Antibody removal therapy in transplantation

Antibodv Removal Transplantation

Therapy

in

RobertM. Higgins andDeborahJ. Beuan

A

ntibody-antigen reactions play a major role in clinical transplantation. The problem of possible antibody-mediated graft damage is generally dealt with by avoiding any interaction between antibody and graft.‘?* There is routine prohibition of transplantation across species, many anti-I-IL4 reactions, and blood group barriers. Because the supply of human organs is limited, restriction of access to transplantation by attention to antibody barriers further reduces the chances for certain patients to receive a graft. Therefore, techniques that allow transplantation to be performed across antibody barriers are desirable. In this article we examine the requirements for successful antibody removal and the results of the various techniques that have been applied in clinical practice. Attention is also given to strategies that might both reduce antibody production and the likelihood of graft damage because of the presence of antibodies.

Which Antibodies

May be Damaging?

Table 1 shows the examples of antibody types encountered in clinical transplantation. Destruction of a transplanted organ is not an inevitable consequence of exposure to antibody. Successful transplantation across major blood group barriers3:’ and in the presence of generally prohibitive anti-human leukocyte antigen (HLA) antibodies’ has been reported without deliberate antibody removal. Therefore, the presence of a given antibody is not prohibitive of transplantation per se, but the outcome after engraftment depends on o;her factors.

How Does Graft Damage Occur? The histological appearances of graft damage are classically described in renal transplantation after From the Renal Unil, King’s Colkge, and the Regional Tissue ‘Tyjing L&raw, Gup Hospital, London, UnitedKingdom. Addmss rep& requests lo Lkbbic Bevan, MSc, Regional Tissue Typing Labora@, Guy’s Hospital, London SEl, United Kingdom. Copright 0 I995 by W.B. Saunders Company 0955-470x/95/0904-ooo3fi.00l0 Tranrplantation

Reviews,

exposure to blood group, anti-HLA, or antispecies antibodies.5*6Categories of rejection are listed below. Hyperacute Rejection In renal transplantatidn, this ii characterised by a change in the appearance of an allograft within 20 minutes of transplantation, the organ becoming blue and flabby with reduced blood flow and no urine output.7-g Histological examination shows masses of fibrin and platelets deposited in glomerular capillaries and other blood vessels. In the early stages, immunoglobulin (1g)G or IgM and Complement C3 (C3) are detected in glomeruli and peritubular capillaries. Within a short time, there are numerous neutrophil leucocytes within the graft, with interstitial haemorrhage and then infarction. . Immediate graft failure of a transplanted liver, or of a liver perfused ex viva with blood, is not so dramatic, asjudged by the macroscopic appearances at operation. However, at retransplantation the liver may appear enlarged, mottled, and cya.notic.1°Immunoglobulin deposition with thrombosis is seen, together with necrosis of hepatocytes.‘@‘2 The smaller degree of susceptibility of the liver to hyperacute rejection compared with the kidney may be related to organ size, secretion of soluble antigen, relatively low levels of HLA class I expression by the liver, or activity of Kupffer cells in the liver.J3 Furthermore, the kidney may be at particular risk from damage by thrombosis because of the anatomic nature of blood flow and glomerular architecture. Classically, hyperacute rejection has been regarded as irreversible. However, graft damage occurring within a few minutes of vascularisation may be reversible. Glomerular thrombosis occurring at the time of transplantation, followed by eventual graft function, has been observed by us after anti-HLA antibody removal immediately before the transplantation.14 A phenomenon of reversible hyperacute rejection may therefore, need to be recognised. Accelerated Rejection Severe rejection occurring within a few days of transplantation, with histological appearances similar to those of hyperacute rejection is termed acceler-

Vol9, No 4 (Cktti),

1995:pp

177-199

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Higgins and Bevan

Table 1. Antibodies Encountered Transplantation

in Clinical

Potentially harmful; antibodies directed against: Species (xenoantigen)n*27~7~zio~*6~*z7 Blood groups3=* m1,7-9,17.‘8329

tion of antibody to the pathogenesis of chronic vascular rejection is uncertain. The intimal arterial changes may be a responseto low-grade damage caused by antibody with fibrin and platelet aggregatesforming on the vessel~al1.5~~

Endothe~um20,2’,230.23’

Epitheliumn2 Cardiolipin233 Protein immunosuppression drugs234-236 Glomerular basement membrane2nvm*237 Antimyeloperoxidasens Cold agglutininsis*239 Causing recurrent focal sclerosis (antigen unknown)225 Apparently unimportant: Autolymphocytotoxic antibodies’vz4 Potentially beneficial; antibodies directed against: Idiotypes of harmful antibodies7s*7s242-2* T-cell receptor idiotypes of recipient lymphocyte&” Noncomplement fixing or “blocking” antibodies competing with any harmful antibody for antigen”lJ29

Autolymphocytotoxic

antibodies24734s

ated rejection. It is distinguished from hyperacute rejection by either function of the graft with urine output in the first few days, or when a satisfactory biopsyhaspreviously beenobtained. Although accelerated rejection is often irreversible, recovery can occur, even after the development of capillary and glomerular thrombi.15 Acute Rejection Acute cellular

rejection with mononuclear

cell infiltra-

tion of a renal allograft and tubulitis can occur independentlyof humoral immunity. However, vascular changesmay occur in the presenceof anti-I-L4 antibodies,“j and a range of potentially damaging antibodies may be eluted from renal allografts after failure owing to acute rejection.“Js The vascular changesconsist of mononuclear cell infiltration of the arterial endothelium with fibrinoid necrosis. Arterial thrombosis,glomerular thrombosis,and interstitial haemorrhagemay occur.‘g Chronic Rejection Chronic vascular rejection may occur months to years after transplantation, and is characterised by arterial intimal thickening. Immunofluorescence studiesoften showIgM and complement within the vessel wall. Chronic vascular rejection leading to graft failure is a feature of all types of vascularised organ transplantation, and is a particular problem in cardiac transplantation.*@**However, the contribu-

Pathology of Antibody-Mediated

Rejection

Hyperacute and accelerated rejection are mediated primarily by a thrombotic processin which platelet deposition is a major event. Platelet deposition is secondary to antibody binding to vascular endothelium in most circumstances.Experimental work with xenoantibodies23~24 has suggestedthat under some circumstances antibody-independant complement binding and thrombosis may occur. Complement, principally via the alternative pathway, may bind to activated endothelial cells. However, this phenomenon has not been describedin human or primate transplantation under convincingly antibody-free circumstances.Although there is one report of seven patients undergoing vascular rejection of renal allografts with complement deposition in the apparent absence of immunoglobulins bound to the graft, thesepatients all had circulating anticlassI antibodiess5s2’j Therefore, either low levelsof antibody binding or a high rate of turnover of cell-surfaceantigen are possible explanations of apparent antibcdyindependant rejection in suchsettings. Anticoagulation using agents such as heparin, warfarin, citrate, or aspirin is insufficient to protect a graft againstirreversibledamagein hyperacute rejection.22v27-29 Platelet adhesion is also mediated by platelet endothelial cell adhesion molecule-l (PECAM-1, CD3 I), thrombomodulin, (which may be shed from the endothelial surface at the time of transplantation), and heparan sulphate.30,3’ At present, there are few data that could indicate whether manipulation of the expressionor function of these moleculesmight have a therapeutic effect. The action of complement may be modified by pharmacologicalagentssuch ascobra venom factor, but in experimental systemsthis is unable to prevent irreversible graft damage, although platelet adhesion may be substantially reduced.242g Membraneassociated molecules that regulate the action of complement are found within the human kidney, and their action is upregulated in the presenceof membrane-associated complement.32-35 Someof these moleculeshave been selected as candidates for genetic manipulation in an attempt to facilitate porcinehuman xenografting, but the clinical results of this approachare pending.

