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The successful treatment of idiopathic thrombocytopenic purpura with low dose non specific IgG component of anti D immunoglobulin
Abstract
Five patients with ITP were treated with 2 gram intravenous infusions of intramuscular human non specific immunoglobulin (IMIg). Increased platelet counts similar to those achieved with intravenous Rhesus anti D immunoglobulin were observed in four patients. 5000 iu anti D immunoglobulin contain up to 2 g of IMIg, and the clinical responses seen in ITP patients treated with anti D may therefore be attributed to this non specific fraction. This was supported by the in vitro finding that adsorption of the rhesus specific IgG from anti D immunoglobulin did not reduce its inhibitory effect on monocyte Fc receptor function. The dose of intravenous IMIg which produced a response in ITP was less than 2% of the recommended standard dose of intravenous immunoglobulin. This correlated with the higher concentration of IgG polymers in IMIg, and we suggest therefore that the mechanism of action of this material is due to the inhibitory effect of its polymeric IgG fraction on low affinity monocyte/phagocyte Fc receptors.
... 13 However, some findings suggest that this mode of action of anti-D immunoglobulin is incorrect or at least debatable. 14 It has been reported that the anti-D specific fraction of anti-D immunoglobulin is *To whom correspondence should be addressed: Tel: +44 (0)1707 654 753; Fax: +44 (0)1707 650 223; E-mail: rthorpe@nibsc.ac.uk not the active substance responsible for e#icacy in ITP patients 15 and monoclonal anti-D has been shown to be ine#ective in treating ITP. 16,17 In addition, an ITP patient treated with varicella zoster intramuscular immunoglobulin IMIG for haemorrhagic varicella showed significantly improved platelet counts within five days of treatment, 18 suggesting that anti-D potency is not required for e#icacy of IMIG therapy in ITP. ...
... 19 It has also been suggested that immunoglobulin polymer (dimer and higher aggregates) may be the active fraction of ''normal'' Ig and anti-D immunoglobulin as these are particularly e#ective in mediating reticuloendothelial Fc receptor blockade. 15,20,21 It has also been proposed the ''old'' batches of IMIG, near to their expiry date contain relatively greater amounts of polymeric IgG compared to ''younger'' batches and may therefore be more e#icacious in ITP. 21 In order to investigate these hypotheses we have analysed numerous batches of several immunogobulin products (''normal'' and specific including anti-D) for molecular composition to establish if polymer content varies significantly between di#erent types of product and di#erent batches of the same product. ...
... It might be possible that batches of anti-D used for ITP therapy contained a high polymer content by chance, but considering the numerous reports proposing increased e#icacy of anti-D immunoglobulin, this seems unlikely. If the mechanism for action of anti-D in ITP is not simply due to its anti-D activity as has been suggested, [14][15][16][17][19][20][21] then some factor other than polymer content must be responsible for the enhanced e#icacy noted. ...
Several reports have suggested that low dose anti-D immunoglobulin is superior to high dose immunoglobulin for treatment of idiopathic thrombocytopenia purpura (ITP). However, some findings suggest that it is not the anti-D activity per se that is responsible for efficacy for treatment of ITP with anti-D immunoglobulin. Amongst alternative explanations for the mechanism of action is a relatively higher immunoglobulin polymer content of anti-D compared to other immunoglobulin products, which is more efficient in causing reticuloendothelial Fc receptor blockade. In order to investigate this we have evaluated the polymeric IgG content of anti-D and other immunoglobulin products. Different products showed considerable variation in immunoglobulin polymer content. There was no clear correlation between aggregate or dimer content and product type and anti-D as a class of product did not contain higher amounts of either dimer or aggregate compared to other products. Some manufacturers' products increased in polymer content on storage, but others did not show this effect. Therefore, higher immunoglobulin dimer and/or aggregate content cannot explain the increased efficacy of anti-D immunoglobulin for treatment of ITP. The role of polymeric Ig in efficacy for treatment of ITP is unclear.
