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ABO histo-blood group system-incompatible allografting
International Immunopharmacology 5 (2005) 147 – 153 www.elsevier.com/locate/intimp
ABO histo-blood group system-incompatible allografting Urs Nydeggera,*, Paul Mohacsia, Simon Koestnera, Andreas Kappelerb, Thomas Schaffnerb, Thierry Carrela a
Swiss Cardiovascular Center, University Clinic for Cardiovascular Surgery and University for Cardiology, Inselspital, CH-3010 Bern, Switzerland b Institute of Pathology, University of Bern, Switzerland
Abstract Most of the 29 blood group systems known today are not restricted to erythroid tissues hence their more recent identification as histo-blood group systems. Beyond the uncontested importance of the HLA system in human allograft survival, some of the histo-blood group systems might increasingly become recognised to play a role in graft-host interaction and peritransplant transfusion therapy. At least the ABO histo-blood group system has drawn a lot of interest since both, elective ABO-mismatch with living kidney donor/recipient pairs and infant heart recipients have been described as radical, but effective treatments of endstage organ dysfunction. More recently, at least in part successful efforts to overcome unintentional ABO-mismatched lung and heart grafts spark interest in more precisely avoiding hyperacute transplant rejection due to complement-activating anti-A/B antibodies of the recipients. Such options as to prepare the recipient with plasma exchange and following him up with polyspecific intravenous immunoglobulins, monoclonal antibodies and targeted immunosuppression using mycophenolate, rabbit antithymocyte globulin and anti-CD20 antibody rituximab are bound to efficiently remove anti-A/B antibodies and apparently inhibit their resynthesis. The present contribution overviews recently acquired knowledge on the ABO histo blood group system and the role it plays in solid organ transplantation leant against a patient observed at our institution. D 2004 Elsevier B.V. All rights reserved. Keywords: Histo-blood group; Cardiac allograft; ABO-mismatch; Monoclonal anti-A/B; Vascular endothelial cells
1. Introduction In contrast to antigens of the MHC, those of the ABO histo-blood group system are referred to as * Corresponding author. Tel.: +4131 6322337; fax: +4131 6322919. E-mail address: [email protected] (U. Nydegger). URL: http://www.immune-complex.ch. 1567-5769/$ - see front matter D 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.intimp.2004.09.020
minor incompatibility system in organ transplantation. This classification is no more justified and perhaps emanates from the fact that surgeons have always attempted to choose ABO-identical organs from cadaver and living donors. Following ABO allotype discovery at the beginning of the last century, their mere phenotypic characterisation using hemagglutination technique was able to satisfy clinical needs. Up to the present day, transfusion medicine remains safe
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using hemagglutination with technical perfection thanks to microhemagglutination systems such as the gel test [1]. Preview of compatibility is also possible using completion examination for naturally occurring anti-A/B allo-antibodies with test red blood cells (RBC) of known specificity. A second level of perfection came with improved knowledge of ABO-subgroups encompassing a large spectrum of polymorphism, to name just a few: A1, A2, A3 Ax and Aend and B3, Bx . The discovery of the molecular genetic basis of three major alleles at the origin of this polymorphism on chromosome 9 [2] provided for an insight that still remains beyond the need for clinical management of RBC transfusion. Molecular genetic typing of the ABO system legally is not required for good laboratory practice ABO-typing in any country around the globe. ABO-typing of RBC in order to transplant ABOmatched solid organs remains indirect, non the least because ABH antigens on tissues of endodermal and mesodermal origin (for example primary sensory neurons, skin, vascular endothelium, and bone marrow). Thus, the glycolipid type of ABH substances found on endothelial cells are not identical to those found on RBCs; direct tissue typing might help to elucidate the relationship between RBC- and tissue-associated histo-blood group ABO type [3]. The recent interest in ABOI stems from three major sources: (i) Some Asian countries have a cultural reluctance to use brain-dead human donors hence the transplantation from living donors is now considered as routine including, if unavoidable, the ABOI setting. (ii) The scarcity of heart donors in infant heart transplantation has driven some specialised centers to perform ABOI for infant allografting [4]. (iii) Accidental ABOI remains rare [5] but, as in transfusion medicine with RBC, persists as a residual risk: whereas many a case has been published with surprisingly low rejection rate, one must assume that lethal cases remain underreported since international transplant-vigilance reporting centers, like the hemovigilance system in transfusion medicine, do not exist. The possibility to cross the ABO barrier in solid organ transplantation could get some kind of a grip [4,6–8]. Evidencebased medicine at stake prohibits clinical studies
that would yield conclusive statistical power; the unforeseen, thus unprepared transplantation of solid organs across the ABO barrier remains a severe transplantation accident [9].
