International Reviews of Immunology, 33:174–194, 2014 C Informa Healthcare USA, Inc. Copyright  ISSN: 0883-0185 print / 1563-5244 online DOI: 10.3109/08830185.2013.857408

REVIEW

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Molecular Deciphering of the ABO System as a Basis for Novel Diagnostics and Therapeutics in ABO Incompatible Transplantation Jan Holgersson,1 Lennart Rydberg,1 and Michael E. Breimer2 1

Department of Clinical Chemistry and Transfusion Medicine and; 2 Department of Surgery, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden

In recent years ABO incompatible kidney transplantation (KTx) has become a more or less clinical routine procedure with graft and patient survival similar to those of ABO compatible transplants. Antigen-specific immunoadsorption (IA) for anti-A and anti-B antibody removal constitutes in many centers an important part of the treatment protocol. ABO antibody titration by hemagglutination is guiding the treatment; both if the recipient can be transplanted as well as in cases of suspected rejections if antibody removal should be performed. Despite the overall success of ABO incompatible KTx, there is still room for improvements and an extension of the technology to include other solid organs. Based on an increased understanding of the structural complexity and tissue distribution of ABH antigens and the fine epitope specificity of the ABO antibody repertoire, improved IA matrices and ABO antibody diagnostics should be developed. Furthermore, understanding the molecular mechanisms behind accommodation of ABO incompatible renal allografts could make it possible to induce long-term allograft acceptance also in human leukocyte antigen (HLA) sensitized recipients and, perhaps, also make clinical xenotransplantation possible. Keywords: ABO blood group system, blood group ABH antigens, blood group ABO antibodies, carbohydrate antigens, glycoengineering, mucins, transplantation

ABO INCOMPATIBLE SOLID ORGAN TRANSPLANTATION History The first human kidney transplantation (KTx) was performed in Kherson in April 1933 by the Ukranian surgeon Yurii Voronoy. It also happened to be the first ABO incompatible (ABOi; blood type B to O) KTx. The patient died 2 days after transplantation [1]. In the early days of solid organ transplantation, the general belief was that the ABO blood group barriers had to be respected and followed as practiced in blood transfusion policies. This was based on the very poor outcome seen in a short series of accidental ABOi KTx due to donor ABO mistypings [2]. Even if occasional successful cases of ABOi Tx were reported, the classic Landsteiner law (i.e. preformed, or natural, anti-blood group A or B antibodies (Abs) are present in individuals lacking the corresponding antigen/s) for blood transfusion was also accepted in solid organ transplantation. The first Accepted 15 October 2013. Address correspondence to Michael E. Breimer, Department of Surgery or Jan Holgersson, Department of Clinical Chemistry and Transfusion Medicine, Sahlgrenska University Hospital, SE-416 85 Gothenburg, Sweden. E-mail: [email protected] or jan.holgersson@ clinchem.gu.se

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intentional ABOi organ transplantation trial was initiated in the 1970s when kidneys from donors of the blood group A2 subgroup were transplanted to O recipients [3]. The immunosuppression was azathioprine and steroids, and no antibody removal was performed. Graft outcome was similar to that of ABO compatible KTx at that time [4]. In the beginning of 1980s, Alexandre and coworkers initiated the use of blood group A1 and B live donors (LDs) for ABOi KTx [5]. Their protocol included anti-A and -B Ab removal using plasmapheresis (PP), pre-operative injection of soluble A or B saccharides to neutralize remaining Abs, splenectomy, anti-thymocyte globulin (ATG) induction therapy followed by azathioprine/steroids/cyclosporine [6, 7]. This protocol resulted in a graft outcome similar to that of ABO compatible grafts. ABOi KTx programs were initiated in several centers in Europe, Japan and the United States [8–10]. However, grafts were occasionally lost due to antibody-mediated rejection (AMR) [9, 11, 12] and this, together with the need for splenectomy with its documented side effects in renal graft recipients [13, 14], meant that the procedure did not get general acceptance in countries with established diseased donor (DD) transplant programs. In Japan, however, ABOi KTx programs were continued because there were no DD programs. Several hundred patients were grafted between 1980 and 2000 with very good outcome [15, 16]. In the early 2000s, two centers in Sweden restarted ABOi living donor (LD) KTx programs [17, 18], and today more than 250 patients have been transplanted corresponding to 2.5 Tx/million inhabitants and year. The incentive was, as in the early days, to expand the LD pool and to shorten the long waiting time for blood group O patients on the waiting lists. ABO Abs were removed by specific immunoadsorption (IA) using an IA column with matrix carrying A or B trisaccharides [19]. The anti-CD20 mAb, rituximab, was used as induction therapy to deplete B-cells, and a combination of tacrolimus, mycophenolate mofetil (MMF) and steroids was used as maintenance therapy. Graft outcomes were excellent and ABOi KTx programs were initiated/expanded in several countries using either antigen-specific IA [18, 20, 21] or PP [22–24]. Such programs are now clinical routine in many centers. ABOi liver transplantations (LTxs) are also performed [25, 26], and especially A2 to O LTx recipients have been doing well [27–29]. There are now several reports on successful cases of ABOi lung [30, 31], heart [32] and pancreas [33] Tx as well. Clinical Protocols Treatment protocols in ABOi organ transplantation include standard maintenance therapy usually comprised of a calcineurin inhibitor (CNI; often tacrolimus), a proliferation inhibitor (often MMF) and steroids. In selected cases also other immunosuppressive agents, such as anti-IL2 receptor antibodies, are used. In addition, the level of recipient anti-A and/or anti-B as well as expected graft ABH antigen expression levels dictates supportive treatment regimens. Below we describe these considerations in more detail. Donor blood group The blood group ABO system consists of several subgroups based on their red blood cell (RBC) serological reactivity [34]. Two major blood group A subgroups exist in the Caucasian population, A1 (80%) and A2 (20%). Additional several minor subgroups constitute less than 1% of the population. Blood group B subgroups are rare. There is a quantitative and qualitative difference between the A1 and A2 subgroups with regard to the A antigen expression on RBC [35] and other tissues [36]. A1 individuals have considerably more A antigens on their cell surfaces compared to other A subgroups. This is most likely the explanation for the successful grafting of blood group A2 kidneys C Informa Healthcare USA, Inc. Copyright 