... Their thinking was that the mechanism of IVIg amelioration of ITP may involve an antibody-RBC interaction that results in hemolysis. These investigators were the first to use RhIg containing high levels of anti-D to treat ITP patients; and it worked (233)(234)(235). Thus, use of RhIg (anti-D) became a first-line of therapy for ITP patients (9). ...
Intravenous immunoglobulin (IVIg) has been used for almost 40 years as a biologic therapeutic for the treatment of immune thrombocytopenia (ITP). Originally found to ameliorate ITP in pediatric patients, IVIg is now used to treat adult patients with acute and chronic ITP and has become a first-line therapy for this autoimmune disease. Treatment in adult ITP usually consists of high-doses of IVIg, usually 1-2 g/kg given as one bolus dose or over 4 to 5 days. Success rates vary but in adults with acute ITP, response rates are around 60% but often the response is transient. In chronic ITP, IVIg is not as efficacious and is often used in combination with other therapeutics, such as glucocorticoids or rituximab or, rarely, these patients will undergo splenectomy. Despite its many years of use, the mechanism of action of IVIg in ITP remains controversial. Although IVIg has a good record of low toxicity in adult patients, most products contain anti-A and anti-B iso-agglutinins, which can cause hemolysis in non-blood group O patients, sometimes life-threatening, with blood group AB patients being at highest risk for a severe hemolytic episode. In addition, IVIg is expensive and is susceptible to world-wide shortages due to its human source material and expanding use to treat various autoimmune/inflammatory diseases. Despite these caveats, IVIg will likely continue to be a first-line therapy for adult ITP, particularly if bleeding.
... The chemical cationization protocol used in the present study did not induce polymerization of the IgG molecules present in IVIg. Although the therapeutic effect of IVIg in experimental thrombocytopenia was previously attributed to IgG dimers [23,24], the importance of such dimers has been revisited recently [17]. In fact, IgG monomers are sufficient to protect platelet from clearance; therefore IgG oligomerization will not necessarily lead to improve therapeutic activity. ...
... 88 "" 93 Other investigators reported similar results. [94][95][96][97][98][99][100] The same approach has been used for treating HIV-related thrombocytopenia in D+ patients. 98 < 10°-i°3 In about 25% of D+ patients, Rh(D) IVIgG therapy does not seem effective. ...
The problem of passively acquired alloantibodies is an old one. Since group O blood was first transfused to patients who were not group O, clinicians and immunohematologists have had to deal with the passive transfer of anti-A, anti-B, and anti-A,B to group A, B, or AB recipients. As more plasma products (eg, platelets, fresh frozen plasma, coagulation factors) were used for recipients who were sometimes not ABO identical, the problems grew. With the advent of bone marrow transplantation (BMT), the increasing use of intravenous immune gamma globulin (IVIgG), and, more recently, the use of intravenous (TV) anti-D, an Rh (D) immune globulin, in Rh+ recipients, new problems have arisen. The last problem initiated this review.
... The importance of FccRIII in platelet clearance has also been shown in ITP patients, following the demonstration that treatment with anti-FccRIII resulted in an increase in platelet counts (Clarkson et al, 1986;Bussel et al, 1990). Some investigators have shown that high molecular weight IgG aggregates, which represent a minor fraction of IVIg or anti-D immunoglobulins, could interact with low affinity monocyte/phagocyte FccRs and mediate the inhibition of antibody-coated platelet clearance in ITP Smith et al, 1990). Recently, Teeling et al (2001) showed, in a mouse model of thrombocytopenia, that a dimer-enriched preparation of IVIg protected antibody-coated platelets from clearance, while normal IVIg preparations did not. ...