Antibody

Removal

In summary, whatever the secondary mechanisms of damage, graft survival and function are dependent on exposure of the graft to an antibody concentration below a certain threshold, which under some circumstances may only be achieved after antibody removal.

When is an Antibody Accommodation

Not Damaging?

Table 2 lists some of the factors that may determine the outcome of transplantation in the presenceof

potentially damaging antibodies. Although the kidney is particularly sensitive to antibody-mediated damage and the liver rather less so,all transplanted organsare susceptibleto antibodies under certain circumstances,including the heart and 1ungs.22,3U7 Antibody

removal

therapy

179

Therapy in Tramplanlalion

and the

control of antibody production are, therefore, relevant to all types of vascularisedorgan grafting. A concentration of antibody that would be expected to causehyperacute or accelerated rejection may be either harmlessor may be associatedwith reversible rejection at some time after transplantation. This has been described in associationwith

tion.23*ss The

mechanisms

of accommodation

may

include quantitative or qualitative alterations in either the compositionof antibodies,or of antigen, or of other graft related elements.2s*srJ~si Although the mechanismsof accommodationare not the major subject of this review, a recognition of the phenomenon is of paramount importance if antibody removal techniquesare to be usedin clinical practice. It seemslikely that a graft is most vulnerable to antibody at the time of transplantation, when antigen is presentedbut any protective mechanisms may not be operative. Transient alteration in the permissiveantibody concentration could also occur at other times after transplantation, for example if I-IL4 antigen expressionis modified by cytomegalovirus infection or by cellular rejection.i4 Accommodation offers an opportunity for successful transplantation after only intermittant antibody removal, provided that at other times the antibody level does not rise above the threshold at which irreversible damageoccurs.

Control

of Antibody

Production

anti-HLA antibodies,‘J6n26@53 blood group system A, AB, B, and 0 (ABO) antibodies,5656 and antispecies

In somecases,antibody production is transient and transplantation can occur without either antibody removal or long-term restriction of accessto trans-

antibodies.57s58 A graft may continue to function,

plantation

both in the presence of circulating

simultaneousexpression of antigen on the graft.5g

gradual decline in anti-HLA antibody production occursin many dialysispatients if antigenic stimula-

This

tion by blood transfusion

phenomenon

has been

antibody, termed

and with

accommoda-

Table 2. SomeFactorsDeterminingthe Outcome of a Potentially Damaging Antibody-Transplant Antibody dependent Antibody concentratiorW” Antibody class or subclass’ Rate of antibody production”“Jt7 Presence of any blocking or anti-idiotypic

Interaction

by avoidance

strategies.

For example,

ceases. However,

a

in many

casespersistent sensitisationor antibody production occurs.In the South Thames Regionof England, 30% of the patients awaiting transplantation are persistently highly sensitisedagainstI-IL4 antigens. Strategy of Immunosuppression and Antigen lkposure

anti-

~y7s,79,242-246

Temperature (some antibodies only)igPs-s4i Antigen or organ dependent Type of organ36 Size of organ24g Antigen concentration and rate of production55,68,250254

Presence of soluble antigen7ap255P6 Complement receptor density and activity of complement regulatory molecules32-35~6’ Other potentially protective molecules (thrombo modulin, heparan sulphate)23Jo Effector dependent Complement concentration and activi@3~24,257 Platelet concentration and activityr2~2~29J1 Antibody dependent cellular cytotoxicityt7*2ss*25g

Antibody removal would not be necessaryif antibody production could be regulated with specificity and safety. Table 3 shows the requirements for induced nonresponsiveness in clinical transplantation, asdemonstrated at Ring’s and Guy’s Hospitals in London. Exposure to antigen and someform of immunosup pression are the common factors.14*6264 Antibody removal does not appear to be obligatory to the development of nonresponsiveness of this type, and on its own is quite ineffective. However, the strategy of antigen exposure and simultaneous

immunosuppression

has only been suc-

cessful in our practice under two conditions. First, powerful immunosuppressionmust be administered. We have usedeither cyclophosphamidebefore trans-

180

Higgins and Bevan

Table 3. Requirementfor InducedNon-Responsiveness has indicated that splenectomy is associatedwith significantly lessrebound of antibody after plasma Invnu7w.ru~n Anwy Antigen exchange.‘j5It is not clear whether splenectomy Removal Exwure Cjwhphos ATG ou&ume would also be of benefit in patients with anti-HLA + Sensitisation or antibodies,where the regulation of IgG production graft loss may not be sodependenton the spleenasthe natural + + Usuallydesensitisa- IgM production of ABO or anti-speciesantibodies. tion The additional nonspecificlossof antipneumococcal + + Usuallyengraftimmunity is also a major complication of splenecment + Antibody rebound tomy in clinical practice, and splenectomy is not + -.+ Usuallyantibody widely used. reboundunless intenseimmunosuppression Pharmacological Agents + + Usuallyengraft+ + ment The drugs that have been usedwith the most success to downregulate antibody production in transplantaNOTE. Experience with antibody removal combined with antigen tion are ATG and cyclophosphamide.62*ss66 Theoretiexposure or immunosuppression in various combinations at King’s College Hospital and Guys Hospital, London. Antigen exposure in cally powerful becauseof polyclonal activity against the form of blood transfusion or transplantation. (See references both B and T cells,ATG has alsoproven effective in 14,62,99, I 14-I 16.) the induction of nonresponsiveness in experimental Abbreviations: Cyclophos, cyclophosphamide; ATG, antithymccyte globulin. transplantation.66 Cyclosporin and azathioprine, although effective agentsin the suppressionof cell-mediated rejection plantation, or antithymocyte globulin (ATG) with responses,are not particularly effective in the regulacyclophosphamideafter transplantation. Secondly, tion of antibody production in humans.67 successfulclinical transplantation hasgenerally taken Other pharmacologicalagents have been used to place only solong asthe graft doesnot expressthose regulate antibody production, although detailed cliniantigensagainstwhich the principal specificantibody cal studies have not yet been reported. Tacrolimus responseshave previously been developed.‘j3Thus, if a patient has produced high titres of anti-HLA As (FK506) hasbeen reported as effective in the treatantibody in responseto a graft carrying this antigen, ment of vascular rejection, and has been used in primate-to-man transplantation, although antibody we will not rechallenge this particular patient with HI&42 again.63This rule iscurrently followed in our levelshave not been reported.sO@sg Deoxyspergualin is a promising agent that inhibits B cells without unit, even if a programme of immunoadsorption could render the cross-matchagainstHLA A2 negacausing generalisedbone marrow depressionof the tive. The reasonfor this is that conventional immunotype that can occur with cyclophosphamide.s7Jg,7a73 suppressionwith ATG and cyclophosphamidecannot Other agents under investigation are mycophenoreliably prevent antibody resynthesisby high-affinity late,74brequinar,” rapamycin,75and leflunomide.76 producers,or possiblythat cellular immunity is also Antibody therapy directed specifically at B cells specificallyprimed in thesecircumstances. has not been used in clinical practice, but the antiIt seemsthat theserulesmay currently be broken CD3 preparation OKT3 hasbeen usedin transplanin clinical transplantation under certain circumtation acrossABO barriers.” Two cell-surface molstances.For example, somepatients will stop produceculesfound on B lymphocytes, CD19 and CD40, ing antibody after antibody removal combined with have been proposed as candidates for immunoimmunosuppressionalone, but intense immunosup therapy. Their functions are signal amplicification pression is required and some patients do not reand the development of memory B lymphocytes, spond.‘js respectively, and some experimental data indicate that antibody production may be modified by their Splenectomy blockade?7 Splenectomy as additional immunosuppressionhas Although antibody removal may not be obligatory beenused,and proposedasan obligate requirement, in transplantation acrossantibody barriers, we bein ABO-incompatible transplantation.54Experimenlieve it doesplay a critical role in facilitating rapid tal xenotransplantation in a swine-to-baboonmodel engraftment, to avoid, asfar aspossiblethe adminis-