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into O recipients [37–39]. A similar inter-individual difference in B antigen expression levels in various tissues is lacking [37, 40], although a range of B RBC reacting weakly or not at all with anti-B has been described [41]. Anti-ABO antibody removal Reduction of recipient anti-A and -B Ab titers prior to ABOi transplantation including A1 or B donors has been considered necessary for a successful outcome. The exact maximal anti-A or -B titer that permits a safe ABOi Tx has not been determined. Titers suggested being safe range from 1:8 [17, 42] to 1:16 [24] or 1:32 [43]. In recipients of A2 grafts, a slightly higher anti-A titer is accepted [17] because of less A antigens in A2 kidneys [37]. The difference between centers in terms of maximal titer allowed probably has many explanations, but the most significant one is likely to be the poor reproducibility and inter-center variation of the hemagglutination techniques’ uses to determine the titer [22, 44, 45]. Contributing to this is the use of a panel of individual donor RBCs versus organ donor RBCs as targets in the hemagglutination assay. In this respect, it should be noted that A2 RBCs give, on average, a two-titer step lower response compared to A1 RBCs (Rydberg, L. unpublished observation). PP, using the single or double filtration technique, has been used for anti-ABO antibody removal [16, 46]. Recently, an IA column having blood group A or B trisaccharides on spacer arms linked to sepharose was developed [47] and successfully used in the clinic [17, 18, 20]. Antigen-specific IA has been claimed to have the advantage over PP that it does not remove Abs of other specificities, e.g. Abs against viruses and bacteria, or coagulation factors. However, recent investigations have challenged this view [48, 49]. To inhibit B cell function and prevent Ab synthesis, MMF treatment is started prior to grafting in most protocols [50]. One IA procedure usually results in a 2–4 Ab titer step reduction that is followed by a 1–2 titer step increase over night due to redistribution of Abs from the extracellular space. Agishi et al. compared the efficacy of IA and double filtration plasmapheresis (DFPP) with regard to removal of anti-A or anti-B. Their conclusion was that DFPP is more effective than IA, but they still preferred selective removal and thus considered IA as the first choice for pretreatment of candidate recipients of ABOi grafts [51]. Furthermore, we compared the efficiency of IA and PP in terms of human anti-pig antibody removal, and showed that PP was more efficacious than IA on a protein A column [52]. Anti-A and -B Ab titers are monitored daily after transplantation. A two-titer step increase, or one-titer step on consecutive days, is regarded as a significant change. Many centers perform protocol IA/PP post-Tx, even if Ab titers are unchanged, to prevent an Ab increase [17, 18]. However, this has not been the case for Japanese programs except if anti-A and anti-B titers suddenly rose within the first week post-Tx and biopsies indicated signs of AMR [16]. A rise in anti-A or -B Ab titers during the first 2–4 weeks will usually trigger IA/PP treatments [20]. Thereafter, ABO Ab will be allowed to return if not associated with signs of organ dysfunction. A state of immune tolerance called accommodation (see below) has been achieved [53–56]. Splenectomy/Anti-CD20 Alexandre et al. stated that splenectomy was necessary based on the observation that three patients in his A1 or B to O KTx series that were not splenectomized all rejected their grafts [5]. Splenectomy was not performed in the initial trial using kidneys from A2 donors [4], and was later confirmed not to be necessary for A2 donors if anti-A Ab titers were low [57–59]. The need for splenectomy in major (A1 and B grafts) ABOi KTx has been questioned [60, 61]. The humanized anti-CD20 Ab, rituximab, developed for treatment of B-cell lymphoma has been successfully applied in ABOi organ Tx [17, 18]. It eliminates most International Reviews of Immunology