2. Animal experiments with ABO histo-blood groups now becoming possible Until recently, basic research of ABOI transplantation with animals remained infrequent. The assumed uniqueness of the ABO-system in humans has made researchers feel that no solid basis for deductions into human medicine would be possible from animal experiments. Nevertheless, the need to improve the management of ABOI grafting in human medicine has sparked interest for refinement of animal experiments. Moreover, pathophysiologic mechanisms of antibody- and complement-mediated rejection are of major scientific interest. Cloning of genomic and complementary DNA sequences from murine ABO gene equivalents has confirmed the earlier suggestion that such sequences are arranged around exon– intron units similar but not identical to human counterpart [2]. In addition, the transgenic technology gives promising results, rats being able to encode paralogous gene equivalents of the human histo-blood group ABO genes [10]. It will also be possible to produce knockout (group O) mice at the ABO locus using cloned genomic DNA sequence from the murine AB gene. Such mice with different ABO phenotypes in the same genetic background will help our understanding of the meaning and role of ABO polymorphism in the future. To study anti-A/B response, NOD/SCID mice can be engrafted with human lymphocytes allowing appraisal of B lymphocyte surface IgM receptors recogizing A determinants. A specific sIgM has been found in a small B cell subpopulation only, i.e. sIgM+CD11b+CD5 and B1 in blood group O human peripheral blood mononuclear cells [11]. Pigs do express an AO system as yet anti-A/B alloantibodies of man do not agglutinate pig RBC although porcine RBC membranes contain glycolipids with A and H antigenicity, taken up, at least in part, from the plasma. Attempts to improve xenotransplantation protocols use human plasma to
U. Nydegger et al. / International Immunopharmacology 5 (2005) 147–153
prolong survival of porcine working hearts in experimental settings [12], and they test stable plasma derivatives like i.v. immunoglobulins [13] or complement inhibitors [14] for efficacy to prevent acute rejection.
3. Detection of ABH antigens on human cells and tissues; our own B to O cardiac allotransplant The chief disadvantage of the agglutination phenomenon is that the reaction is semiquantitative. Besides that, agglutination is a secondary immune reaction, the primary event involving recognition of antigenic determinants by the cognate antibody. Sensitivity may be enhanced by lowering the negatively charged electrical coat charge of RBC, expressed as the so called zeta-potential, using low ionic strength buffers, and/or adding antihuman globulin serum (Coombs test) or polybrene. More recently, we have used fluorescence flow cytometry [15] for semi-quantitative estimation of A antigens on blood cells. Detection of these antigens in tissues takes advantage of immunofluorescence techniques and chromogenic immunohistochemistry, used alone or in combination [16]. Such technology has lead to an unprecedented enhancement of the sensitivity for studies interested in cell surface properties [17]. Immunohistochemistry can be performed on formalin-fixed tissue samples preserved for routine histology, or on sections from fresh frozen tissue, where ABH molecular structures are best preserved [18]. We have recently used immunohistochemistry to extend histology examination of endomyocardial protocol biopsies that were routinely collected over the observation time in a patient who inadvertently received a B type allograft himself being of histo blood-group O type [7,16]. Expression of ABOtype antigens on vascular endothelial cells of the cardiac allograft progressively changed from B to O, first detectable a year post transplantation and most prominent further 3 years later when immunohistochemical investigation of the transplanted heart using specific monoclonal antibodies and lectins revealed a heart of O type histo-blood group [16,19].