Antibo&

Removal

Thera@

in Transplantation

181

tration of any pharmacological agents to patients for long periods of time before transplantation.

ered, if the goals set for antibody removal are to be achieved (Table 4). Determining the target for the maximum permissable antibody concentration is often difficult. ConvenOther Approaches tional methods for measuring antibody concentration, such as lymphocytotoxicity or flow cytometry, Both soluble antigen and anti-idiotypic antibodies are removed from the in vivo interaction between form part of the normal immune network and have potentially beneficial effects in transp1antation.7Bs0 antibody and vascularised graft so that a test result Soluble antigen can result in reduced antibody bindmay not indicate clinical outcome. For example, ing to the graft by direct competition for antibody hyperacute rejection may occur with a negative binding. Blood group A or B has been administered lymphocytotoxic crossmatch, and graft function after to patients receiving ABO-incompatible transplants, transplantation may be normal in the presence of a either in the form of purified antigen, or as plasma, positive cross-match performed using the same techor whole blood.8’s4 Likewise, intravenous infusion of nique. soluble xenoantigen may result in reduced availabilOnce a target for permissable antibodyconcentraity of antibody to bind to antigen.%- Infusion of tion has been set, consideration must be given to the terminal disaccharide or trisaccharide, components technical aspects of the antibody removal system to of the natural Gal pentasaccharide, has ameliorated be used and the necessary blood flow or plasma flow the hyperacute rejection of porcine kidneys by hurates. We have found that predictions of the efficacy man blood in an in vitro model.88 of antibody removal therapy cannot be made solely A preliminary report suggests that the use of on the basis of the rate of total immunoglobulin DL-pencillamine as a reducing agent to chemically removal. The rate of decline of anti-HI+4 antibody modify IgM molecules could have a role in circumbinding does not necessarily parallel the reduction in stances in which IgM is important in causing graft total antibody concentration. The flow cytometric damage.sQ IgM antibody has also been modified cross-match may remain almost unchanged despite experimentally by the administration of anti-p antithe removal of immunoglobulin from several plasma bodies.gO*Qi volumes by immunoadsorption (Fig 1).ss There are Pooled intravenous Ig may have a degree of several possible explanations for this. One is that if anti-idiotypic blocking activity against anti-HLA antisubstantial titres of anti-idiotypic antibodies are prebodies and xenoantibodies.s2-96 Perturbation of antisent in the serum, these may be removed together idiotypic networks by pooled intravenous Ig may also with the idiotypic antibodies. This may result in little downregulate antibody production in some cases.94ss*Q7 change in antibody-antigen binding measured by Modification of a graft to reduce antigen expresflow cytometry, even if total immunoglobulin levels sion, or to upregulate its ability to survive antibody are substantially reduced. We have, therefore, develdeposition, are aims of several groups currently oped an in vitro system that can reliably predict the working with gene therapy. Strategies include the course of in vivo immunoadsorption. This uses small development of transgenic animal lines in which volumes of plasma and a miniature protein Aspecific functional molecules are overexpressed, and sepharose column. However, the use of laboratory genetic modification to reduce graft antigenicity.9s techniques to plan in vivo antibody removal schedThe introduction of some of these techniques into ules is not widespread. As antibody removal becomes clinical practice will take place before the end of this more demanding, for example in the removal of decade, but may still need to be combined with antibody removal in clinical practice.

Principals of Antibody Removal Therapy Antibody removal therapy should be attempted only if the processes discussed above have been addressed, particularly the control of antibody production and the possible extent of accommodation. This being so, there are a number of factors that must be consid-

Table 4. Factors That may Influence the Success of Antibody Removal Antihoclyconcentration Antibody volume of distribution Duration and rate of antibody removal Rate of antibody synthesis Simultaneous removal of potentially beneficial antibody Type, size and condition of transplanted organ Extent of accommodation

182

_ qPatient

H&gins andBevan

#1

to achieveeffective antibody depletion, the perceived risksof transmitted viral infection in the modern era are too high. However, it may continue to have a role in experimental transplantation, when extracorporeal perfusionscircuits may be technically difficult.iss Table 5 showsthe publishedclinical experience of exchange transfusion in clinical transplantation. A modest exchange transfusion wasperformed by Vorony after the first human allograft operation in 1933,without preventing graft failure.loi Exchange blood transfusion hasalso been used in preparation of patients for bone marrow and liver transplantation from ABO-incompatible donors, generally in combination with plasmaexchange.imJo3 Plasma Exchange

1

’ Patient

#2

The removal and simultaneous infusion of whole plasma is readily achieved in modern clinical practice. Plasma can be removed using either of two techniques. These are filtration through a membrane (molecular weight cut off over 900,000d), and centrifugation of whole blood. The latter approach may remove high-molecular-weight immune complexes more efficiently than plasma filtration, but otherwise, the two techniques are equivalent. Once filtered, plasmais discardedand the patient is given human-albumin solution, saline, and coagulation factors. Plasmaexchange has been usedfor the removal Figure 1. T-cell flowcytometriccross-match beforeand of anti-blood group and anti-HLA antibodies, and after immunoadsorption. Eachpatientreceivedimmunoaclexperimentally, for the removal of xenoantibodies sorptionwith treatment of 5 plasmavolumes.Patient (Table 6). serumversusperipheralbloodlymphocytesfrom a normal donorcarryingHL4 classI antigensto whichthe patient Standard treatment sessionsconsist of 3 to 4 L hasraisedcross-reactive antibodies. Y axis,cell number,X exchanges, or the equivalent of approximately 1 axis, fluorescenceintensity. (A) Negative control, (B) plasma vol. Plasma exchange of approximately 1 preimmunoadsorption, (C) postimmunoadsorption. Paplasmavol results in only about a 60% reduction in tient 1; acute pretransplantimmunoaclsorption only retotal IgG levels,‘04which would only be effective for quired.Patient2; repeatedimmunoaclsorption required. the therapeutic removal of low titre antibodies. antispeciesantibodies,careful considerationwill have Higher volume exchanges have not routinely been to be given to thesetechnical aspects. used becauseof the difficulties in replacing clotting factors, calcium, and other elements possibly not contained in human albumin solutions. We have Techniques of Antibody Removal found that, in somecases,up to 40 L of plasmamay Exchange Transfusion need to be treated by protein A immunoadsorption in patients with high titre anti-I&4 antibodies to This comprises third-party blood transfusion and simultaneousvenesection.Recipient plasmais effecTable 5. AntibodyRemovalbyExchangeTransfusion tively diluted with normal plasma. No equipment other than peripheral venousaccessis required. Voronoyl”r 1933 Curtiset al’” 1982 Exchange transfusion alone cannot be recomBensingeret ala* 1987 mended as effective antibody therapy for anti-HLA Tokunaga et allo 1993 or antispeciesantibodies. Apart from the considerable volumes of blood that would have to be treated NOTE. (Small animal experiments not included)

B

AntWy

Renwual Therae in Transplantation

183

Table 6. Antittocly Removal in Transplantation By Plama Exchange Anti-specier Aalibodies