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B-cells after a single dose [62] and seems to lack serious side effects [63, 64]. Rituximab treatment may not be necessary in case of A2 donors [17] and now it has been questioned if it is needed following A1 or B to O KTx as well [65]. However, since the side effects of a single dose of rituximab are limited, many centers use rituximab in all cases of ABOi Tx. IVIG High- and low-dose intravenous immunoglobulins (IVIG) have been used in different desensitization protocols developed to make highly human leukocyte antigen (HLA) sensitized patients transplantable (reviewed in [66]). The high-dose protocol includes up to four monthly infusions of 2 g/kg of IVIG and was shown to result in a significant reduction in panel-reactive antibodies and a higher transplant rate in a multicenter prospective trial [67]. However, the effect of this treatment has been questioned in a recent report [68]. With the rationale to block complement activation and suppress antibody re-synthesis, most protocols for ABOi KTx using PP for antibody removal include low-dose (0.1 g/kg) IVIG administration after each PP [22, 66]. In the IA-based protocol developed by Tyd´en and coworkers, 0.5 g/kg of IVIG was given after the last pre-Tx IA on the day before Tx [18]. Anti-A and anti-B antibody-mediated rejection In the early days of solid organ transplantation, ABO AMR in non-planned ABOi organ Tx usually resulted in graft loss. The majority of these were most likely A1 and B grafts. Graft loss due to AMR in non-splenectomized recipients of A2 grafts has been reported [12, 42, 69, 70]. The greatest predictor of AMR has been proposed to be the baseline – before any treatment – anti-A and -B IgG Ab titers [8]. Also in the current ABOi KTx program, anti-A and anti-B AMR are rare, but occur occasionally and sometimes result in graft loss [17]. In fact, a retrospective analysis of the Scientific Registry of Transplant Recipients in the United States revealed that there were significantly more graft losses in the first 14 days post-Tx in the ABOi group than in the control group receiving ABO compatible grafts [71]. However, there were little to no difference after day 14 [71]. Following transplantation of different organs, ABO AMRs have been reversed using intense Ab removal [72] in combination with complement inhibition [30, 33, 73, 74]. Kidney Paired Donation as an Alternative to ABOi Transplantation Kidney paired donation (KPD), involving several LD-recipient pairs, has been successfully introduced to overcome HLA antibody sensitization as well as ABO incompatibility between individual donor-recipient pairs [75, 76]. Therefore, participating in a KPD program is an alternative to ABOi Tx for ABOi donor–recipient pairs. However, the successful application of ABOi Tx has excluded an important source of nonsensitized recipients from potential KPD pools [77]. As a consequence of the success of ABOi Tx, it should be possible to accept ABOi, HLA-acceptable donors for patients with low to moderate anti-blood group antibody titers in KPD programs, which should result in a higher transplantation rate in these programs [77]. BIOCHEMICAL CHARACTERISTICS OF THE ABO BLOOD GROUP SYSTEM ABH Determinant Structures and Their Outer Core Chains Blood group A and B determinants are formed following addition of the monosaccharide N-acetylgalactosamine or galactose, respectively, in an α-linkage to the third carbon of the galactose residue in the blood group H determinant (Fucα2Galβ-R) (Figure 1). The blood group ABH determinants are then linked to different carbohydrate outer core chains that considerably increase the structural complexity of C Informa Healthcare USA, Inc. Copyright 

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FIGURE 1. Chemical structures of the blood group ABH antigen determinants and the genes/ enzymes involved in their biosynthesis.

these antigens (Figure 2). Five different outer core chains have been identified in humans: type 1 (Galβ3GlcNAc), type 2 (Galβ4GlcNAc), type 3 (Galβ3GalNAcα), type 4 (Galβ3GalNAcβ) and type 6 (Galβ4Glc) (Figure 2). It should be noted that these core chain numbers should not be mixed up with the serologically defined A1 and A2 subgroups. Besides Their Presence in Body Fluids as Soluble Saccharides, ABH Determinants are Carried by Lipids or Proteins Besides their presence as soluble saccharides in body fluids, e.g. serum, urine, milk and saliva [78–82], ABH determinants are found as glycan side chains on proteins as well as linked to ceramide [83]. Glycans on proteins can be N-linked to asparagine residues in the Asn-X-Ser/Thr consensus sequence, or O-linked via serine or threonines residues in the peptide chain [83]. Oligosaccharide side chains are normally attached to the peptide chain while this is processed for export to the exterior of the

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FIGURE 2. Different core saccharide chains to which the blood group ABH di-and trisaccharide determinants are linked. International Reviews of Immunology