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4. Detection of complement activation in tissues It is acknowledged, that Ig and C-deposits in tissue, transplanted tissue included, are consistently associated with inflammation and functional impairment. The localisation of complement components at definite anatomical sites helps to diagnose specific diseases, hallmark being kidney disease [20] direct therapeutic measures. Distinction must be made between nonspecific occurrence and primary-lesion dependent fixation of complement fragments that reflect local activation by the disease causing event. Use of monoclonal antibodies against the C3-fragment C3d, or the C4-fragment C4d held to have formed locally will probably become standard[20,21]. In heart allografts, antibody-mediated rejection events now strive at detection of IgG and C3 as rejection criterion [22]. In another study, deposits of C4d in protocol biopsies performed in the first 3 months following transplantation was announcing fatal outcome suggesting a so far overlooked refractory rejection component [23]. Demonstration of complement deposition, most significantly of C4d, traditionally detected by immunofluerescence of fresh frozen tissue, becomes possible with the availability of an antibody that is suitable for formalin-fixed, paraffinembedded tissue [24]. Whereas the local formation of immune complexes preceeds complement deposition in many cases [25], it is also possible, that damaging local complement activation may occur independently of a complement activating antibody, C1q activation by h-amyloid in Alzheimers disease [26] and complement activation by C-reactive protein during acute myocardial infarction [27] being two recent examples.
5. Immunosuppressive regimen in ABOI allotransplantation Successful organ and cell transplantation is driven by combinations of drugs that suppress or selectively modulate (down- and upregulation) specific portions of the immune system. Heart and lung recipients with preformed anti-HLA antibodies are at a certain risk for early acute rejection and poor graft outcome. Plasma exchange (PEX) and i.v. immuno-
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globulin (IVIG) transfusion protocols are now acknowledged to reduce the antibody levels and to thwart rejection lesions. PEX/IVIG [28–31] in a framework of well prepared ABOI transplantation are recommended both as pretransplant measure as well as ready intervention in the face of neutrophil infiltration, microvessel thrombi, fibrinoid necrosis and C4d-deposits [8]. They also could allow for individualization of therapy [32,33] (Fig. 1). 5.1. In the pretransplant period In this period, the recipient of an expected ABOI transplantation needs to be thoroughly investigated on an immunohematological level. Red cells might be stored away with glycerol protection in liquid nitrogen and DNA might be layd aside to perform molecular biologic analysis of A/B, Lewis and secretor-type and anti-A/B antibodies need to be quantified in plasma/ serum not only by hemagglutination but ideally also by ABO-ELISA to distinguish anti-A/B IgM/G [34]. The recipient of an ABO-incompatible graft ought to be prepared by extracorporeal immunoadsorption of the anti-A/B antibodies (see below). In patients awaiting ABOI heart or lung transplantation, low-dose azathioprine or sirolimus might
come to reduce the level of presensitization [35] or newer drugs, like rapamycin or mycophenolic acid [36] might help to suppress immunoglobulin production by B cells. 5.2. In the peritransplant period Slow transfusion of ABOI-RBC to in vivo absorb the anti-A/B antibodies is possible [37]. If anti-A/B antibodies ought to be removed in recipients of elective transplantation of say a B kidney into an Orecipient, then intraoperative transfusion at very low speed and by intensive care monitoring of vital signs might be adequate. Such measure was included in our therapeutic strategy along with PEX/IVIG and or extracorporeal immunoadsorption (EIA) [7]. 5.3. In the immediate posttransplant period The basic immunosuppresive maintenance therapy to prevent rejection of elective or accidential ABOI transplants so far does not seem to be different compared to ABO identical constellations. In ABOI, the immunosuppression aims at keeping the anti-A/B reactivity at a lowest possible activity. Reluctancy to repeat ABO-incompatible red blood cell transfusion is
Fig. 1. Flow chart for management of ABO histo-blood type incompatible (ABOI) solid organ transplantation: Selection of emerging diagnostic (upper half) and rejection-prophylaxis (lower half) measures. PEX: plasma exchange. IVIG: i.v. immunoglobulin.