Anti-Al30 Antibodies Slapak et a12M Brynger et alis” Alexandre et aI% Alexandre et ap5 Welsh et all’jg M&lack et altM Schonitzer et a1t70 Reeling et al17’ Shapira et al172 Jakobsen et al%’ Piial et al’7g Bensinger et ala2 Mendez et aI” Agishi et allo * Renard et a1212 Takahaahi et a12’j2 Hanto et alI& Mendez et a12’js Tanabe et alt7* * Hasegawa et aIt5 Rydberg et a1’76 Larsen et allo

Anti-HI.4 AntibodieJ

Giles et a12@’ Merkel et a12t3 Moberg et al29 Shorn et a12t4 Yoshioka et a12t5 Alexandre et al265 Fischel et a1216 Taniguchi et a12s* Sat0 et a12@j* Kawauchi et aP * Besse et alffi Leventhal et a173

Cardella et a1200 Cardella et al”’ Naik et aim Kirubakaran et a1203 Rifle et a12a, Power et a1205 Soullilou et a1206 Allen et a1207 Taube et aP2 Hillebrand et al67 Minakuchi et a1267 Raftery et a12ss Fehrman et all’s Fauchald et al”g Gannedahl et a170 Halloran et al= Aswad et al’73 Masri et al26g Reisaater et al27o Grandtnerova et a1208 Miura et allas

other Antibodk Almkuist et aln2 Zlabinger et aln4 Kashtan et aln3

Non.$xe$c (whole Ig) Antibody Removal b Extracorjmeal Immunoa&mpion Anti-HLA Antibodis Palmer et allI Palmer et alIt Gil-Vernet et al’s2 Fehrman et all’s Esnault et aIll Fauchald et alIt Kupin et al’s3 Heisse et allffl Ross et alI@ Alarabi et a1’25 Martinelli et a140 Higgins et aIt4 Ruiz et al27’ Reisaater et aP70 Bevan et al’j”

Anti-Specie Antibodk Shapiro et al120 Welsh et al155 Henry et a1210 Leventhal et a173

Other Antibodies Dantal et ains

Note. Small animal exp&iments not included. *Double filtration plasmapheresis. achieve a negative crossmatch. Although plasma exchange sessions of up to 16 L have been performed in patients with liver failure, high-volume plasma exchange is not widely used.to5Btas To avoid the problems associated with disc&ding and replacing large volumes of plasma, doublefiltration plasma exchange has been developed. Plasma filtered in the normal way is passed through a second filter with a molecular weight cut off below

that of IgG. The filtrate from the second filter, containing albumin and other low-molecular-weight plasma constituents, can be passed back to the patient. to7*tesOnly the fraction ofplasmawith molecular-weight components of approximately 50,000 to 900,000 d is discarded. This technique has not yet been widely used, and because neither filter can operate at 100% efficiency, double filtration plasma exchange may be unable to process large volumes of

1.84

H&gins and Bevan

plasma effectively. However, Agishi et alto7 have found double filtration plasmapheresisto be superior to specific-antibodyremoval columnsin somecases. Nompecific Ig Removal The removal of Igs, without the depletion of other plasma components,such as albumin and coagulation factors, can be performed by passingplasma through an al&&y column (Table 7). This is most readily achieved in modern clinical practice by the use of staphylococcal protein A. Protein A is a constituent of the cell wall of certain strains of Staphyhmxus,and binds to immunoglobulins by a nonimmunologicalaction. IgGl, IgG2, and IgG4 are bound powerfully; other Ig lesswell so. Protein A is a robust molecule, and can be immobilisedonto sepharosein sucha way that a column can be purged of bound antibodywith an acid denaturing solution and then re-exposedto plasmaimmediately, once the eluting solution has been washed off. A systemfor plasmaexchange and immunoadsorption with protein A-sepharose has been widely used in transplantation, aswell asa range of other antibodyTable 7. Donor-Specific Antibody Removal Anti-HL4Antibodies Williams et aI9 Fung et al’4g Flye et al272 L&o et a136

Antispecies Antibodies In vivo Organ Perfusion (Large animal organ) Giles et al264 Moberg et al2g Cooper et a1217 Fischel et a1216 Roslin et al’s3 Brewer et al130 Wolf et a113* Brewer et a1130 Powelson et a113’ Henry et a1210 In vitro Antigen Perfusion Ye et a115’ Cooper et aIs7 Cairns et alss

Anti-ABO

Antibodies

McAlack et aIljo Schonitzer et a1170 Bannet et al147 Agishi et allo Takahashi et a1262 Aswad et al’73 Rydberg et all76 In Vitro Organ Perfusion (large animal organ) Lim et a1lM Bryan et a114’ Young et a114* Natafet a1’43 DiStefano et alI@ Mudsam et al274 Ross et al*‘s Tuso et a121g Pohlen et a1145 Fukushima et a157 In vivo Organ Perfusion (Human) Makowka et al” Collins et a1l3g

NOTE. Donor-specific antibody removal, using extracorporeal techniques of either whole organ perfusion (small animal work and some porcine-to-dog

or purified antigen work not included27).

mediated conditions.lOs-lilProtein A has also been coupled onto silica in a nonrenewable single pass system, which has been used in the treatment of ‘I2 The capacity of the prohaematologicaldiseases. tein A-silica column for Ig is only 1 to 2 g, and it is thought that this system may work by immune modulation after removal of some immune complexes. It does not have a role in acute antibody removal before organ grafting, as the currently available systemcannot remove sufficient quantities of antibody. The principal disadvantagesof protein A-sepharose immunoadsorption are, first, that total Ig is removed; This includes any beneficial IgG. Second, IgM antibodies are poorly removed. This is not a significant problem in the treatment of anti-I-&A antibodies becausethose of the IgM class do not seemto be of great significance,but doesprevent the successfulapplication of this technique to the removal of antispeciesantibodies.The useof staphyloccal protein G may overcomethis limitation.rt3 In our centre, immunoadsorption with protein A-sepharose columns has been used in over 25 patients for the removal of anti-HLA antibodies.‘” 116 It has been used in many other centres for the removal of anti-I-IL4 antibodies in renal transplantation 109-“2~117-121 and alsoin other antibody-mediated dise~es.109J22J23 We have found the technique to be safeand efficient, allowing removal of large amounts of antibody over periods of hours. We believe this is currently the technique of choice for the removal of anti-I-IL4 antibodies, becausethe treatment is fast and efficient, and the lesseffective removal ofantibodiesof IgM classis not of clinical importance. Polyclonal or monoclonal antibodies may also be bound onto sepharosecolumnsand usedfor antibody removal. du Moulin et ali2*have effectively removed low-densitylipoprotein (LDL) usinga column containing polyclonal anti-LDL antibodies.In vitro work by the same group has shown effective depletion of anti-I-IL4 antibodieswith an antihuman IgG-sepharose column, and successfultransplantation after a desensitisationprogramme using this technique for antibody removal hastaken placein Vienna, Austria (W. Druml, personalcommunication October 1994). Because anti-IgG and anti-IgM antibodies can be usedin sepharosecolumnsof this sort, they may have an application in the removal of antispeciesantibodies.Prevention of hyperacute rejection in a porcine-toprimate model hasbeen reported after the use of a combination of plasma exchange and IgG and IgM rernoval.!j7 Other techniques for immunoadsorption have

