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J Clin Pathol 1988;41:1249-1255

Review

Mechanism of action of intravenous immunoglobulin inimmune-mediated cytopeniasH I ATRAH, R J L DAVIDSON

From the Department ofHaematology, Aberdeen Royal Infirmary, Foresterhill, Aberdeen, Scotland

The value of immunoglobulin (Ig) for replacementtherapy in patients with primary antibody deficiencywas realised in the early 1950's and its immuno-suppressive effects a decade later.' Initially maternalsource Ig preparations were used to enhance cadavericrenal graft survival2 and plasma, as a source of Ig, wasused to treat idiopathic thrombocytopenic purpura.34As an immunosuppressive agent, Ig did not, however,gain wide application until 1981; this followed achance observation by Imbach et al,5 who in the courseof intravenous immunoglobulin treatment of childrenwith hypogammaglobulinaemia noted that the plateletcount of two such children with coincidentalidiopathic thrombocytopenic purpura suddenlyimproved after the infusion of intravenous Ig. Thisobservation was soon confirmed both in children67and adults"'0 with acute and chronic forms ofidiopathic thrombocytopenic purpura. It has beensubsequently and amply shown that the plateletresponse is more favourable in the acute form of thedisease" 12 where it may, however, be difficult todistinguish sustained increases in platelet count fromspontaneous remissions. Prolonged and unmaintainedremission after intravenous Ig treatment is rare inchronic idiopathic thrombocytopenic purpura, butmost such patients obtain a transient rise in the plateletcount (for a few weeks), often ensuring adequate timeand haemostasis for splenectomy or other essentialsurgery.Apart from preoperative preparation, intravenous

Ig may also be successful in deferring or avoidingsplenectomy while booster infusions may sustainremission in patients in whom steroids are contra-indicated. In recent years the potential therapeuticvalue of intravenous Ig has been extended to a broadspectrum ofdisorders, particularly those with a confir-

Accepted for publication 21 July 1988

med or suspected autoimmune aetiology includingother blood cytopenias and diseases affecting thenervous, cardiovascular, endocrine, alimentary andother systems. The treatment protocols and clinicalresults are detailed in recent reviews.'3 14

Despite this relatively long background of intensiveresearch and clinical application the mechanismunderlying the immunomodulatory effect of intra-venous Ig has tantalisingly eluded a unified anduniversally acceptable explanation. This deficiencymay result from several factors: (i) intravenous Ig mayhave more than one mode of action; (ii) subtlevariations in the constituents of different intravenousIg preparations or batches may lead to differences intherapeutic activity, potency, and efficacy; and (iii) thedisease being treated, immune based thrombo-cytopenia although superficially, a single clinicalentity is more likely to be a syndrome of covert andvariable pathenogenesis. Our prime objective in thisarticle is to review critically and evaluate the bewilder-ing number of explanatory mechanisms which havebeen proposed to date.

Reticuloendothelial system blockadeAfter intravenous Ig treatment the clearance ofautologous anti-Rh(D) sensitised radiolabelled redcells is impaired for about one month consistent withtransient interference of reticuloendothelial systemmacrophage FcyR (the receptor for Fc portion ofIgG)function.9"' Because the same receptor is responsiblefor the elimination of antibody-coated platelets, therise in platelet count after intravenous Ig treatment hasbeen similarly attributed to inhibition of FcyR func-tion. It is generally agreed that the immediate rise inplatelet count effected by treatment results fromreticuloendothelial system blockade, but the actualmechanism of the blockade itself remains contro-versial and unresolved. It has been suggested that thefollowing five main mechanisms may account for theblockade.

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1 REVERSIBLE BINDING OF THE Fc PORTION OFMONOMERIC IgG TO RETICULOENDOTHELIAL SYS-TEM MACROPHAGE FcyR16High dose intravenous Ig treatment leads to about athreefold increase in serum IgG and theoretically thenumber ofFcyR reversibly occupied by Ig monomers.Consequently, the number of receptor sites availablefor binding the Fc portions of platelet-associated IgG(PA IgG) is reduced. This hypothesis is supported bythe increase in IgG detected within monocytes afterintravenous Ig treatment, presumably via internalisa-tion of the receptor with its bound IgG.'7

2 IRREVERSIBLE BINDING OF THE Fc PORTIONSOF IgG AGGREGATES TO RETICULOENDOTHELIALSYSTEM MACROPHAGE FcyR 8After the irreversible binding IgG aggregates arereadily phagocytosed because of multipoint attach-ment with internalisation and loss of FcyR expres-sion.'6 Intravenous Ig contains only small quantities ofIgG aggregates'9 but by this mechanism may con-tribute to the reticuloendothelial system blockade.20

3 ANTIMICROBIAL ANTIBODIESIntravenous Ig may contain antimicrobial antibodieswhich interact specifically (via their Fab portions) withpersistent microbial antigens to form immune com-plexes.2' The latter in turn are phagocytosed in amanner similar to that of IgG aggregates with result-ing reticuloendothelial system blockade. Eliminationof the infection itself may also normalise the plateletcount.