U. Nydegger et al. / International Immunopharmacology 5 (2005) 147–153
based on its formal prohibition on every level of hospital care. We propose that ABOI-RBC transfusion be avoided, since EIA is currently becoming possible with increasing efficacy [38]. PEX with AB-type fresh frozen plasma (FFP) can be used with success. Replacement with FFP that contains soluble A and/ or B substance might provide for anti-A/B neutralizing capacity [39]. EIA is however more effective to remove alloreactive, complement-activating IgM and IgG antibodies. We have been successfully preparing an O-type kidney-recipient of a B-type kidney by extracorporeal immunoadsorption [40]. 5.4. In the late posttransplant period Proceeding to a few weeks after ABOI transplantation the picture changes insofar, as the danger of hyperacute and acute rejection is over. Therefore, the long term follow up aims at allowing the graft to develop accommodation in the disparate ABOtyped recipient [41] allowing the host to develop accommodation against the disparate ABO-typed organ. Both immediate and later posttranslant period ought to be followed-up by protocol biopsies to detect subtle histological abnormalities that were recently successfully prevented from worsening by PEX/IVIG [33].
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basiliximab (SimulectR), several pharmaceutical companies own licensing agreements for such selective interactions as with IFN-h, endogenous gene activation (JAK) as well as mab against TNF (J and J Centocor, Abbott) or TNF binding protein (Serono, Geneva). A tacrolimus-simulect combination decisively helped to prevent rejection of an A1O kidney transplantation [8]. At the 2003 American Society of Hematology Meeting, Dickinson et al. [43] have reviewed and extended the original studies that within the solid organ transplant setting, patients with particular regulatory cytokine gene polymorphisms for TNF (high producers) and IL-10 (low producers) were more likely to reject their solid organ graft: the genetic make up of the recipient and the donor can strongly influence the success or failure of a given therapeutic strategy. In conclusion, our case of an accidental B O heart allograft surviving 5 years and changing the ABO type of the transplant from B to O fits into a trend that prospectively will improve the survival rate of ABOI allografting of solid organs. For such cases, only experienced centers should ascertain professional, well prepared, recipient conditioning and immunsuppressive regimens including, PEX, IVIG, new monoclonal antibodies [44], as a function of immunopathological monitoring with protocol biopsies [8]. Proposal is made to report such cases to http:// www.abomismatch.org.