Intravenous immunoglobulins (IVIg) have immunomodulatory effects in vivo and are widely used in the treatment of autoimmune diseases, such as idiopathic thrombocytopenic purpura (ITP). The mechanisms by which IVIg can prevent platelet clearance in ITP patients are not fully understood but are known to require the participation of low affinity Fcgamma receptors (FcgammaRs), which interact poorly with monomeric immunoglobulin G (IgG). Given the importance of low affinity FcgammaRs in the treatment of ITP, we hypothesized that immune complexes (IC) produced in vitro could reproduce the effects of IVIg. Small-size tetramolecular IC were prepared using mouse monoclonal anti-human IgG and human Fc fragments. The effects of tetramolecular IC and IVIg on the in vitro and in vivo inhibition of phagocytosis of opsonized blood cells were compared. The results obtained showed that tetramolecular IC were at least six times more efficient than IVIg to prevent phagocytosis of opsonized red blood cells in vitro, and clearance of platelets in the thrombocytopenic mouse model.
BACKGROUND: Several mechanisms have been proposed to explain the therapeutic effects of intravenous immunoglobulin (IVIG) in immune thrombocytopenia (ITP). Noteworthy, a major role has been attributed to immunoglobulin (Ig)G dimers present in IVIG. It has also been suggested that immune complexes formed between IVIG and the patient's proteins after infusion could contribute to the therapeutic effect of IVIG in several autoimmune disorders. We recently observed that in-house preparations of polyclonal human IgG derived from small pools of plasma and devoid of IgG dimers were as efficient as IVIG in a mouse model of thrombocytopenia. In this work, we revisited the role of IgG dimers in the therapeutic effects of IVIG in ITP.
STUDY DESIGN AND METHODS: We used the passive mouse model of ITP to determine the therapeutic efficacy of human IgG preparations devoid of IgG dimers and of dimer-enriched and -depleted commercial IVIG. Immune complex formation between IVIG and mouse plasma proteins was evaluated using a combination of chromatography and immunoprecipitation procedures.
RESULTS: All preparations tested showed the same efficacy to alleviate ITP, regardless of their dimer contents. Significant amounts of immune complexes formed between IVIG and mouse plasma proteins were detected. However, the amount of immune complexes detected using the in-house preparation of human polyclonal IgG and mouse plasma was significantly lower, although the in-house preparation exhibited the same therapeutic efficacy as commercial IVIG.
CONCLUSION: IgG dimers and immune complexes are dispensable to prevent thrombocytopenia in a mouse model of the disease.
A chromatographic fractionation method has been developed for the production of a liquid-stable anti-D immunoglobulin product for intravenous and intramuscular use. An immunoglobulin fraction, highly enriched with anti-D immunoglobulins, was isolated by cation-exchange column chromatography and further polished, first by anion-exchange chromatography, followed by an aluminium hydroxide gel treatment. The process includes two specific steps for virus inactivation and removal, namely S/D treatment and nanofiltration. The overall anti-D process yield is about 56%. The final product is stabilised with human albumin and glycine and placed in ready-to-use syringes. The anti-D product was shown to be stable in liquid state for at least 30 months at 4°C.
Significant advances have been made in the understanding of organ specific autoimmune disorders and parallels can now be drawn with autoimmune thrombocytopenia (AITP). In AITP, the platelet surface glycoprotein target antigen epitopes are now well characterised and reliable autoantibody assays are available. Most patients can be treated effectively, and in refractory patients, experimental treatment has given new insights into the pathogenesis of the disorder. This article reviews the immunological aspects of AITP and suggests a diagnostic and therapeutic strategy in responsive and refractory patients.
To assess the efficacy of home treatment with intramuscular anti-D immunoglobulins (anti-D IgG) in patients with idiopathic or HIV-related chronic immune thrombocytopenic purpura (ITP), we conducted an open label, non-controlled, prospective study with a follow-up of 6 months in 51 consecutive patients with HIV-related (n = 24) or idiopathic ITP (n = 27). Anti-D IgG (13 micrograms/kg) were infused intravenously for three consecutive days (induction therapy). Patients whose platelet counts failed to increase above 50 x 10(9)/l were given a second course of the same therapy. If their platelet counts remained lower than 50 x 10(9)/l, they were considered non-responsive. Patients who responded to induction therapy were injected intramuscularly with 6 micrograms/kg/week anti-D IgG if platelets were between 50 and 100 x 10(9)/l or 13 micrograms/kg/week if they dropped to less than 50 x 10(9)/l. After induction therapy, responses occurred in 20/24 HIV-related chronic ITP patients (83%) and in 14/27 idiopathic chronic ITP patients (52%). During follow-up, platelets remained above 50 x 10(9)/l in 17/20 HIV-related chronic ITP patients (85%) and in 8/14 (57%) idiopathic chronic ITP patients. We conclude that anti-D IgG are a valid therapeutic option for treatment of idiopathic and HIV-related chronic ITP, since they are safe, cheap and can be given intramuscularly at home.