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cells [83]. The glycosyltransferases, enzymes involved in oligosaccharide biosynthesis, are organized in the Golgi apparatus [84, 85]. The ABH blood group antigens are widely expressed on erythrocytes, mucosal tissues of the digestive, respiratory and urinary tracts and endothelial cells (EC). In the red cell membrane, ABH determinants can be found on band 3, the predominant integral polypeptide of the red cell membrane, as well as on the major sialoglycoprotein, glycophorin A (GPA) [86–88]. On GPA, A and B determinants can be found both on O- and N-glycans [87, 88]. ABH determinants are detected also on proteins in milk, urine, saliva and other body fluids [41]. Human plasma von Willebrand factor, coagulation factor VIII and a portion of α 2 -macroglobulin have been found to carry ABH determinants [89]. For Tx and the potential immune injury caused by anti-A and -B Abs, the expression of ABH antigens on EC of the different vascular beds of transplanted organ is of utmost importance. Most of the information on EC expression of ABH antigens is derived from immunohistochemical studies [37, 90–92], and very few investigations on the chemical structure of EC ABH determinants have been performed. However, proteomics and glycomics techniques are likely to change that in a near future [93].

ABH Antigen Biosynthesis ABH antigen biosynthesis The biosynthesis of the blood group H disaccharide and A/B trisaccharide determinants is initiated by α1,2 fucosylation of the precursor chain; an enzymatic step catalyzed by the H (FUT1) or Se (FUT2) gene encoded α1,2 fucosyltransferases (FT) [94–96]. The A and B determinants, respectively (Figure 1), are generated by addition of an α-linked N-acetylgalactosamine by the A gene-encoded α1,3 Nacetylgalactosaminyltransferase (α1,3 GalNAcT) and an α-linked galactose by the B gene-encoded α1,3 galactosyltransferase (α1,3 GalT) [97]. Compared to the A1 enzyme, the α1,3 GalNAcT of A2 individuals carries an extra domain in the carboxyl terminal of the enzyme because of a nucleotide deletion leading to a reading frame shift [98]. Biosynthesis of core saccharide chains The family of galactosyltransferases is responsible for the biosynthesis of the type 1–4 outer core saccharide chains (reviewed in [99–101]). Following transfection of CHO cells with cDNAs encoding a protein carrying only N-linked glycans or a mucin-type protein with mainly O-glycans, respectively, we have shown that type 1 chain on Nlinked glycans can be synthesized by β3Gal-T1, -T2 and -T5, while type 1 chain on O-glycans was only generated by β3Gal-T5 [102]. β3Gal-T5 can from Gb4Cer make Gb5Cer and, thus, the Galβ3GalNAcβ (type 4) outer core chain [103]. This sequence has not been found protein-linked in humans, at least not in blood group P erythrocytes where Yang et al. specifically looked for it [104]. This sequence may therefore be restricted to the glycosphingolipid compartment. The O-linked type 3 chain (Galβ3GalNAcα), i.e. the core 1 O-glycan, is generated by the β3Gal-T7 enzyme [105]. Of the seven β4Gal-Ts described [100], β4Gal-T1–6 can all support the synthesis of type 2 chains by adding a galactose in a β1,4 linkage to GlcNAc residues of Nglycans. β4Gal-T1 and -T2 can biosynthesize lactose (Galβ4Glc) in the presence of αlactalbumin [100]. β4Gal-T7 is involved in the biosynthesis of the glycosaminoglycan core by adding a galactose residue to xylose [106]. The fine specificity on O-glycans of the different β4Gal-Ts is to our knowledge not known. In addition to the presence/ absence of glycosyltransferases, carbohydrate antigen biosynthesis is depending on C Informa Healthcare USA, Inc. Copyright 

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other factors such as glycosyltransferase organization [107] and the availability of activated sugars [108] in the Golgi. The role of other blood group systems for the expression of ABH determinants Besides the ABO blood group system, several other blood group systems in man are of carbohydrate nature. They include the Lewis, the P, the Ii, and the recently described Forssman systems [83, 109]. Glycosyltransferases involved in the biosynthesis of these determinants and core chains may influence the expression of the A and B determinants (Figure 3). Because there are partly common biosynthetic pathways for the ABO, Lewis, P and Forssman blood group systems, there may be competition between glycosyltransferases using common precursor structures but that are formally involved in the biosynthesis of antigens belonging to another blood group system [83, 109]. Further, the expression of these different blood group systems in non-RBC cells is poorly defined. Thus, it can be anticipated to be very difficult to predict expression levels of ABH antigens in various organs (see below) based on genetic analyses of genes encoding enzymes responsible for the biosynthesis of the A or B determinant. Instead, methods for direct assessment pre-Tx of ABH antigen expression levels in graft biopsies by the use of mAbs may be needed.