6. New trends in immunomodulation: applicable to ABOI? References Progress in development of new immunosuppressive agents is directed at more specifically target signalling pathways of the immune system. Thus, cytoplasmic tyrosine kinase, Janus kinase-3 (JAK-3) is in a focus of interest: JAK-3 transmits signals through cytokine receptors that contain the common m-chain with receptors such as for IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21. Insights in pharmacogenomics [42] allows to tailor drug therapy to the individual, then the genetic polymorphisms encompassed in the cytokine gene polymorphisms enables us to work on a better therapeutic strategy for the individual. Monoclonal antibodies now heavily humanised and chimeric, devoid of anti-HAMA induced immune complex disease, represent a good potential to improve precision in this field: in addition to
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U. Nydegger et al. / International Immunopharmacology 5 (2005) 147–153 [36] Jonsson CA, Carlsten H. Mycophenolic acid inhibits inosine 5V-monophosphate dehydrogenase and suppresses immunoglobulin and cytokine production of B cells. Internat Immunopharmacology 2003;3:31 – 7. [37] Tichelli A, Gratwohl A. ABO-incompatible bone marrow transplantation: in vivo adsorption, an old forgotten method. Transplant Proc 1987;19:4632 – 7. [38] Takahashi K. ABO-incompatible kidney transplantation. Amsterdam7 Elsevier; 2001. [39] Nydegger U, Julmy F, Achermann F, Carrel T. Soluble ABO-blood group A-substance (SAS) in fresh frozen plasma (FFP). Vox Sang 2002;83(S2):224. [40] Aeschbacher B, Wiedmer W, Stuck A, Gaenger KH, Frey FJ, Nydegger UE. Immunoadsorption of anti-B
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ABO histo-blood group system-incompatible allografting Urs Nydeggera,*, Paul Mohacsia, Simon Koestnera, Andreas Kappelerb, Thomas Schaffnerb, Thierry Carrela a
Swiss Cardiovascular Center, University Clinic for Cardiovascular Surgery and University for Cardiology, Inselspital, CH-3010 Bern, Switzerland b Institute of Pathology, University of Bern, Switzerland
Abstract Most of the 29 blood group systems known today are not restricted to erythroid tissues hence their more recent identification as histo-blood group systems. Beyond the uncontested importance of the HLA system in human allograft survival, some of the histo-blood group systems might increasingly become recognised to play a role in graft-host interaction and peritransplant transfusion therapy. At least the ABO histo-blood group system has drawn a lot of interest since both, elective ABO-mismatch with living kidney donor/recipient pairs and infant heart recipients have been described as radical, but effective treatments of endstage organ dysfunction. More recently, at least in part successful efforts to overcome unintentional ABO-mismatched lung and heart grafts spark interest in more precisely avoiding hyperacute transplant rejection due to complement-activating anti-A/B antibodies of the recipients. Such options as to prepare the recipient with plasma exchange and following him up with polyspecific intravenous immunoglobulins, monoclonal antibodies and targeted immunosuppression using mycophenolate, rabbit antithymocyte globulin and anti-CD20 antibody rituximab are bound to efficiently remove anti-A/B antibodies and apparently inhibit their resynthesis. The present contribution overviews recently acquired knowledge on the ABO histo blood group system and the role it plays in solid organ transplantation leant against a patient observed at our institution. D 2004 Elsevier B.V. All rights reserved. Keywords: Histo-blood group; Cardiac allograft; ABO-mismatch; Monoclonal anti-A/B; Vascular endothelial cells
1. Introduction In contrast to antigens of the MHC, those of the ABO histo-blood group system are referred to as * Corresponding author. Tel.: +4131 6322337; fax: +4131 6322919. E-mail address: [email protected] (U. Nydegger). URL: http://www.immune-complex.ch. 1567-5769/$ - see front matter D 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.intimp.2004.09.020
minor incompatibility system in organ transplantation. This classification is no more justified and perhaps emanates from the fact that surgeons have always attempted to choose ABO-identical organs from cadaver and living donors. Following ABO allotype discovery at the beginning of the last century, their mere phenotypic characterisation using hemagglutination technique was able to satisfy clinical needs. Up to the present day, transfusion medicine remains safe
148
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using hemagglutination with technical perfection thanks to microhemagglutination systems such as the gel test [1]. Preview of compatibility is also possible using completion examination for naturally occurring anti-A/B allo-antibodies with test red blood cells (RBC) of known specificity. A second level of perfection came with improved knowledge of ABO-subgroups encompassing a large spectrum of polymorphism, to name just a few: A1, A2, A3 Ax and Aend and B3, Bx . The discovery of the molecular genetic basis of three major alleles at the origin of this polymorphism on chromosome 9 [2] provided for an insight that still remains beyond the need for clinical management of RBC transfusion. Molecular genetic typing of the ABO system legally is not required for good laboratory practice ABO-typing in any country around the globe. ABO-typing of RBC in order to transplant ABOmatched solid organs remains indirect, non