In chronic autoimmune thrombocytopenic purpura (AITP), an indirect monoclonal antibody immobilised platelet antigen (MAIPA) assay detected serum glycoprotein (GP) IIb/IIIa antibodies in 16/39 (41%) cases. In patients with clinically active AITP, a direct MAIPA assay detected platelet-associated GP IIb/IIIa kantibodies in 8/13 (62%) cases. Platelet bound and serum antibody concentrations suggested a high antibody affinity for platelet membrane glycoprotein IIb/IIIa. Five AITP patients with platelet associated glycoprotein IIb/IIIa antibodies were treated with intravenous anti D immunoglobulin. All showed an increase in platelet counts and a decrease in platelet associated autoantibody. These responses could be due to immunosuppressive anti-idiotype antibodies in anti D immunoglobulin.
Seven patients with chronic immune thrombocytopenic purpura (ITP) were treated with intramuscular anti-D (anti-D IgG) five times, on an alternate-day basis, or until a platelet count of 100 x 10(9)/l was achieved, and, subsequently, when necessary to maintain platelet counts above 50 x 10(9)/l. Five patients responded to therapy, two of whom entered long-term remission. Although signs of haemolysis were present in all patients, anaemia was never a problem. No patient developed haematomas at the site of injection. We suggest that intramuscular anti-D represents a safe and relatively inexpensive alternative to intravenous gamma globulins (IVGG) for children with severe chronic ITP.
We report the results of intravenous anti-D (WinRho, WinRho SD) therapy in 261 non-splenectomized patients treated at the New York Hospital-Cornell Medical Center over the period from 1987 to 1994. Children (n = 124) and adult patients (n = 137) with classic immune thrombocytopenic purpura (ITP; n = 156) or human immunodeficiency virus (HIV) related thrombocytopenia (n = 105) and acute (n = 75) or chronic (n = 186) disease at the time of the initial anti-D treatment were studied. In addition, 11 previously splenectomized patients were treated as a separate group. Our objectives were to evaluate the following. (1) Efficacy of anti-D: The response after the initial infusion was analyzed according to clinical parameters, such as patient's age, HIV status, gender, disease duration, pretreatment platelet count, and hemoglobin value, as well as treatment-related factors, including the dose of anti-D, the solvent detergent treatment of the preparation, and the type of administration. (2) Use of anti-D as maintenance therapy: The duration of response after the initial infusion and the results of subsequent treatments were evaluated. (3) Safety/toxicity of anti-D: Postinfusion reactions and hemoglobin decrease after treatment were studied. Anti-D is a safe treatment providing a hemostatic platelet increase in greater than 70% of the Rh+ non-splenectomized patients. The group with the best results is HIV- children, but all patient groups respond and the effect lasts more than 21 days in 50% of the responders. Duration of response is not influenced by HIV status; furthermore, HIV+ patients show no adverse effects on hemoglobin decrease or HIV disease progression. Patients with chronic ITP after splenectomy have minimal or no response to intravenous anti-D.
Twenty-one patients with autoimmune thrombocytopaenic purpura (AITP) were treated with anti-D immunoglobulin. There was no significant difference with low and high dose anti-D treatment in the platelet count response between homozygous and heterozygous Rh(D) positive patients. The heterogeneous responses seen in Rh(D) positive AITP patients treated with anti-D immunoglobulin cannot therefore be explained by differences in Rh(D) phenotypes.