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FIGURE 3. The biosynthetic pathways of different blood group systems may overlap to influence the final A and B antigenic structures. International Reviews of Immunology

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ABH Antigens as Histo-Blood Group Antigens Organ/tissue/cell distribution–ABH determinants/core chains/type of glycan Lipid-carried A and B antigens on the different core chain types are expressed in a tissue-specific manner [36, 78, 110]. In short, epithelial tissues are rich in type 1, mesodermal tissues such as erythrocytes are rich in type 2, and the pancreas and kidney are rich in type 4 ABH antigens [36]. It should be noted though that most of the studies on which these conclusions were based dealt solely with glycosphingolipid-based ABH antigens [36]. On the other hand, knowledge of the tissue-specific expression of protein-carried ABH antigens regarding the different core chain types is much more limited. Lack of knowledge with regard to the tissue distribution of ABH antigens on different core chains, glycan types and protein/lipid carriers in the context of organ transplantation All organs express blood group ABH and related carbohydrate antigens (reviewed in [36, 92]). In general, cells of parenchymatous organs, e.g. liver and heart, contain low amounts of ABH antigens, while organs with abundant epithelial tissues such as salivary glands, pancreas and the gastrointestinal tract contain large amounts. However, the expression levels vary considerably on a cellular level within an organ. Further, the distribution of ABH determinants on different core chains and types of glycans (Nor O-glycans) on the cellular level is very poorly characterized, as is the overlap with antigens of other blood group systems such as the Lewis system (discussed above). Vascular EC, the barrier between the host’s immune system and the grafted organ, mainly carry ABH determinants on the type 2 core chain [90]. Again, this knowledge was based on immunohistochemical studies [90] and isolation of glycosphingolipidbased ABH antigens [36, 111, 112]. Recently, vascular EC at sites of inflammation were shown to aberrantly express A type 3 determinants [113]. This can be of relevance to transplantation in that an ischemic organ may mount an inflammatory response to reperfusion, and thus carries activated EC [114]. Unfortunately, the knowledge on the tissue-specific expression of protein-carried ABH antigens on different chain types is very limited. Interestingly, the core chain distribution between lipid- and proteincarried ABH determinants may differ within the cell. In human small intestinal enterocytes, lipid-carried ABH determinants were carried mainly on the type 1 outer core saccharide chain, while ABH determinants on proteins were mainly carried on N-glycans with type 2 outer core saccharide chains [115, 116]. All blood group A1 kidneys express considerable amounts of A antigens in the vascular tree, while A2 kidneys can be divided into two groups; those having low amounts and those with only trace amounts in their peritubular capillaries [37]. The distal tubules in both A1 and A2 kidneys express A and B antigens. Human kidney lipidlinked A and B antigens are based on all outer core chains (types 1–4) with the type 4 being the predominant one [117]. Recently, Tasaki and coworkers reported on the identification of at least 55 proteins carrying N-glycans with blood group A determinants in human kidney [93]. Among them were platelet EC adhesion molecule-1 (PECAM-1), plasmalemmal vesicle-associated protein (PLVAP) and von Willebrand factor (vWf ), all of which had a tissue distribution suggesting EC expression [93]. Further studies combining proteomics and glycomics techniques are warranted in order to also define the fine structure of the glycans carrying the ABH determinants. In general, livers contain relatively low amounts of ABH antigens that are found in bile ducts and arteries, while hepatocytes and sinusoid veins are negative [92, 118]. Biochemical analysis of a liver graft from a blood group A1 secretor positive donor perfused with blood group O blood in situ during transplantation was shown to contain only type 1 core chain A glycolipids [119]. Because type 1 chain ABH determinant expression is secretor gene dependent, it may be assumed that non-secretor individuals C Informa Healthcare USA, Inc. Copyright 

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FIGURE 4. Immunohistochemical staining of human livers using an anti-A antibody (A851, DAKO, Denmark). This antibody recognizes the terminal blood group A trisaccharide linked to all different core saccharide structures. Top (plate a) shows a blood group A1 individual that expresses A antigens in the bile duct, artery and lymphatic capillaries. The middle figure (plate b) is from an A2 secretor individual showing a weak staining mainly in lymphatic capillaries. The liver from an A2 non-secretor (plate c) shows only faint staining in lymphatic capillaries. The hepatocytes and sinusoidal veins are negative in all cases.

should express low amounts of A and B antigens in their livers [120, 121]. Immunohistochemistry (Figure 4) supports the notion that livers from A2 individuals contain considerably less A antigens than livers from A1 individuals. This may explain reports stating that ABOi LTx can be performed using livers from A2 donors [27, 29]. In the heart, ABH antigens are found mainly in ECs (type 2 outer core chains) while cardiomyocytes are negative [92, 122]. In contrast, pancreas contains large amounts of International Reviews of Immunology

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ABH type 1 antigens in the exocrine glandular part [123], while the islets of Langerhans are negative [124–126]. EC of the pancreatic gland are A antigen expressing as in other organs [124–126].