4 BLOOD GROUP ANTIBODIESThe presence of specific blood group antibodies inintravenous Ig may cause low grade haemolysis orphagocytosis of antibody-coated red cells.' Con-sequently, the rate of removal of antibody-coatedplatelets may be reduced because of the limitedcapacity ofthe reticuloendothelial system. Proponentsof this mechanism cite the accompanying absence orreduction in haptoglobins following intravenous Ig assubstantive evidence although such haptoglobin chan-ges have not been recorded in all studies.' '

Furthermore, patients with Evan's syndrome mayhave clinically important immune destruction of redcells by the reticuloendothelial system withoutimprovement in their immune thrombocytopenia.2" Ifthis hypothesis is valid one might also anticipate thatpatients belonging to blood group 0 would be lesslikely to respond to intravenous Ig,20 but in one largestudy no association between patient response rateand blood group was established.27 Finally, a strongcounterargument to this hypothesis is that intravenousIg has a beneficial therapeutic effect in autoimmunehaemolytic anaemia.'4

Atrah, Davidson

5 ANTI-FcyR ANTIBODIESThe presence of specific anti-FcyR antibody inintravenous Ig causes reticuloendothelial systemblockade (as detailed below).

It must be emphasised that although the reticulo-endothelial system blockade theory is, in the main,accepted as the basis for the immediate plateletresponse, it by no means accounts for all the wellfounded observations and experimental data relatingto intravenous Ig treatment. The most cogentarguments against the theory include the following:the reticuloendothelial system blockade is transientand limited to about four weeks' duration9"' whereasthe therapeutic effect may last in some patients forseveral months; although intravenous Ig may haveachieved reticuloendothelial system blockade in somepatients, there may be little or no accompanyingplatelet response2' and vice versa29; if reticuloendo-thelial system blockade is regarded as a percentage ofthe initial clearance all patients seem to have anidentical pattern of immune particle clearance but thechanges in platelet count are variable and show noconstant relation with the corresponding reticulo-endothelial system changes28; each of the hypotheses(1-4) hinges on the presence of intact (unmodified)IgG molecules with functional Fc portions, yet thisapparent and structural prerequisite is at variance withthe ability of intravenous Ig consisting of only ormainly Fab portions (modified IgG) to elicit responsescomparable with those of unmodifiedpreparations.'2 3032From the evidence thus far presented it must be

concluded that reticuloendothelial system blockadenot only fails to account for the long term therapeuticresponses of intravenous Ig but additionally fails toconcur with certain well authenticated features of themore immediate responses.25 2 Not unexpectedly,several other mechanisms have therefore been advan-ced which attempt to elucidate the immediate plateletresponse. These mechanisms include:

Inactvation (or neutralisation) of platelet antibodiesby intmrven IgThis hypothesis emanated from the work of Sultanand coworkers,33 which showed that intravenous Igcontained anti-idiotype antibodies for the idiotypes offactor VIII autoantibodies. They speculated thatintravenous Ig may similarly contain anti-idiotypeantibodies to other antibodies, including plateletautoantibodies, and that its therapeutic efficacy insome autoimmune diseases may depend on suchidiotypic/anti-idiotypic interactions.

Protectio of platelet or megakaryocytes, or both, fromplatelt antibodiesThe proposition is that this protection may be afforded



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Role ofintravenous immunoglobulin in immune-mediated cytopeniasby non-specific attachment of the Fab or Fc portionsof IgG in intravenous Ig to platelets or mega-karyocytes, or both. Such a mechanism would therebyeffectively eliminate or reduce any specific reactionbetween platelet antibodies and their target.3' Theinhibitory effects of monomeric intravenous Ig onplatelet activation by polymeric IgG is often quoted assupporting evidence for this mechanism, but thevalidity of such an assumption must be questionedbecause specific anti-platelet antibody was not used inthe original experimental model." On the other hand,when normal platelets are incubated with plateletantibodies, no important difference is detected in theamount ofplatelet-associated IgG bound to untreatedplatelets and those treated with intravenous Ig.3' Thisfinding confirmed by others both in vivo" and invitro38 indicates that intravenous Ig is unlikely to exertany protective role via this suggested mechanism.