Approximately 70% to 80% of Rh-positive adults and children with acute or chronic immune thrombocytopenic purpura or HIV-related thrombocytopenia respond to infusions of anti-D immunoglobulin. The speed of onset of response is slower than that seen with intravenous immunoglobulin. Anti-D immunoglobulin is well tolerated, with occasional adverse reactions similar to those seen in treatment with polyclonal intravenous immunoglobulin, but anemia requiring blood transfusion can occur. Response is generally better in younger patients and those who have responded to other forms of treatment. Inhibition of Fc receptor-mediated platelet destruction by anti-D immunoglobulin-opsonized erythrocytes is the most likely mechanism of action, although the relative ineffectiveness of a monoclonal anti-D immunoglobulin preparation in treatment of immune thrombocytopenic purpura suggests that other mechanisms may exist. Hepatitis C has been transmitted by intravenous anti-D immunoglobulin preparations when used in the prevention of Rh immunization, prior to the introduction of screening donor plasma for hepatitis C virus antibodies. However, an intravenous solvent-detergent-treated preparation is now available.
The use of i.v. anti-Rh(D) IgG for conditions other than prevention of Rh(D) sensitization is discussed. Besides highlighting the platelet response in ATP, a putative distinctive effect on the hemorrhagic threshold is suggested. Accordingly, we have included discussion of cases of aplastic anemia, myelodysplasia, heavy chemotherapy, coagulation deficiency, and senile vascular atrophy. We have also considered attempts to replace the high-dose pooled i.v. IgG (IVIG) with the much smaller amounts of IgG present in anti-Rh(D) preparations used to prevent Rh-sensitization in pregnancy. Both Fc and variable fragments of the IgG molecule may play a role, the former potentiated by manufacture-induced IgG aggregation and the latter by donor hypersensitization. A role for IgG-anti-F(ab')2 molecules cannot be ruled out.
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.
Since recent observations indicate that treatment with high-dose intravenous polyvalent intact immunoglobulin leads to a rapid reversal of thrombocytopenia in the idiopathic thrombocytopenic purpura (ITP) of childhood, we decided to apply this treatment to adults with ITP and to test the possibility that the effect of the immunoglobulin might be attributable to transient blockade of the reticuloendothelial system. Using sequential clearance studies of autologous 99mTc-labeled and anti-Rh(D)-sensitized erythrocytes in four adults with ITP who were treated with total doses of 1 to 1.5 g of immunoglobulin per kilogram of body weight, we found that a transient rise in platelet counts to normal levels within four to five days was accompanied by a marked temporary prolongation of the immune-particle clearance time. These data suggest that commercial intravenous immunoglobulin preparations may interfere with phagocyte Fc-receptor-mediated immune clearance. Since platelets in ITP treated with immunoglobulin were fully hemostatic, this type of therapy may allow surgical procedures to be performed safely in patients with this disease.
In this comparative study we investigated 14 immunoglobulin (Ig) preparations for intravenous application; they were prepared by various manufacturers who used either placental or venous blood as the starting material. The pepsin- and plasmin-treated products and a preparation which, according to the manufacturer, was not degraded enzymatically, contained 17-86% of IgG split products. On the other hand, three chemically modified preparations, one preparation treated at pH 4, for products treated with poly(ethylene glycol) (PEG) and one preparation protected by albumin contained 90% or more of non-fragmented IgG. The IgG subclass distribution corresponded to the distribution of subclasses in normal serum only in the nonmodified and not enzymatically degraded preparations. All samples except one contained 0.1 mg/ml IgA or more, all contained only traces of IgM. No product had clinically relevant titers of irregular antibodies against erythrocyte antigens. The content of those antiviral and antibacterial antibodies that were tested for was similar in all preparations. Only the anti-HBs activity exhibited large variations. Some PEG-treated preparations showed an elevated prekallikrein activator (PKA) level, whereas all other preparations contained, if any, only traces of PKA.