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THE BLOOD GROUP ABO ANTIBODY REPERTOIRE INCLUDING CHAIN TYPE-SPECIFIC ANTI-A AND ANTI-B The Blood Group ABO Antibody Repertoire Natural anti-A and -B antibodies can be of the IgM, IgG and IgA class in healthy individuals [127]. IgM and the IgG1 and IgG3 subclasses are effective in activating complement. In normal, healthy individuals, IgG anti-A and -B are mostly of the IgG1 and IgG2 subclasses [127]. Blood group A, B and O individuals all have their corresponding ABO Abs of IgM class, while O individuals in general have higher titers of anti-A and anti-B of IgG and IgA class [127]. ABO Abs are believed to be produced following exposure to the intestinal microflora. It has been shown that a substantial number of bacteria express A, B or H activity [128], and which is also true for viral surfaces [129]. Chain Type-Specific Antibodies ABOi KTx provided the opportunity to study the A Ab repertoire following exposure to incompatible ABH antigens. Blood group O recipients of A2 kidneys developed anti-A Abs of IgM, IgG and IgA class. The IgG Abs were mainly of the IgG1 and IgG2 subclass, and the IgA Abs were of the IgA1 subclass [70]. In some patients, anti-A Abs were induced that required the A determinant to be presented on a particular outer core saccharide chain in order to bind [130, 131]. Healthy blood donors were recently also shown to have chain type-specific A and B Abs in their serum [132, 133]. Furthermore, mouse monoclonal antibodies (mAbs) specific for the different A antigens have been generated [78], suggesting that the human and mouse antibody response can distinguish between structurally distinct A and B antigens. In some cases, anti-ABO Ab titers cannot be reduced enough using specific IA columns to allow a safe ABOi transplantation even if the number of IA sessions are increased. If this is due to an inability of antigen-specific IA columns carrying the A and B trisaccharides to remove chain-type specific Abs (discussed below) remains to be shown [49, 133, 134]. An alternative explanation may be that the synthesis rate by anti-A and anti-B producing plasma cells in some patients keep up with the pace of Ab removal. The rebound of Ab titers after each IA due to redistribution between the extracellular space and blood should be possible to overcome by increasing the number of IA procedures.

ACCOMMODATION–THE PHYSIOLOGICAL RESPONSE OF ENDOTHELIAL CELLS TO ABO ANTIBODY BINDING Definition Accommodation is defined as a state during which a vascularized organ is resistant to AMR despite the reoccurrence post-Tx of Abs binding the endothelium and the presence of normal complement plasma levels [53–55]. It was first observed clinically in cases of ABOi KTx [6, 135], but has been most extensively investigated in xenotransplantation models between discordant species [56, 136]. The mechanisms responsible for accommodation are still not fully elucidated. Three hypotheses have been advanced to explain the phenomenon. The first holds that graft EC develop a resistance post-Tx against the insult caused by Abs. The second hypothesis suggests that the EC target antigens are somehow modified such that the Abs do not bind anymore, and the C Informa Healthcare USA, Inc. Copyright 

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third explanation suggests that the Ab themselves are changed with regard to specificity, avidity or functionality [53–55]. Graft Resistance to the Insult of Antibodies One explanation put forward to explain how a graft can resist the insult of Abs entails an increased expression of complement-regulatory proteins following Ab exposure [53, 54]. Ding et al. showed that rat hearts transplanted to Rag/αGal-T deficient mice and exposed to low titer IgG1 upregulated decay accelerating factor (DAF; CD55), Crry and CD59 as revealed by immunohistochemistry [137]. Such hearts resisted a bolus dose of anti-α-Gal IgG1, while freshly transplanted second grafts were rejected [137]. Similar findings have been reported using porcine EC in vitro [138]. In a seminal paper published in 1997, Fritz Bach and coworkers showed that accommodation of vascularized xenografts was associated with expression of cytoprotective genes by donor EC [136]. These genes included A20 and bcl-2, and were shown to protect ECs from apoptosis [136]. Likewise, accommodated renal allografts of highly sensitized recipients with HLA Abs had upregulated Bcl-xL expression [139], while accommodated ABOi grafts appeared to have a completely different set of genes upregulated suggesting that a different mechanism may be responsible for accommodation of ABOi renal grafts [140]. Modification of Antigen Expression Including Endothelial Chimerism Medawar proposed already in the 1960s that replacement of donor organ endothelium with that of the recipient, i.e. endothelial chimerism, could serve as a way for the organ to adapt to its new host and avoid rejection [141]. Since then a number of studies have verified the phenomenon of EC chimerism [142–144]. However, it appears as if EC chimerism is associated with vascular rejection and poor graft survival, rather than graft acceptance [142–144]. In a material of 49 ABOi KTx, 12 exhibited EC chimerism and 9/12 patients had either acute or chronic AMR or severe CNI toxicity [144]. Interestingly, the A glycosphingolipid expression pattern in a donor pair of A2 kidneys transplanted into two blood group O recipients differed in that the kidney removed on day 12 contained less A glycolipids than the kidney removed on day 5 [39]. Whether this can be explained by EC chimerism, or whether other mechanisms can explain this observation is currently not known. Changes in Anti-Graft Antibody Functionality By the use of porcine EC, Yu et al. showed that IgG Abs specific for the pig to human xenogeneic determinant, Galα1,3Gal (anti-Gal), could block binding of IgM specific for the same epitope [145]. Further, the presence of IgG anti-Gal, which in human serum is dominated by the IgG2 subclass, attenuated by 80% of the fixation of complement factor C1q on anti-Gal IgM [145]. However, the importance of a change in Ab functionality as an explanation for accommodation has been challenged [54]. IS THERE A CLINICAL NEED FOR DIAGNOSTIC TOOLS ALLOWING BETTER QUANTIFICATION AND SPECIFICITY-DETERMINATION OF ANTI-A AND ANTI-B? Methods for ABO-antibody quantification should be cheap, simple, reliable and reproducible. The results of multicenter studies have given reasons to question the accuracy of the current agglutination techniques used for determination of anti-A and anti-B Ab titers. Despite using the same gel agglutination method in three European centers, the inter-center variation on the same sample was up to four titer steps [44]. The same degree of variation was seen with the tube agglutination technique in a study including 30 Japanese centers [15]. It may also be of great value to determine the IgG subclass of International Reviews of Immunology