AnGb+y Removal Therab in Tramplan&ativn

been investigated. Tryptophan or phenylalanine immobilised in columns by chitosan beadsor a polyvinyl alcohol gel have been used for antibody removal.‘25-‘27IgM and IgC may be adsorbed using thesecolumns. Donor-Specific Ig Removal This can be achieved either by donor organ perfusion, or by the use of antigen in an extracorporeal circuit (Table 7). Ogpn Perfusion Antigen carried by a donor organ was first used for antibody removal in the 1960s.After a positive lymphocytotoxic cross-matchwas identified by Morris in Boston in 1967,12”hyperacute rejection occurred within a few minutes of transplantation. Transplantation of the other kidney was then attempted after a short interval. The cross-matchtitre had fallen from 1/52 to ‘mby adsorption of antibody on the first kidney. As we would now expect, the second kidney suffered the samefate asthe first.9J2a Over the next 25 years, this approach to antibody removal was not used again in clinical practice. However, antibody removal by organ perfusion is currently being reinvestigated asa technique for the removal of antispeciesantibodies. The liver is the organ of choice for the removal of antibodiesdirected againstcommonendothelial antigens.lmThe kidney has a much smaller capacity for antibody, and even if two kidneys are used en bloc, they are unable to remove enough antibody to prevent hyperacute rejection in porcine-to-human transplantation. ‘I The liver has also been shown to remove antibody more efficiently than the kidin experimental ex vivo ney,‘30,131 or the spleen’30J32 systems.Although the spleen was effective in one experimental xenotransplant mode1,‘33it has the potential to releaselarge amounts of solubleantigen. Dependingon the circumstance,this might of course theoretically be either beneficial or lead to an increasedrisk of sensitisation.The lung hasbeen used by one group, but was not efficient in removing antibody.5g A limiting factor in antibody removal by wholeorgan perfusion is that removal of high-titre antibodies may activate the hyperacute rejection process. The effects of platelet depositionin an organ can be serious,and a marked reduction in the circulating platelet count has been observedin hepatic failure patients undergoing pig liver perfusion,‘3“-‘38and in an experimental pig-to-primate model.13’Although in an experimental model with rhesus monkeys,

185

removal of IgC and IgM antibodiesto lessthan 10% of initial levelswasachievedwith perfusion of whole blood through pig livers,‘32the efficiency of antibody removal was poor when patients with liver failure perfused pig livers extracorporeally.‘3g This differencecould be related to the larger plasmavolume of an adult human comparedwith a rhesusmonkey and consequently,greater amount of antibody present. Therefore, it would seem advisable when using human recipients, to remove high-titre antibodies using plasma perfusion so that whole blood is not exposed to an organ until the titre is reduced. An acceptablelymphocytotoxic titre would appear to be between s and YM. Unfortunately, perfusion of a whole organ with plasmais likely to result in deterioration of the tissue from hypoxia and release of potassium,‘40liver enzymes,‘N-‘+’and cytokines such as tumor necrosisfactor (TNF) alpha and IL6.‘45 Even if oxygenated plasma is used, total oxygen delivery will be too low for prolonged organ survival or function. This is a major problem as plasma perfusion for the removal of high titre antibodies may take severalhours, becausecurrent technology placesa limit of approximately 100 mL/min on the plasma-flowrate, which can be achievedusing either filtration or centrifugation techniques.Further development of safe and reliable whole-organ perfusion systemsare required. However, it is encouraging that, in the absenceof prohibitive antibody levels, extracorporeal organ perfusion with whole blood may be possiblefor considerableperiodsof time with effective organ function.lG Whole-organ perfusion would seem to have its primary indication in xenotransplantation, as other techniques are of proven value in transplantation prohibited by the presence of ABO or anti-I-IL4 antibodies. An exception in clinical practice occurs when a combinedliver-kidney transplant is indicated in a recipient with high titres of anti-I-IL4 antibodies. This could occur in patients with conditions such as adult polycystic kidney diseasewith severe hepatic involvement, or in childhood cystic diseasesof the kidney associatedwith hepatic fibrosis.It seemsthat under such circumstancesthe liver could be transplanted first, and a few minutesafter vascularisation, renal transplantation might safely be performed. One highly sensitisedpatient has recently received liver-kidney transplantation at King’s CollegeHospital without any evidence of hyperacute rejection in the kidney, even though there wasa positive lymphocytotoxic cross-matchwith the donor before the liver was perfused, at a titre of Ya. A similar combined procedure in a patient with polycystic liver and

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kidneys has been reported, although major blood transfusion during the liver transplant operation effectively reduced the anti-I-&4 antibody titre by exchange transfusion.147Other experts have also noted the ability of the liver to remove anti-HLA antibodies in combined liver-kidney transplantation.l‘%l49 higen Carbohydrate antigens are the most promising for antibody removal using purified antigen, with relative easeof purification comparedwith protein antigens that may only be produced in small amounts and be lessstable. This has been achieved in both Al30 systemsand in experimental xenotransplantation.s*~~~‘07~150~‘5’ The rate of antibody removal by columnscontaining A or B bloodgroup substancehas proved limited in clinical experience, and plasma exchangehasbeen equally effective in somecircumstances.ro7 However, the use of antigen in columns rather than whole-organ perfusion appears attractive. When chemically purified antigen is not available, donor tissuein a column hasbeen used.Anti-bloodgroup antibodies have been removed by passing plasmaover red blood cells of the appropriate type, and then returning the plasma to the patient.r50 Porcine red blood cells have been immobilisedon a column,which hasremovedxenoantibodiesinvitro.15’ Although this technique may be of clinical use, immobilisation of tissuesuch asred blood cells on a column so that large amounts of antibody can be removed without sheddingsolubleantigen is technically demanding.

Complications

of Antibody

Removal

Technical and Nonimmunological Whichever technique is used, there are potential technical complicationsof antibody removal. If blood or plasma is to be circulated in any extracorporeal circuit, anticoagulation must be given, with a risk of haemorrhage. If human albumin or other blood products such as pooled Ig are given, there may be reactions of hypotension and vomiting. Use of a plasmafilter may occasionallybe associatedwith an anaphylactoid reaction, particularly in dialysis patients receivingangiotensinconverting enzymeinhibitors. We have seen one such reaction during antiHLA antibody removal. There are also two further important technical

complicationsof staphylococcalprotein Aimmunoadsorption. First, any significant release of protein A into the circulation could cause adverse reactions. The protein A-sepharosesystemdoesnot appear to have this drawback,but reactionshave beenreported with the protein A-silica system that have been attributed to possibleprotein A release. These include vomiting, hypotension, and fever.‘52-‘54 Second, regeneration of a saturated sepharosecolumn is performed with acid-eluting buffer. This is then rinsed away, and a pH electrode is attached to fail-safe mechanismsto prevent circulation of any acid buffer back into the patient. Obviously, any failure of this systemwould be harmful. The use of perfused organs has a number of potential adverse effects. Because some perfusion experiments may need to use plasma rather than whole blood, there may be problems with oxygen delivery with necrosisof the organ and release of potentially harmful substancesincluding inflammatory mediatorsand potassium.‘40J41J45 However, serious adverse events of this nature have not been reported in the seriously ill patients with hepatic failure who received extracorporeal organ perfusion.134-138 Significant antibody binding to an organ may alsoresult in platelet adhesionand subsequent thrombocytopaenia if whole blood is used, as discussedabove.13”138 There is a risk of acquired infection if human blood or plasmaare exposedto animal tissue.Extracorporeal pig organ perfusion has only been performed in a small number of patients with long-term survival. 135~155 No casesof apparently xenoacquired zoonoseshave been reported in these patients. Recent infection surveillanceof both pigsand primates bred in diseasefree surroundings has not indicated a high prevalenceof known pathogensthat might cause diseasein humans, excepting uncertainty over viral infection, including retroviruses, in higher primates.156-15g

Immunological These can be categorized into acute and chronic effects. Acute Effects Possibleacute adverse effects of an immunological nature have been reported in patients receiving antibody removal therapy using protein A-silica columns. Diseaseworsening has been observedover a few minutes or hours after treatment, and hasbeen

