti-GPIIb/IIIa and two with anti-HLA alloantibodies). F(ab')2 fragments of IVIgG also inhibited the binding of both plasma autoantibodies and purified anti-GPIIb/IIIA autoantibodies prepared by elution from antigen affinity columns. A portion of the anti-idiotypic antibodies could be adsorbed from IVIgG using insolubilized, purified anti-GPIIb/IIIa autoantibody. These results show that IVIgG preparations from normal donors contain anti-idiotypic antibodies directed against idiotypes located on GPIIb/IIIa autoantibodies but do not have anti-idiotypes to platelet alloantibodies against the same or different molecules. The importance of these anti-idiotypic antibodies in the therapeutic response to IVIgG remains to be established.