Elimination of infection(see reticuloendothelial system blockade, point 3)

Modulation of the FcyRIntravenous Ig treatment is associated with a decreasein the affinity of human monocyte FcyR for the Fcportion of rabbit IgG coating sheep red cells.'7Although observed under highly artificial andexperimental conditions, this finding was attributed toa qualitative rather than a quantitative change in theFcyR. No such change was observed, however, in asubsequent study in which only human componentswere used.25

Suppression of natural killer cell activityThe activity of natural killer cells is increased inidiopathic thrombocytopenic purpura, autoimmuneneutropenia, and some other autoimmune disorders39and may be lytic in the presence of platelet orneutrophil antibodies. Intravenous Ig diminishesnatural killer activity of lymphocytes of healthydonors in vitro in a dose-dependent pattern,39 40 and inone patient with idiopathic thrombocytopenic pur-pura and another with autoimmune thrombo-cytopenia receiving high dose intravenous Ig (2 g/kg),natural killer activity decreased in correlation with theclinical response and increased peripheral cell counts.39No mechanism was suggested for these findings.Even more difficult to rationalise than the early and

transient rise in the platelet count is the prolonged andlong term response to intravenous Ig. Again, manydisputable hypotheses have been advanced, somefounded on reliable experimental observations, otherson mere conjecture. They include:

Decrease in platelet antibody synthesisINCREASED SUPPRESSOR LYMPHOCYTE ACTIVITYSuppression of platelet antibody production mayresult from an intravenous Ig induced increase,absolute or relative, in suppressor (cytotoxic)lymphocytes,24 '" or alternatively enhancement oftheir functional activity.'2 Indeed, it has beendocumented that IgG inhibits pokeweed mitogen-induced B cell differentiation and causes non-specificsuppression ofpolyclonal IgG biosynthesis in vitro.'3While the decrease in platelet-associated IgG follow-ing intravenous Ig treatment has been interpreted assignifying suppression of platelet antibody produc-tion,'336 some have regarded the fall as indicating ablocking effect by intravenous Ig against the attach-ment of platelet antibody to platelet'5" or even simplyas representing dilution of the platelet antibody by therising platelet count."' Even more perplexing arereports of actual increases in platelet-associated IgGfollowing intravenous Ig treatment4"l' and of plateletantibody titres in the serum having increased'5 ordecreased'0 with treatment. Such contradictory andbaffling discrepancies may, however, merely reflectmethodological differences or unreliability in the assaytechniques currently used for measuring plateletantibodies.ANTIBODY AUTOREGUILATIONIn 1974 Jerne proposed that antibody-producing cellsmay autoregulate by a network of idiotype/anti-idiotype interactions.5' There is no current evidence,however, to indicate that intravenous Ig influences thisautoregulatory process.IGG2 DEFICIENCYIt has been suggested that IgG2 deficiency may have arole in the pathogenesis of idiopathic thrombo-cytopenic purpura and that intravenous Ig correctsthis defect and by an unknown mechanism suppressesautoantibody production.28SPECIFIC ANTI-FCyR ANTIBODYThe presence of specific anti-FcyR antibody inintravenous Ig reduces autoantibody production (asdetailed below).

Increased platelet production and releaseUchida et al found no evidence to support thishypothesis but confirmed that platelet survival isprolonged by intravenous Ig treatment.52 It is pertinentthat in several studies where plasma, as a source ofIgG, has been used in idiopathic thrombocytopenicpurpura, the platelet response has been similar to thatof intravenous 1g.53 The thrombocytopenia might not,however, have had an immune basis-at least in somesuch patients. Thus plasma infusions were found tomaintain an adequate platelet count for several yearsin a patient with congenital thrombopoietin deficien-cy5' and similarly in an adult patient with thrombo-

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cytopenia. Atrah et al, although failing to elicit aclinically important increase in the platelet count withtwo courses of high dose intravenous Ig, repeatedlyinduced a sustained platelet remission with plasmainfusions (unpublished observations).

Suppression of natural killer cell activityThis may be partly responsible for the immediate aswell as the delayed responses to intravenous Ig.