the least because ABH antigens on tissues of endodermal and mesodermal origin (for example primary sensory neurons, skin, vascular endothelium, and bone marrow). Thus, the glycolipid type of ABH substances found on endothelial cells are not identical to those found on RBCs; direct tissue typing might help to elucidate the relationship between RBC- and tissue-associated histo-blood group ABO type [3]. The recent interest in ABOI stems from three major sources: (i) Some Asian countries have a cultural reluctance to use brain-dead human donors hence the transplantation from living donors is now considered as routine including, if unavoidable, the ABOI setting. (ii) The scarcity of heart donors in infant heart transplantation has driven some specialised centers to perform ABOI for infant allografting [4]. (iii) Accidental ABOI remains rare [5] but, as in transfusion medicine with RBC, persists as a residual risk: whereas many a case has been published with surprisingly low rejection rate, one must assume that lethal cases remain underreported since international transplant-vigilance reporting centers, like the hemovigilance system in transfusion medicine, do not exist. The possibility to cross the ABO barrier in solid organ transplantation could get some kind of a grip [4,6–8]. Evidencebased medicine at stake prohibits clinical studies
that would yield conclusive statistical power; the unforeseen, thus unprepared transplantation of solid organs across the ABO barrier remains a severe transplantation accident [9].
2. Animal experiments with ABO histo-blood groups now becoming possible Until recently, basic research of ABOI transplantation with animals remained infrequent. The assumed uniqueness of the ABO-system in humans has made researchers feel that no solid basis for deductions into human medicine would be possible from animal experiments. Nevertheless, the need to improve the management of ABOI grafting in human medicine has sparked interest for refinement of animal experiments. Moreover, pathophysiologic mechanisms of antibody- and complement-mediated rejection are of major scientific interest. Cloning of genomic and complementary DNA sequences from murine ABO gene equivalents has confirmed the earlier suggestion that such sequences are arranged around exon– intron units similar but not identical to human counterpart [2]. In addition, the transgenic technology gives promising results, rats being able to encode paralogous gene equivalents of the human histo-blood group ABO genes [10]. It will also be possible to produce knockout (group O) mice at the ABO locus using cloned genomic DNA sequence from the murine AB gene. Such mice with different ABO phenotypes in the same genetic background will help our understanding of the meaning and role of ABO polymorphism in the future. To study anti-A/B response, NOD/SCID mice can be engrafted with human lymphocytes allowing appraisal of B lymphocyte surface IgM receptors recogizing A determinants. A specific sIgM has been found in a small B cell subpopulation only, i.e. sIgM+CD11b+CD5 and B1 in blood group O human peripheral blood mononuclear cells [11]. Pigs do express an AO system as yet anti-A/B alloantibodies of man do not agglutinate pig RBC although porcine RBC membranes contain glycolipids with A and H antigenicity, taken up, at least in part, from the plasma. Attempts to improve xenotransplantation protocols use human plasma to
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prolong survival of porcine working hearts in experimental settings [12], and they test stable plasma derivatives like i.v. immunoglobulins [13] or complement inhibitors [14] for efficacy to prevent acute rejection.
3. Detection of ABH antigens on human cells and tissues; our own B to O cardiac allotransplant The chief disadvantage of the agglutination phenomenon is that the reaction is semiquantitative. Besides that, agglutination is a secondary immune reaction, the primary event involving recognition of antigenic determinants by the cognate antibody. Sensitivity may be enhanced by lowering the negatively charged electrical coat charge of RBC, expressed as the so called zeta-potential, using low ionic strength buffers, and/or adding antihuman globulin serum (Coombs test) or polybrene. More recently, we have used fluorescence flow cytometry [15] for semi-quantitative estimation of A antigens on blood cells. Detection of these antigens in tissues takes advantage of immunofluorescence techniques and chromogenic immunohistochemistry, used alone or in combination [16]. Such technology has lead to an unprecedented enhancement of the sensitivity for studies interested in cell surface properties [17]. Immunohistochemistry can be performed on formalin-fixed tissue samples preserved for routine histology, or on sections from fresh frozen tissue, where ABH molecular structures are best preserved [18]. We have recently used immunohistochemistry to extend histology examination of endomyocardial protocol biopsies that were routinely collected over the observation time in a patient who inadvertently received a B type allograft himself being of histo blood-group O type [7,16]. Expression of ABOtype antigens on vascular endothelial cells of the cardiac allograft progressively changed from B to O, first detectable a year post transplantation and most prominent further 3 years later when immunohistochemical investigation of the transplanted heart using specific monoclonal antibodies and lectins revealed a heart of O type histo-blood group [16,19].