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.
The results of high-dose intravenous gammaglobulin therapy (IVGG) of adults with immune thrombocytopenic purpura (ITP) were reviewed in 28 published reports which included 282 patients. Overall, 64% of the patients responded to IVGG with a peak platelet count greater than 100,000/mm^3; 83% had peak platelet counts greater than 50,000/mm^3. Unmodified immunoglobulin was superior to modified immunoglobulin; 70% of the patients treated with the former having platelet increases to > 100,000/mm^3 compared to only 49% of those treated with the latter. More patients were refractory among those who had had ITP for at least 3 years. A higher peak platelet count immediately after IVGG administration was correlated with a longer duration of the platelet response. Patients above the age of 60 tended to have a weaker response to IVGG than did younger patients, and females tended to respond better than males. A pre-IVGG platelet count of
Intravenous administration of standard human γ‐globulin can lead to untoward reactions.
This is due to at least one endogenous and an exogenous factor.
The “endogenous” factor is revealed by the finding that certain subjects only ‐ especially patients with an antibody deficiency syndrome ‐ react to intravenous infusions of γ‐globulin administered under standard conditions.
The “exogenous” factor resides in the γ‐globulin preparation itself and is related to its anticomplementary activity.
The “endogenous” factor can be temporarily eliminated by “desensitizing” the patient; the “exogenous” factor may be eliminated by ultracentrifugation, enzymatic breakdown of the γ‐globulin, or other treatment involving exposure to low pH values.
Upon clinical trial, the preparations obtained by enzymatic degradation or by exposure to pH 4 at 37 °C displayed the best tolerance after intravenous application. Enzymatically degraded γ‐globulin is partially eliminated by the kidney and has no desensitizing effect. On the other hand, pH 4 exposed γ‐globulin does not pass through the kidney and is still capable of desensitizing “sensitive” individuals.
Résumé
L'administration intraveineuse de γ‐globuline bumaine peut provoquer chez l'homme des réactions sérieuses.
Ces phénomènes d'intolérance sont dus à l'existence au moins d'un facteur endogène et d'un facteur exogène.
Le facteur “endogène” se manifeste en ce sens que seul certains malades ‐ spécialement ceux souffrant d'un syndrome par carence d'anticorps ‐ tolèrent mal l'injection intraveineuse de γ‐globuline.
Le facteur “exogène” est associé à la γ‐globuline même et est en relation directe avec son action anticomplémentaire.
Le facteur “endogène” peut être éliminé temporairement par une désensibilisation du malade; le facteur “exogène” peut être éliminé par ultracentrifugation, par dégradation enzymatique de la γ‐globuline ou par d'autres traitements tels qu'une exposition prolongée à des acides très dilués.
Ce sont les préparation obtenues par dégradation enzymatique ou par l'action d'acides dilués qui sont le mieux tolérées lors de l'injection intraveineuse.
La γ‐globuline digérée sous l'action d'un enzyme est éliminée partiellement par les reins et n'exerce aucune action désensibilisante. Par contre, la γ‐globuline exposée à un pH de 4 ne passe pas le seuil rénal, et sa capacité de désensibiliser des individus sensibles, persiste.
Zusammenfassung
Die intravenöse Applikation von menschlichem Standard‐γ‐Globulin kann zu schweren Zwischenfällen Anlaß geben.
Diese Unverträglichkeit beruht zumindest auf einem exogenen und einem endogenen (individuellen) Faktor.
Der “endogene” (individuelle) Faktor äußert sich darin, daß nur gewisse Individuen—in der Regel handelt es sich dabei um Patienten mit einem Antikörpermangelsyndrom ‐ auf eine i.v. γ‐Globulingabe mit Unverträglichkeitserscheinungen reagieren.
Der “exogene” Faktor liegt im γ‐Globulinpräparat; er steht mit dessen anti‐komplementärer Wirkung in direkter Beziehung.