Ant&&

Rmaval

lXera/y

attributed to the possible removal of proportionately more beneficial (anti-idiotypic) than harmful antibody. However, the diseases in which this phenomenon has been reported do not lend themselves easily to quantification of antibody levels, so these conclusions are speculative.152J53J60 We have reported that anti-I-&J antibody removal using protein A-sepharose immunoadsorption may be associated with a transient increase in antibody binding, as measured by flow cytometry, during the first few hours of treatment.gg This increase in binding is not accompanied by an increase in the titre of the lymphocytotoxic cross-match, but we suspect that removal of anti-idiotypic blocking antibodies may be responsible for this finding. Chronic

Effects

The removal of whole Ig, or the administration of immunosuppressive drugs, will reduce the patient’s resistance to infection. This is obviously undesirable, especially if the proposed regimen may involve long periods of treatment before transplantation. We have observed two cases of relapse or worsening of immunological disease during a course of protein-A sepharose immunoadsorption. In one case, a patient with systemic lupus erythematosis in remission developed a relapse whilst receiving immunoadsorption for anti-I-LA antibody removal.i6r This relapse could have been caused either by an effect on immune regulation after antibody removal, or by a viral infection associated with hypogammaglobulinaemia. We treated another patient with idiopathic thrombocytopaemic purpura, who became worse during a course of immunoadsorption. The pretreatment antiplatelet antibody titres showed a continual increase, despite an effective reduction in titre during each session. The platelet count fell and immunoadsorption was terminated. It is, therefore, most important that any type of antibody removal treatment is accompanied by regular testing of antibody levels, with constant awareness that perturbation of the immune system could have adverse as well as beneficial effects. If antigen in any form is used for antibody removal, it may be released in soluble form, and lead to sensitisation of the recipient.*0*162In one study using baboons treated with total lymphoid irradiation, blood was perfused sequentially through three pig organs, reducing the titre of antipig antibodies from 1~56to ‘$4.However, 14 days later the titre had risen to greater than lh. r30Such sensitisation could, under

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in Tranr/dantation

some circumstances, transplantation.

Antibody Practice

prove prohibitive

Removal

to eventual

in Clinical

The current usage of antibody removal therapy in clinical practice, and the likelihood of advances in the near future, are discussed below.

Blood Group Antibodks Renal transplantation across a major blood group barrier into a recipient unmodified by antibody removal is generally unsuccessful, with graft loss caused by hyperacute rejection. Although a few isolated successful transplants have been reported,4J63 the outcome is generally very poor.3 It has been shown that blood group A and B antigens may be expressed on vascular endothelium in the kidney, and the interaction of these antigens with the appropriate antibody mediates graft 10ss.~*‘~* Transplantation from a group As donor across blood group barriers may be successful. It seems that about only 25% of such grafts are lost from antibody-mediated rejection.‘64-168The As antigen is generally expressed at relatively low levels on the vascular endothelium, which presumably explains the feasibility of transplantation in the presence of anti-As antibody. Although transplantation of a kidney from an As donor into an 0 or B recipient is generally uneventful if the pretransplant anti-As titre is less than l/M,rss graft survival cannot be accurately predicted from the recipient anti-As titre, suggesting that antigen expressionon the graft may be an important factor.iti Owing to a shortage of cadaver kidneys, several centres have attempted to perform transplantation across major blood group barriers, mainly using living-related donors. The first large series of such patients was reported by Alexandre et al.” Antibody removal has been performed by various workers using plasma exchange,54~5,82~‘50~‘7~‘~affinity columns containing A or B antigen,107JMJ70J73-175 or by double-filtration plasmapheresis.‘5J07*174Transplantation without hyperacute rejection is generally reported if grafting takes place in the presence of low levels of antibody, as measured by standard isoagglutination techniques. Graft survival rates after antibody removal have generally been reported to be in the region of 80% at 1 or 2 years.15J72J74A 2-year survival rate of 83.3% reported by Reding et ali7’ compares to 92% in patients transplanted under

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similar circumstancesin their institution, but who were ABO-compatible. Successfultransplantation may take place in the presenceof donor specific antibody at the time of surgery, but at the low IgG or IgM titres of ‘$4to l/s, respectively,measuredby conventional isoagglutination.‘76Antibodygenerallyreappears after transplantation, often at high titre, and often without deleterious effect.56~ss*WJ70J72J77 Unless the titre becomes very high (> lb), the outcome of the graft doesnot appear to be related to antibody concentration.‘77 Antigen may still be expressedby the kidney in the presence of circulating antibody.17t’Although the functional efficiency of this accommodationisremarkable, the mechanismsare not fully understood. Immunosuppression administered after ABOincompatible transplantation hasgenerally included a polyclonal antilymphocyte globulin as induction However, additional immunosup therapy. 165~170~173-175 pression has also been administered by the two groupswho have performed the largest numbersof transplantsafter removalof anti-bloodgroup antibodies.The Brusselsgroup of Alexandre et al” perform routine splenectomy,and have observedalmostinvariable graft failure in recipients with intact spleens.i7’ The Tokyo group of Tanabe et al’74 also perform routine splenectomy, and administer an induction course of deoxyspergualin. A or B antigen has also been infused at the time of transplantation to block remaining circulating antibodies,using purified antigen, or fresh frozen plasma.54284 The importance of theseadditional measuresis uncertain. The liver may be successfullytransplanted across ABO-incompatibilitywithout graft loss,againindicating that organ type or size playsan important role in outcome after donor-specificantibody exposure.83A recent survey of the United Network for Organ Sharing (UNOS) registry reported a 71% l-year graft survival rate for ABO-incompatible liver grafts in paediatric recipientscomparedwith 83%and 87% l-year survival rates in ABO-identical and compatible combinations,respectively.155ABO-compatibility seemsto be a requirement in cardiac transplantation, where antibody-mediated graft damage has been reported, despite intensive plasma exchange after transplantation.17g Blood group antibodies may also play a role in transplantation acrossspecies.One chimpanzee-toman transplantation performed by Reemstmafailed becauseof blood group incompatibiity, and retransplantation with a blood-group-compatible organ was

followed by successfulearly engraftment.5* The rarity of bloodgroup 0 amongstbaboonshasresultedin blood group incompatibility in some baboon-to human transplants, which appears to have contributed to graft failure.ls”JB1 In summary, renal transplantation can be successful after removal of anti-blood-group antibodieswith graft survival rates only slightly lower than those achieved in comparable ABO-compatible combinations. Transplantation after the removal of bloodgroup antibodies may have a role in the management of patients who do not have a realistic chanceof transplantation except from an ABO-incompatible living relative. Attempts should be made to avoid blood group incompatibility when performing xenotransplantation.