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4. Detection of complement activation in tissues It is acknowledged, that Ig and C-deposits in tissue, transplanted tissue included, are consistently associated with inflammation and functional impairment. The localisation of complement components at definite anatomical sites helps to diagnose specific diseases, hallmark being kidney disease [20] direct therapeutic measures. Distinction must be made between nonspecific occurrence and primary-lesion dependent fixation of complement fragments that reflect local activation by the disease causing event. Use of monoclonal antibodies against the C3-fragment C3d, or the C4-fragment C4d held to have formed locally will probably become standard[20,21]. In heart allografts, antibody-mediated rejection events now strive at detection of IgG and C3 as rejection criterion [22]. In another study, deposits of C4d in protocol biopsies performed in the first 3 months following transplantation was announcing fatal outcome suggesting a so far overlooked refractory rejection component [23]. Demonstration of complement deposition, most significantly of C4d, traditionally detected by immunofluerescence of fresh frozen tissue, becomes possible with the availability of an antibody that is suitable for formalin-fixed, paraffinembedded tissue [24]. Whereas the local formation of immune complexes preceeds complement deposition in many cases [25], it is also possible, that damaging local complement activation may occur independently of a complement activating antibody, C1q activation by h-amyloid in Alzheimers disease [26] and complement activation by C-reactive protein during acute myocardial infarction [27] being two recent examples.
5. Immunosuppressive regimen in ABOI allotransplantation Successful organ and cell transplantation is driven by combinations of drugs that suppress or selectively modulate (down- and upregulation) specific portions of the immune system. Heart and lung recipients with preformed anti-HLA antibodies are at a certain risk for early acute rejection and poor graft outcome. Plasma exchange (PEX) and i.v. immuno-
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globulin (IVIG) transfusion protocols are now acknowledged to reduce the antibody levels and to thwart rejection lesions. PEX/IVIG [28–31] in a framework of well prepared ABOI transplantation are recommended both as pretransplant measure as well as ready intervention in the face of neutrophil infiltration, microvessel thrombi, fibrinoid necrosis and C4d-deposits [8]. They also could allow for individualization of therapy [32,33] (Fig. 1). 5.1. In the pretransplant period In this period, the recipient of an expected ABOI transplantation needs to be thoroughly investigated on an immunohematological level. Red cells might be stored away with glycerol protection in liquid nitrogen and DNA might be layd aside to perform molecular biologic analysis of A/B, Lewis and secretor-type and anti-A/B antibodies need to be quantified in plasma/ serum not only by hemagglutination but ideally also by ABO-ELISA to distinguish anti-A/B IgM/G [34]. The recipient of an ABO-incompatible graft ought to be prepared by extracorporeal immunoadsorption of the anti-A/B antibodies (see below). In patients awaiting ABOI heart or lung transplantation, low-dose azathioprine or sirolimus might
come to reduce the level of presensitization [35] or newer drugs, like rapamycin or mycophenolic acid [36] might help to suppress immunoglobulin production by B cells. 5.2. In the peritransplant period Slow transfusion of ABOI-RBC to in vivo absorb the anti-A/B antibodies is possible [37]. If anti-A/B antibodies ought to be removed in recipients of elective transplantation of say a B kidney into an Orecipient, then intraoperative transfusion at very low speed and by intensive care monitoring of vital signs might be adequate. Such measure was included in our therapeutic strategy along with PEX/IVIG and or extracorporeal immunoadsorption (EIA) [7]. 5.3. In the immediate posttransplant period The basic immunosuppresive maintenance therapy to prevent rejection of elective or accidential ABOI transplants so far does not seem to be different compared to ABO identical constellations. In ABOI, the immunosuppression aims at keeping the anti-A/B reactivity at a lowest possible activity. Reluctancy to repeat ABO-incompatible red blood cell transfusion is
Fig. 1. Flow chart for management of ABO histo-blood type incompatible (ABOI) solid organ transplantation: Selection of emerging diagnostic (upper half) and rejection-prophylaxis (lower half) measures. PEX: plasma exchange. IVIG: i.v. immunoglobulin.