Es ist möglich, den “endogenen” Faktor vorübergehend durch “Desensibilisierung” des Patienten (rnit Standard‐γ‐Globulin) auszuschalten. Der “exogene” Faktor kann entweder durch Ultrazentrifugierung, durch enzymatische Verdauung, oder durch bloße Ansäuerung (pH 4) eliminiert werden.
Bei der klinischen Prüfung erwiesen sich diejenigen Präparate als gut verträglich, die durch enzymatische Verdauung oder durch Ansäuern gewonnen wurden. Enzymatisch abgebaute γ‐Globuline gehen teilweise durch die Niere verloren; sie besitzen außerdem keine desensibilisierende Wirkung. Demgegenüber erscheint das durch Aneäuern gewonnene Präparat nicht im Urin des Patienten. Es verhält sich auch in bezug auf seinen desensibilisierenden Effekt wie Standard‐γ‐Globulin.
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Summary Anti-Rho(D) immunoglobulin (anti-D) contained more high molecular weight (HMW) IgG polymers than intravenous non-specific immunoglobulin (i.v. Ig). The low-dose anti-D and high-dose i.v. Ig regimens used to treat idiopathic thrombocytopenic purpura (ITP) therefore contained similar total amounts of HMW IgG. In vitro, the HMW IgG polymers were more effective competitive inhibitors of monocyte phagocyte Fc receptors than monomeric IgG. The IgG subclass composition of anti-D and i.v. Ig were both similar to normal human plasma. We conclude that the HMW IgG content but not the IgG subclass composition of anti-D may explain its low-dose therapeutic efficacy in ITP.
The results of high-dose intravenous gammaglobulin therapy (IVGG) of adults with immune thrombocytopenic purpura (ITP) were reviewed in 28 published reports which included 282 patients. Overall, 64% of the patients responded to IVGG with a peak platelet count greater than 100,000/mm3; 83% had peak platelet counts greater than 50,000/mm3. Unmodified immunoglobulin was superior to modified immunoglobulin; 70% of the patients treated with the former having platelet increases to greater than 100,000/mm3 compared to only 49% of those treated with the latter. More patients were refractory among those who had had ITP for at least 3 years. A higher peak platelet count immediately after IVGG administration was correlated with a longer duration of the platelet response. Patients above the age of 60 tended to have a weaker response to IVGG than did younger patients, and females tended to respond better than males. A pre-IVGG platelet count of less than 10,000/mm3 was not associated with a poor response to IVGG. While there is still no way to reliably predict response prior to therapy in an individual patient, the above information may help in the decision of whether or not treatment with IVGG is likely to be successful. It also suggests that inhibition of antiplatelet antibody production is an important mechanism of IVGG effect at least in some patients.
A patient with chronic ITP relapsed after conventional therapy but following an infusion with low dose anti D (Rho) immunoglobulin, she entered a remission which has now lasted 10 months. This is difficult to explain on the basis of long term macrophage Fc receptor blockade and suggests an alternative mechanism of action.
Twenty-three courses of i.v. anti-D (Rho) immunoglobulin were administered to 13 Rh D-positive patients with chronic idiopathic thrombocytopenia (ITP). Clinically significant responses were seen in a proportion of patients treated with 500-2500 i.u. anti-D, but all those treated with 12,500 i.u. (180 i.u./kg) responded. Patients refractory to other forms of treatment responded well to anti-D, and previous splenectomy did not influence the clinical response. No adverse reactions were observed. The anti-D response was preceded by a lag period of 3-16 days and was maintained for 14-145 days. Platelet-associated IgG was increased after treatment, due to improved survival of immunosensitized platelets or platelet Fc receptor binding of high molecular weight IgG in the therapeutic material. There was no clinical or biochemical evidence of haemolysis. The erythrocyte direct Coombs' test remained positive for 3-45 days, and histological examination of splenic material showed no erythrophagocytosis. We conclude that anti-D (Rho) immunoglobulin is a safe and effective treatment for chronic ITP and that the therapeutic dose is now established in standardized units. The mechanism of action appears to be complex and is probably not due to macrophage Fc receptor blockade with immunosensitized red cells.