Anti-HLA

Antibodies

Pretransplantation Several strategies have been used to remove antibody, and thus to facilitate renal transplantation in patients with antiHL4 antibodies. Early protocols relied on antibody removal combined with immunosuppressionto produce a window of time in which panel-reactive antibody levelswere significantly reduced (perhaps from 95% to 50%). If this window was open for a period of weeks to months, a suitable kidney could then be found that would have a negative cross-matchwith the recipient, and transplantation could occur in a routine fashion.Taube et a16*treated five persistently highly sensitisedpatients with coursesof plasmaexchange and administered cyclophosphamideand prednisolone by mouth. All patients experienced a sustained fall in panel-reactive antibody levels and, in four cases,blood transfusion containing deliberately mismatched antigens elicited no antibody response. Renal transplantation was performed in all five patients, with successfulengraftment in four. However, cyclophosphamidewas administered in doses that induced neutropaenia in all patients. One patient experienced septicaemia during plasma exchange and 6 weeks after transplantation one patient died ofserratia septicaemia.This protocol, with considerable immunosuppressionin the pretransplant period, hasnot been adopted by other centres, although the results were in principle, very promising. Immunoadsorption with protein A-sepharose columns has been used in a number of centres in broadly similar protocols, but with much lessimmu-

Antibo& Remvval lhrab

nosuppressiveload in the pretransplant period.ir5Ji7I ‘9,‘2’,‘82-Ills

Three problemswith this approach have become apparent. First, antibody rebound rather than sup pressionhasgenerally occurred, even if immunosup pression is also given (Fig 2). Therefore, there is difficulty in obtaining a transplant with a negative cross-match.’14~117~184~1*5 This can present suchpractical difficulties that it has been suggestedthat antibody removal hasonly a marginal application in this context until new pharmaceutical agents that sup press antibody production more safely are developed.‘*6 Two new and promising agents, namely, mycophenolate and deoxyspergualin, are currently being tested in combination with antibody removal. Our approach to this problem has been to try and restrict immunoadsorption to intensive sessionsin a short period of time after a suitable kidney becomes available. A positive cross-match may be rendered negative over a 24hour period with intensive immunoadsorption. There is obviously a possibility of reappearance of antibody postoperatively, despite induction immunosuppressionwith ATG and cyclophosphamide.However, return of antibody has not occurred in all our casesand when it has, it was not invariablyassociatedwith rejection. One patient with a pre-immunoadsorption lymphocytotoxic crossmatch titre of l/512did not have detectable donor specific antibody in his circulation after transplanta-

tion, despiteacute removal immediately before transplantation.” Second,once a highly sensitisedpatient hasbeen started on a course of antibody removal, a kidney that has a negative preimmunoadsorption crossmatch may becomeavailable.In otherwords, successful transplantation could have taken place without performing antibody removal. Transplantation with a negative historical cross-match has occurred in nearly all centres using immunoadsorption, to a greater Isi or lessertt4*rt7;121 extent. Our approach to this problem hasbeen to developantibody removal so that, in suitable patients, it need only occur after a kidney with a positive crossmatchhas been identified. If a kidney with a negative cross-matchshould becomeavailable, transplantation can occur without exposure to the risksand costsof antibody removal. Furthermore, we only considerimmunoadsorptionin patients who are persistently highly sensitisedand who have failed to receive transplants, despite waiting at least 2 years on the national and regional kidney sharing schemes. Third, transplantation with a negativelymphocytotoxic cross-match,even after immunoadsorption, has been followed by hyperacute rejection.‘@ This may be because the conventional cytotoxic crossmatch, even with techniques such as prolonged incubation, is not sensitive enough to detect low levels of antibody that can causegraft failure. Our approach is to use flow cytometric cross-matching, and only to perform a transplantation when the cross-match is negative as measured by this most sensitive technique.47Jss-1g5 Even so, in our hands, a negative flow cytometric cross-matchallowsthe peak fluorescenceof the test sample to be up to 0.5 log shift above control. Therefore, we permit measurablequantities of antibody to be present at transplantation. In some caseswe have seen histological changescompatible with hyperacute rejection, even with thesevery low levelsof antibody. However, this hasnot yet causedgraft lossin our patients. The l-year graft survival rates after transplantation, facilitated by protein A-sepharose,average 50%, or slightly more, in the published series.Wkl~4,lW

Figure 2. Reboundeffect after immunoadsorption. Patient serumversusperipheralbloodlymphocytesfrom a normal donorcarryingHLA ClassI antigensto whichthe patient hasraisedcross-reactiveantihoclies.Y axis, cell number, X axis, fluorescenceintensity. Histogram (A) negativecontrol,(B) preimmunoadsorption, (C) postimmunoadsorption, (D) 5 dayspostimmunoadsorption.

189

in Transplantation

W2lJ82-l85

This

rate

of

successful

en-

graftment compareswith virtually zero chanceif the patient is merely left on dialysis. Two contributing factors to this low graft survival rate may be important. First, flow cytometric cross-matchingwasgenerally not usedwhen protein A-sepharoseimmunoadsorption was introduced. It is likely that someof the

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mediated rejection can occur very quickly, so that its immediate graft lossesthat have been reported would now be avoided if this more sensitive cross- detection and effective treatment must take place within aslittle as48 hours.One recent study in which match technique was to be used.Secondly,we have patients with vascular rejection and donor-specific experienced more graft lossesfrom technical and antibodies were treated with protein A-sepharose vascular problemsthan from rejection. This reflects immunoadsorption reported graft survival in 12out higher morbidity after long-term dialysis and previof 19 patients. It was possibleto treat 2 to 3 plasma ousfailed transplantation. volumes on the first day, compared with 1 plasma Although the graft survival rates during shortvolume in previousreports usingplasmaexchange.*Os term follow-up are lessthan would be expected for first grafts, we have observedremarkable stability of graft function during longer follow-up in our centre. Antispecies Antibodies The 5-year graft survival rate for the patients who received transplantsby Palmer et al’ I4with a historiAlthough awide range ofapproachesto the immunocal positive cross-matchwas s (62.5%),rg5which is logical difficulties of porcine-to-human transplantanot different from the 5-year graft survival rates in tion are being investigated, successfultransplantaregrafted highly sensitisedpatients who received tion will require crossingan antibody barrier. Because transplantselsewherewithout antibody removal.1ss~‘g7 specificmeasuresto prevent antibody production are Therefore, we believe that transplantation facilitated not yet effective in clinical practice, it is generally by antibody removal should be widely available to agreed that transplantation will be attempted after highly sensitiseddialysispatients who have failed to acute antibody removal.ss*210 receive a transplant through all other conventional Hyperacute rejection of a vascularised porcine measures,although the technique should only be graft by a human or other primate requires only low offerred by a few highly specialisedcentres. levelsof antibody. In porcine-to-human combination, Posttransplantation Donor-specificanti-HLA antibodiesmay causerejection after transplantation, although this often occurs in apparent associationwith cellular rejection sothat their relative contributions to graft damageare not easily quantifiable.47~g~l-53JgsJss There are several reports of the treatment of rejection by plasmapheresis in combination with various pharmacological agentssuchasprotein immunosuppressionor deoxyspergualin.70~200-2ss However, randomised trials of plasmapheresis in vascular rejection20i203~206 have not shown a benefit from treatment. Unfortunately, even these randomised studiesare not fully able to exclude a possiblebenefit from antibody removal in antibody-mediated rejection. The principal entry criterion in somestudieswasvascular rejection, which resulted in recruitment of some patients without detectable antidonor antibody.205J07 Such patients might not be expected to benefit from antibody removal. Soullilou et alsssin a small randomised study, carefully examined the daily titres of donorspecific antibody. Although the group treated with plasma exchange did not show a benefit in clinical outcome, a regimen of daily 4-L plasma exchanges took up to 5. days to substantially reduce the antiHLA titre. Therefore, a benefit from more intensive antibody removal in selectedcaseshasnot beenfully excluded. We believe that graft lossfrom antibody-

antibodiesare predominantly of IgM class,but those of IgG class are also generally present. Human, anti-pig antibodiesare normally present at a lymphocytotoxic titre of more than l/sm,although some individuals with renal failure undergoing anti-HLA antibodieshave been noted to have lower titres. The titre of theseantibodies that is permissivefor transplantationwithout hyperacute rejection in humansis not clearly defined. The removal of greater than 90% of suchantibodiesby extracorporeal organ perfusion was insufficient to prevent hyperacute rejection of a pig liver. 211However, in pig-to-baboon transplantation, reduction in antibodiestitres by 70%to 85%was apparently enough to prevent hyperacute rejection, although there wasno long-term graft ~urvival.‘~~ Although somework with doublefiltration plasma exchangehasbeenperformed,210 conventionalplasma exchange would not appear to be suitable for removalof high titre antispeciesantibodies.2’2-2’5 Fxperimental transplantation of a heart from pig to baboon has been successfullyperformed after plasma exchange and immunoadsorption using anti-IgM and anti-&$ immunoglobulin-sepharosecolumns, but data on the application of this approach to the human are awaited?* Immunoadsorption with protein A-sepharoseis inefficient at IgM removal, and thus, in general is not suitable for this purpose. However, this hasbeen successfullyperformed without subsequenthyperacute rejection in one isolated