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based on its formal prohibition on every level of hospital care. We propose that ABOI-RBC transfusion be avoided, since EIA is currently becoming possible with increasing efficacy [38]. PEX with AB-type fresh frozen plasma (FFP) can be used with success. Replacement with FFP that contains soluble A and/ or B substance might provide for anti-A/B neutralizing capacity [39]. EIA is however more effective to remove alloreactive, complement-activating IgM and IgG antibodies. We have been successfully preparing an O-type kidney-recipient of a B-type kidney by extracorporeal immunoadsorption [40]. 5.4. In the late posttransplant period Proceeding to a few weeks after ABOI transplantation the picture changes insofar, as the danger of hyperacute and acute rejection is over. Therefore, the long term follow up aims at allowing the graft to develop accommodation in the disparate ABOtyped recipient [41] allowing the host to develop accommodation against the disparate ABO-typed organ. Both immediate and later posttranslant period ought to be followed-up by protocol biopsies to detect subtle histological abnormalities that were recently successfully prevented from worsening by PEX/IVIG [33].
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basiliximab (SimulectR), several pharmaceutical companies own licensing agreements for such selective interactions as with IFN-h, endogenous gene activation (JAK) as well as mab against TNF (J and J Centocor, Abbott) or TNF binding protein (Serono, Geneva). A tacrolimus-simulect combination decisively helped to prevent rejection of an A1O kidney transplantation [8]. At the 2003 American Society of Hematology Meeting, Dickinson et al. [43] have reviewed and extended the original studies that within the solid organ transplant setting, patients with particular regulatory cytokine gene polymorphisms for TNF (high producers) and IL-10 (low producers) were more likely to reject their solid organ graft: the genetic make up of the recipient and the donor can strongly influence the success or failure of a given therapeutic strategy. In conclusion, our case of an accidental B O heart allograft surviving 5 years and changing the ABO type of the transplant from B to O fits into a trend that prospectively will improve the survival rate of ABOI allografting of solid organs. For such cases, only experienced centers should ascertain professional, well prepared, recipient conditioning and immunsuppressive regimens including, PEX, IVIG, new monoclonal antibodies [44], as a function of immunopathological monitoring with protocol biopsies [8]. Proposal is made to report such cases to http:// www.abomismatch.org.
6. New trends in immunomodulation: applicable to ABOI? References Progress in development of new immunosuppressive agents is directed at more specifically target signalling pathways of the immune system. Thus, cytoplasmic tyrosine kinase, Janus kinase-3 (JAK-3) is in a focus of interest: JAK-3 transmits signals through cytokine receptors that contain the common m-chain with receptors such as for IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21. Insights in pharmacogenomics [42] allows to tailor drug therapy to the individual, then the genetic polymorphisms encompassed in the cytokine gene polymorphisms enables us to work on a better therapeutic strategy for the individual. Monoclonal antibodies now heavily humanised and chimeric, devoid of anti-HAMA induced immune complex disease, represent a good potential to improve precision in this field: in addition to
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