THE production of antiplatelet antibodies and removal of IgG-coated platelets by the mononuclear phagocyte system play an important part in the pathogenesis of immune thrombocytopenic purpura. The coating of platelets with immunoglobulin results in their removal in the spleen and liver, presumably by receptors for the Fc fragment of IgG (Fcγ).1 , 2 Prolongation of Fcγ-receptor-mediated clearance of opsonized red cells after splenectomy1 , 3 and infusions of high doses of intravenous gamma globulin,4 , 5 in conjunction with favorable clinical responses to these therapies, support this hypothesis. Some patients, however, respond to neither of these treatments nor to other, less specific forms of immunosuppression, such . . .
Now that a number of the receptors for the Fc portion of immunologlobulin molecules have been cloned, information is beginning to accumulate on their molecular structure, their relationship to each other and to other members of the immunoglobulin superfamily, and how they interact with their immunoglobulin ligands. A recent conference{black star} {black star} A Workshop on the Structure and Function of Fc Receptors was organized by Dr D.R. Burton for the Biochemical Immunology Group of the Biochemical Society and the British Society for Immunology as part of the Biochemical Society meeting in Sheffield, UK, 12-15 April 1988. provided a forum for discussion of these recent advances.
Immunoglobulin G (IgG) prepared from pooled human plasma contains variable amounts (up to 40%) of IgG dimer whereas IgG isolated from the plasma of a single individual is essentially monomeric. The amount of dimer increases with the number of donors contributing to the plasma pool from which the IgG is prepared. Dimerization is reversed by increasing the temp or decreasing the pH. Two intact antibody-combining sites (paratopes) are required for optimal dimer formation; the Fc region is unnecessary. These findings strongly suggest that IgG dimer consists of idiotype-anti-idiotype pairs formed between molecules of IgG from different individuals, and that a mechanism exists for suppressing idiotype-anti-idiotype formation in vivo.
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.
Seven children with chronic or intermittent and six with acute idiopathic thrombocytopenic purpura (ITP) were treated with large intravenous doses of polyvalent, intact immunoglobulin (Ig). In all patients the platelet count rose sharply within 5 days, but the initial response and the subsequent course varied from patient to patient. Among children with chronic ITP the initial response was more marked in splenectomised than in non-splenectomised patients. Among those with acute ITP the two who remained Ig dependent had a smaller initial response than the four patients who required no maintenance treatment. During the 90-110 days of observation five of six patients with chronic ITP could be maintained with Ig alone. No untoward effects of Ig therapy were observed.
The rapid rise in platelet count after immunoglobulin treatment in acute and chronic forms of idiopathic thrombocytopenic purpura (ITP), autoimmune neutropenia, and post-transfusion purpura is well documented. It is suggested that the rise in platelet count is due to competitive inhibition of the macrophage binding of platelets by preferential sequestration of immunoglobulin-coated red blood cells. Measurement of haptoglobin levels, a sensitive indicator of haemolysis, suggests that clinically inapparent haemolysis occurs during immunoglobulin therapy of ITP patients. In-vitro experiments confirm that there is immunoglobulin coating of red blood cells. The hypothesis is further supported by the findings that immunoglobulin treatment in autoimmune haemolytic anaemia is ineffective, and that platelet counts rise in some ITP patients after induction of a mild haemolytic syndrome by injection of anti-Rho (D).
Treatment reversal of thrombocytopenia in idiopathic thrombocytopenic purpura by high dose intravenous gammaglobulin
- JULIA
Treatment of chronic idiopathic thrombocytopenic purpura with anti-D (Rho) immunoglobulin: its effectiveness, safety and mechanism of action
- B.J. BOUGHTON
- R.K. CHAKRAVERTY
- T.P. BAGLIN
- A. SIMPSON
- G. GALVIN
- P. ROSE
- P. ROHOLAVA
Characterization of various immunoglobulin preparations for intravenous application: I. Protein composition and antibody content
- ROMER