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the ABO Ab in order to identify patients with complement-fixing Abs that may face a higher risk of rejection after an ABOi transplantation. This is not easily done with an agglutination technique. Due to the problems with hemagglutination, new techniques for ABO Ab quantification have been developed. Among these are flow cytometry, which enables quantification of anti-A/B IgM and IgG classes [146] and IgG subclasses [147]. The flow cytometric methods correlate well with hemagglutination titers. Another technique for rapid and accurate measurements of ABO IgG antibodies is the surface plasmon resonance, which makes it possible to express anti-A/B titers in μg/mL units [148]. Recently, a new technique was developed relying on ABO blood group neoglycolipids comprised of the blood group determinant attached to a lipid (diacyl or sterol) carrier via a spacer (KODE technology [149]). These neoglycolipids spontaneously insert in cell membranes in a controlled and quantifiable manner [149, 150]. For example, blood group O erythrocytes can be made blood group A by incubating them with blood group A neoglycolipids. Such artificially generated blood group A test cells offer a more standardized target than na¨ıve RBC with regard to anti-A and anti-B titrations [150]. Reproducibility and low inter-center variation in anti-A and anti-B quantifications is essential because the titer determines if patients can be accepted for transplantation, may influence which immunosuppressive protocol to use, and if and when to treat with IA post-Tx. STRUCTURE ACTIVITY RELATIONSHIPS IN THE ABO SYSTEM AND IMPROVED THERAPEUTICS FOR ABO INCOMPATIBLE TRANSPLANTATION More Efficient Blood Group A/B IA Columns Blood group A and B immunoadsorbents In addition to the non-specific antibody removal using PP, there are more specific techniques to eliminate anti-ABO antibodies. IA columns based on protein-A or polyclonal antibodies directed against human IgG are clinically used [151]. These columns are effective in removing all antibodies including those that will protect the recipient from various infections such as cytomegalovirus (CMV). The first successful IA column carrying blood group A or B trisaccharides (Biosynsorb) was produced by Chembiomed Ltd. in the 1980s [152], and was used in ABOi kidney and bone marrow transplantations [152–154]. The product was taken off the market because of severe side effects caused by the silica matrix. Subsequently, other saccharide-substituted IA columns were developed and tested in vitro [155–157], but did not reach the market. Currently, an IA column having the A or B trisaccharide R -A/B) is commercially availlinked via a carbon spacer arm to sepharose (Glycosorb able [47] and used in the ABOi KTx as described above. It should be pointed out though that there are no IA columns approved for use in the United States. Limitations in anti-A and anti-B antibody removal Even though anti-A and anti-B Ab titers in plasma for the most part can be efficiently reduced, Abs present in the extra vascular space are re-distributed into the plasma causing the titers to rise over night [158]. It is likely that the continuous synthesis of anti-A and anti-B also contributes to the overnight rebound of plasma Abs. In some cases, IA columns carrying A or B trisaccharides will not reduce the titers sufficiently to allow transplantation [133, 158]. One potential explanation for this may be that subpopulations of anti-A and anti-B require the fourth sugar in the carbohydrate chain for binding, and will therefore not bind the A or B trisaccharide determinant with sufficient avidity [133, 158]. Such Abs are not removed by Biosynsorb [131–133, 158] or R -ABO [158]. PP may then be an effective alternative [158] despite that all Glycosorb C Informa Healthcare USA, Inc. Copyright 