Specific anti-FcyR in intravenous IgThis hypothesis recently postulated by Sandilands et alhas not yet gained wide or adequate recognition.55Because we consider it to be ofparamount importancein unravelling the immunomodulatory action ofintravenous Ig, a more detailed account of themechanism and its implications follows.The main proposition is that intravenous Ig con-

tains an antibody which is directed against and reactsspecifically with FcyR (anti-FcyR) and that its actionmay vary with clinical circumstance and the target cell.Thus in idiopathic thrombocytopenic purpura theFcyR of mononuclear phagocytes blocked ormodulated by the Fab portion ofanti-FcyR have no ora reduced binding capacity for the Fc portion of theplatelet antibody. Consequently, platelets and theirbound antibody complex cannot be phagocytosed bythe effector cells ofthe reticuloendothelial system. Thismechanism provides insight into several differentaspects of intravenous Ig treatment in idiopathicthrombocytopenic purpura and other immune dis-orders. Firstly, it could explain as indicated above theimmediate and transient effect of intravenous Ig.Secondly, the "blocked" FcyR may be internalised ashappens when it reacts with immune complexes,resulting in loss or modulation of target cell reactivitybe it phagocytic, suppressor, helper or natural killer. Itmay therefore be the basis of the less common butsustained effect of intravenous Ig in idiopathicthrombocytopenic purpura through either reducedantibody production or decreased phagocytic activityof the reticuloendothelial system, or both. Thirdly, asthe Fab (and not the Fc) portion of anti-FcyR is thekey reactant with FcyR, unmodified as well asmodified intravenous Ig can exert a therapeutic effectwith the former being more effective because of thelarger molecule exerting greater steric resistance forthe Fc portion of other IgG molecules, includingplatelet antibody from displacing the Fab portion ofthe anti-FcyR. Fourthly, it may account for thedecrease in lymphocytes24 and reduced natural killercell activity39 accompanying intravenous Ig treatmentbecause these cells bear FcyR.56 The proposedmechanism gains additional support from the clinicaldemonstration that infusion of a murine-derivedmonoclonal anti-FcyR is capable of reproducing all

Atrah, Davidsonthe in vivo and in vitro effects of intravenous Ig.57

Because anti-D has been shown to be effective inidiopathic thrombocytopenic purpura,58 9 it has beensuggested that the success of intravenous Ig may berelated to its anti-D content.i' On the other hand,another study using a different anti-D preparation andat higher doses, failed to elicit a clinically importantplatelet response in idiopathic thrombocytopenic pur-pura.6' From these disparate findings, we concludethat the active therapeutic agent may not be anti-Ditself but some other constituent and venture tosuggest that this is most likely to be anti-FcyR which ispresent in both anti-D62 and intravenous Ig63 prepara-tions.The plausibility of this FcyR blockade is further

promoted by some recent findings in aplastic anaemiawhere remission has been achieved by the use ofintravenous Ig.' There, the therapeutic effect has beenattributed to a substantial reduction in the number oflymphocytes belonging to an FcyR bearing subsetknown to suppress haemopoiesis in patients withaplastic anaemia.65 Short ofbone marrow transplanta-tion, the most effective agents in the treatment ofaplastic anaemia are anti-lymphocyte globulin (ALG)or anti-thymocyte globulin (ATG), although theirmode of action remains undefined.6"7 Recently,however, anti-FcyR antibody has been detected inALG and ATG available from three different manu-facturers.68 Based on this and other evidence it hasbeen proposed that in idiopathic thrombocytopenicpurpura and aplastic anaemia the beneficial responsesinduced by ALG, ATG, and intravenous Ig are relatedto the presence of a common therapeutic principle.The recent report of the successful use of anti-D inaplastic anaemia69 supports our contention that anti-FcyR is the active ingredient shared by intravenous Ig,ALG, ATG and Anti-D. Additional confirmationmay be derived from assessing the clinical response ofmonoclonal anti-FcyR in aplastic anaemia or its exvivo influence on marrow culture. It is also relevant tonote that increased amounts of FcyR are present onthymocytes in myasthenia gravis,70 a condition whichresponds favourably to intravenous Ig7' and that inpure red cell aplasia, an immunologically mediateddisorder commonly associated with thymoma, intra-venous Ig has again achieved satisfactory responses.72

THERAPEUTIC IMPLICATIONSFcy receptor is a non-specific marker widely dis-tributed on granulocytes, monocytes, and lymphocytepopulations and also found free in plasma.7374 Whileanti-FcyR antibody develops from exposure to alloan-tigens (such as blood and blood products, in homosex-ual men and during pregnancy),75 it also seems to be anormal component of the immune network,63 with arole in the down-regulation of immune responses. Asintravenous Ig is prepared from pools ofdonor plasma