Antibdy Removal Thera@ in Transplantation

case, in Dulwich Hospital, by Drs Welsh, Taube, Palmer and Bewick.ts5A patient being treated with protein A-sepharoseimmunoadsorption for the removal of anti-I-IL4 antibodies was noted to have unusually low titres of natural antipig antibodies. Accordingly, after repeated immunoadsorption, a porcine kidneywas connectedto the patient’s circulation via lines connected to an arteriovenous dialysis fistula. The organ functioned for somehourswithout sufferring hyperacute rejection. Selective removal of antispeciesantibody would appear to be a better approach than using any of the nonspecific methods of antibody removal currently available. Whole organs are available for this, and a number of in-vivo and in vitro large animal experiments have been performed, using either the pig-todog model, or more recently, pig-to-primate (Table 7).60~~32~1~~~45~21”218 However, the preciseregimen required to remove high-titre antipig antibodies from an adult human using pig liver perfusion techniques hasnot yet beendeveloped,although it appearsto be technically feasible.Somein vitro work hasindicated that antibody may be efficiently removed from fresh, whole blood,218but these results may not be applicable to in vivo situations.Perfusion of pig livers with the blood of liver failure patients for up to 5 hours resulted in only a 35% reduction in antibody titre in one study.‘3gHowever, the blood flow through the organ was not stated in this work. Organ perfusion with plasma has been performed by someworkers, and has indicated effective reduction in antibody levels.Perfusion of 5 to 6 plasmavolumes of baboon plasma through porcine organs was adequate to reduce the antipig titre from ‘~56to s.i30To achievea negative cytotoxic cross-match,it may be necessary to use more than one organ sequentially for perfusion. Human antipig natural antibodies of both the IgM and IgG classeshave been found,s1gJ20 and it is thought that IgM antibodiesare ofgreater physiological importance.22iHowever, whilst the majority of these IgM natural antibodies would appear to be binding to the carbohydrate moeity alpha-galactosyle (Gal) (a Gal 1,3Gal),85.2”thoseof the IgG classhave not been as well defined. To use extracorporeal columns for antispeciesantibody removal, several ligandswould probably have to be bound to an inert matrix. Red blood cells have been immobilised in a column for this purpose,i33and infusionsof soluble o-Gal antigen preparations have been used experimentally to reduce antipig antibody levelsin primate blood.s7-88

191

The problem of acute and chronic rejection mediated by xenoreactive natural antibodies,and antispeties major histocompatibility complex (MHC) antibodiescan only be fully addressedafter preliminary pig-to-human transplantshave beenperformed. Successful primate-to-human renal transplants have failed in associationwith chronic vascular rejection, although this has initially been reversible in some cases.However, induction chemotherapy in these casesdid not include cyclophosphamideand ATG, and any antispeciesresponsehas.often been dominated by an anti-blood-group response,as discussed above.58J80J8r It remainsuncertain whether the techniques that allow accommodationto occur in transplantation acrossanti-I&A antibody and bloodgroup barriers will apply in xenotransplantation. In summary, there now exist enough data to form a clear strategy for the prevention of hyperacute rejection by antibody depletion therapy in discordant xenotransplantation. Successfuluse of this in humans has not yet been reported, apart from one isolated case. The problems of chronic antibodymediated damage have been anticipated, and the proposedapproachesdepend more on assistingthe processof accommodationthan on the repeated use of extracorporeal antibody removal techniques.

Other Antibodies Deliberate removal of other antibodiesencountered in clinical transplantation hasoccasionallybeen performed. Anti-glomerular basementmembrane antibodies have been removed in a small number of cases,with limited success.z2*223 Accidental overdose with ATG hasbeen treated with plasmaexchangein one case, with a successfuloutcome.n4 Recurrent focal sclerosisin renal grafts may respond to the removal of a possibly pathogenic antibody using protein A-sepharoseimmunoadsorption,and a larger study is currently being performed after preliminary experience.225

Conclusions Clinical transplantation has developedover the last 30 years by avoiding potentially damaging graftantibody interactions. This hasultimately proven to be limiting, given the shortage of human organsfor transplantation. Therefore, transplantation in concert with antibody removal techniques has been performed. Transplantation acrosssomeABO barri-

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Higgh

ers and some anti-HLA antibody barriers can be successfullyachieved in clinical practice by special centres. Data from this practice on extracorporeal perfusion techniques,graft antigenicity, and accommodation now permit successfulacute removal of antispecies antibodies in humans. The future of transplantation acrossantibody barriers will depend on a combination of antibody removal techniques, and a better understandingof how to induce accommodation, and limit antibody production to permissiveconcentrations.

References 1. Taylor CJ, ChapmanJR, Ting A, et al: Characterisation of lymphocytotoxic crossmatches causing a positive crossmatch in renal transplantation. Relationship to primary and regraft outcome. Transplantation 1989,48:953 2. Karuppan SS, Lindholm A, Moller E: Fewer acute rejection episodes and improved outcome in kidney transplanted patients with selection criteria based on crossmatching. Transplantation 1992,53:666 3. Cook DJ, Graver B, Terasaki PI: ABO incompatibility in cadaver donor kidney allogralis. Transplant Proc 1987, 19: 4549 4. Stars1 TE, Marchorio TL, HolmesJH, et al: Renal homografts in patients with major donor-recipient blood group incompatibilities. Surgery 1964,55: 195 5. Porter RA: Renal Transplantation, in Heptinstall RA (ed): Pathology of the Kidney (ed 4). Boston, MA, Little Brown, 1992, p 1799 6. Dunnill MS: Histopathologyorrejection in renal transplantation, in Morris PJ (ed): Kidney Transplantation: Principles and Practice (ed 3). Philadelphia, PA, Saunders, 1988, p 439 7. Pate1 R, Terasaki PI: Significance or the positive crossmatch test in renal transplantation. N Engl J Med 1969,280:735 8. Kissmeyer-Nielsen F, Olsen S, Petersen V, et al: Hyperacute rejection or kidney allografts associated with preexisting humoral antibodies against donor cells. Lancet 1966,2:662 9. Williams GM, Hume DM, Hudson RP, et al: “Hyperacute” renal-homograft rejection in Man. New Engl J Med 1968, 279611 10. Demetris AJ, JalTe R, Tzakis A, et al: Antibody mediated rejection of human liver allografts: Transplantation across ABO blood group barriers. Transplant Pmc 1989,2 I:22 17 11. Makowka L, Wu GD, Hoffman A, et al: Immunohistopathologic lesions associated with the rejection oI’ a pig-to-human liver xenograft. Transplant Proc 1994,26: 1074 12. Collins B, Chari R, Magee J, et al: Immunopathology of porcine livers perrused with blood or humans with fulminant hepatic failure. Transplant Proc 1995,27:280 13. Takaya S, Bronsther 0, Iwaki Y, et al: The adverse impact on liver transplantation oP using positive cytotoxic crossmatch donors. Transplantation 1992,53:400 14. Higgins RM, Bevan DJ, Vaughan RW, et al: Transplantation alter immunoadsorption-short and long term follow up. Renal Association, Edinburgh, UK, April 1994, (abstr) 15. Hasegawa A, OharaT, Hirayama N, et al: Reversible anuria

and Bevan

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