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antibodies, including, e.g. anti-CMV Abs, are removed. However, in patients with high titers of anti-A and/or -B repeated PP sessions may be necessary, which are associated with an increased risk for bleeding upon surgery due to the non-specific removal of coagulation factors. The need for a wide range of antigen structures to completely remove anti-A and anti-B Abs from the circulation is shown by the fact that after grafting with an ABOi organ, the anti-A and -B Ab titer fall to zero the day after grafting [61]. This is explained by Abs being adsorbed onto antigenic structures present in the graft. Even if there are remaining Abs in the circulation, this seems not to play any role as long as the total Ab titer is kept below a certain level of about a titer of 1:8 [17, 159]. However, there are single cases when the graft is rejected despite this [17], and if this is due to Abs recognizing the common A or B trisaccharide or because of Ab subpopulations with a chain, type-specific binding epitope is not known. Further development of blood group A and B immunoadsorbents R R -A, Glycosorb -B) The present IA for anti-A and anti-B Ab removal (Glycosorb are based on the A and B trisaccharides linked to sepharose via a spacer arm [47]. Because it has been shown that some anti-A and anti-B Abs need the forth sugar for binding [130–133], future IA matrices for anti-A and anti-B removal may be more efficacious if based on the A and B tetrasaccharides [133, 158]. This has been shown for preformed human Abs specific for the xenogeneic epitope, Galα3Gal, where a mixture of Galα3Gal-terminated saccharides with different lengths gave more complete Ab neutralization [160]. It has also been shown that blood group A mucin-type fusion proteins are more effective in adsorbing anti-A than A-trisaccharides attached to other carriers, possibly due to multivalency as a means to increase binding strength [161]. In order to combine multivalency with the presentation of the A or B determinant on different outer core saccharide chains, stable CHO cells were engineered secreting a mucin-type immunoglobulin fusion protein with multivalent O-glycan substitution of blood group A and B determinants on defined type 1, 2 and 3 outer core saccharide chains [162]. However, it remains to be shown that a mixture of mucin-type fusion proteins carrying A or B on different core chains constitute a better adsorption matrix than a mixture of A or B type 1–4 tetrasaccharides. ABH Glycoconjugates as Injectables Soluble blood group A and B saccharides have been used to neutralize anti-A and antiB Abs in newborn babies of ABO-immunized women in order to avoid hemolytic disease [163, 164]. In the early ABOi KTx trial, Alexandre et al. injected A or B substance extracted from porcine stomach prior to transplantation to eliminate Abs remaining after PP [5]. Infusion of FSL (function-spacer-lipid)-constructs with A-epitopes was recently shown to neutralize anti-A Abs in an animal model [165]. This may be a future treatment option for neutralization of anti-A or anti-B Abs before or following ABOi organ allotransplantation. The blood group B antigen in humans is very similar to the major xenoantigen (Galα1,3Gal; αGal or nonfucosylated B antigen) against which man and higher primates have abundant circulating natural Abs, which constitutes the barrier to xenotransplantation. It has been shown that these Abs in non-human primates can be neutralized by infusion of soluble saccharides with αGal specificity [166, 167]. A major problem though is the fast elimination of the saccharides from the circulation due to rapid urine clearance as well as their low affinity making a lasting neutralization very difficult. To increase binding efficacy and extend their serum half-life different multimers of the carbohydrate determinants have been produced with improved effects [168–170]. Perhaps similar neoglycoconjugates, but with the A and B determinants International Reviews of Immunology

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instead of α-Gal, could have a beneficial effect in patients in which it has been difficult to reduce the anti-A or anti-B titers. Compared to an apheresis procedure, an injection or infusion of a neoglycoconjugate would be less cumbersome for the patient.

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CONCLUSION Despite historically being the strongest immune barrier to transplantation, the ABO barrier can now be successfully crossed in KTx increasing the available donor pool for each patient. This knowledge may also be applied for successful ABOi grafting of other solid organs. Understanding the mechanisms of graft acceptance following ABOi transplantation will allow us to further exploit treatment strategies for circumventing AMR and induce long-term graft survival also in highly HLA-sensitized patients and perhaps also following xenotransplantation. Therefore, even if ABOi KTx now is a routine clinical procedure, research in this field should continue and the recipients be thoroughly investigated to elucidate the molecular mechanisms behind the accommodation phenomenon in order to develop strategies to reach the ultimate goal of transplantation – indefinite graft tolerance. ACKNOWLEDGMENTS The authors are indebted to J M¨olne, Department of Pathology at Sahlgrenska University Hospital for Figure 4. This work was supported by the Swedish Research Council (K2011-65X-3031-01-6 to J.H.) and the County Council of V¨astra G¨otaland (ALF) to J.H. and M.B. Declaration of Interest J.H. is founder and board member of AbSorber AB, and a shareholder in Allenex AB the main owner of AbSorber AB. LR and MEB have no conflicts of interest. The authors alone are responsible for the content and writing of the article. ABBREVIATIONS Ab ABOi AMR DD DFPP EC Gb4Cer Gb5Cer IA KPD KTx LD LTx mAb Tx

antibody blood group ABO incompatible antibody-mediated rejection diseased donor double filtration plasmapheresis endothelial cells GalNAcβ3Galα4Galβ4Glcβ1Ceramide Galβ3GalNAcβ3Galα4Galβ4Glcβ1Ceramide immunoadsorption kidney paired donation kidney transplantation live donor liver transplantation monoclonal antibody transplantation

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Molecular Deciphering of the ABO System

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Molecular Deciphering of the ABO System

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International Reviews of Immunology

Molecular deciphering of the ABO system as a basis for novel diagnostics and therapeutics in ABO incompatible transplantation.

In recent years ABO incompatible kidney transplantation (KTx) has become a more or less clinical routine procedure with graft and patient survival sim...
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