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Role ofintravenous immunoglobulin in immune-mediated cytopenias 1253the anti-FcyR antibody content probably varieswidely between different immunoglobulin productsand batches. Furthermore, it is recognised thatlymphocytes from individual patients responddifferently to material from the same batch of anyparticular preparation, perhaps because of individualvariation in the FcyR epitopes and the anti-epitopes ofthe anti-FcyR; hence "matching" patients with bat-ches of intravenous Ig has been suggested to establishthe most appropriate reagent for each patient beforetreatment.` These observations may explain theextremely variable response of patients to intravenousIg, ALG, ATG, or Anti-D in the treatment ofidiopathic thrombocytopenic purpura, aplasticanaemia, or other immune disorders where currentlythe selection of antibody batch is entirely empirical.

If anti-FcyR is the active ingredient in intravenousIg, it would be wasteful to continue using a crude andexpensive preparation such as intravenous Ig in largedoses for routine treatment; a new product (perhapsprepared from the plasma of pregnant women ordeliberately immunised volunteers or modified mono-clonal antibody) containing a "blend" of anti-FcyRconcentrates which could be used at smaller doses andlower cost would be preferred to conventional highdose intravenous Ig. The substitution of intravenousIg by anti-D in the treatment ofautoimmune disordersis to be discouraged because anti-D is a scarce humanresource primarily intended for the prevention ofRhesus alloimmunisation.76 Furthermore, themechanism of action of anti-D itself is uncertain.77Although supportive evidence is awaited, anti-D mayprevent rhesus alloimmunisation because of its anti-FcyR content. This hypothesis could be verified bycomparing the ability of a standard anti-D prepara-tion from which anti-FcyR has been removed formonoclonal anti-D and anti-FcyR which contains noanti-D to prevent alloimmunisation in rhesus Dnegative male volunteers injected with D-positive cells.Anti-D remains in short supply because only dona-tions with a high anti-D content are avccepted for itspreparation. If the anti-D content is shown to betherapeutically irrelevant, future interest will centre onanti-FcyR activity, and plasmas with high concentra-tions may be more readily available.As intravenous Ig treatment is immunosuppressive

it is therefore prudent to exercise caution in itsadministration to immunocompromised or neutro-penic patients78 where the resultant reduction of FcyRfunction may predispose to fulminant infection. Whileintravenous Ig does not induce generalised phagocyticblockade and is well tolerated by non-immune com-promised patients,79 the effect of its long term adminis-tration in high doses to healthy subjects is not known,particularly with regard to natural killer cell activityand immunosurveillance. Furthermore, it is theor-

etically possible that it may either induce immunecomplex disease if FcyR-anti-FcyR complexes aredeposited in tissues and organs, or amyloidosis fromaccumulation of the degradation products of massivequantities administered over several years. Furtherresearch is required to provide definitive solutions tothose novel challenges and problems.

Finally, despite the considerable volume ofevidencesupporting our hypothesis embodying FcyR blockade,we accept that conclusive proof awaits further elucida-tion ofseveral ofits essential aspects. These include themode of action of anti-FcyR on modifying cellularactivity and the mechanism of the lymphopenia; theassociation between clinical response and the changesin FcyR-bearing lymphocytes; which of the threeknown types of FcyR`t forms the target for the anti-FcyR and the relation of FcyR, a functional marker, tothe currently applied cluster differentiation system oflymphocyte subset typing.

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60 Lucas GS, Jobbin K, Bloom AL. Intravenous immunoglobulinand blood group antibodies. Lancet 1987;l:742.

61 Atrah HI, Templeton JG, Crawford RJ, Gabra GS, Mitchell R.Passive haemagglutination inhibition for quantitation of redcell associated IgG. J Clin Pathol 1987;40:494-9.

62 Petri IB, Lorincz A, Berek I. Detection of Fc-receptor-blockingantibodies in anti-Rh(D) hyperimmune gammaglobulin. Lancet1984;u:1478-9.

63 Cocker JE, Templeton G, Peel MG, Crawford RJ, Crichton WB,Sandilands GP. Lymphocyte Fcy-receptor blocking antibodiesin intravenous gammaglobulin preparations. J Clin LabImmunol 1987;22:85-90.

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68 Atrah HI, Sandilands GP. A proposed mechanism of action ofALG and ATG in acquired severe aplastic anaemia. J Clin LabImmunol 1988;25:59-62.

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Requests for reprints to: Dr H I Atrah, Department ofHaematology, Aberdeen Royal Infirmary, Foresterhill,Aberdeen AB9 22D, Scotland.



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