Humeral Theory of Transplantation

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Overview of Hyperacute, Acute, and Chronic humeral transplantation rejection.
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  Humoral Theory of Transplantation:Mechanism, Prevention, and Treatment  Junchao Cai and Paul I. Terasaki ABSTRACT:  We discuss the potential mechanisms of antibody-induced primary endothelium injury, which in-cludes complement-dependent pathway (membrane attackcomplex formation, recruitment of inflammatory cells, andcomplement-complement receptor-mediated phagocytosis)and complement independent pathway antibody-dependentcell cytotoxicity. Secondary to endothelium injury, the fol-lowing pathological reactions are found to be responsible forprogressive tissue injury and final graft function loss: plate-let activation and thrombosis, pathological smooth muscleand endothelial cell proliferation, and humoral and/or cel-lular infiltrate-mediated parenchyma damage after endothe-lium injury. We also introduce three categories of thera-peuticstrategyinthepreventionandtreatmentofantibody-mediated rejection: (1) inhibition and depletion of antibodyproducing cells (immunosuppressants, antilymphocyte an-tibodies, splenectomy); (2) removal or blockage of preexist-ing or newly developed antibodies (immunoadsorption,plasmapheresis/plasma exchange, intravenous immunoglob-ulin); and (3) impediment or postponement of antibody-mediated primary and secondary tissue injury (anticoagula-tion, glucosteroids). In conclusion, because alloantibodieshave destructive effect on allografts, alloantibody monitor-ing becomes extremely important. It will help clinicians todetermine a patient’s humoral responses against allograftand will therefore direct clinicians to optimize and/or min-imize immunosuppressive drug therapy.  Human Immu-nology 66, 334–342 (2005).  © American Society for His-tocompatibility and Immunogenetics, 2005. Published byElsevier Inc. KEYWORDS:  HLA antibody; antibody monitoring; al-lograft; antibody-mediated rejection; chronic rejection ABBREVIATIONS HLA human leukocyte antigenMIC major histocompatibility complex class I–relatedchainPE plasma exchangePPH plasmapheresis INTRODUCTION We have reviewed accumulated evidence regarding therole of antibody in graft injury [1]. Antibodies are associated with hyperacute, acute, and chronic rejection[2]. In a prospective trial, it has already been foundthat by using antibody screening tests with flow cy-tometry or enzyme-linked immunosorbent assay, about14%–23% of transplant recipients with functioninggrafts have detectable human leukocyte antigen (HLA)antibodies [3]. Within a 1-year follow-up period, 21 (8.6%) of 244 antibody-positive patients experiencedgraft rejection, which is significantly higher than thatfound in the HLA antibody–negative patient group(43/1421    100%    3%,  p    0.00003). These datasuggest that some transplants may still function well inthe presence of alloantibodies, which might be becauseof the compensational reactions of the transplantedorgan to tissue injury. However, the graft may finallybe rejected when the tissue repair system can not fullycompensate for the antibody-mediated injury. Thisdamage-repair-damage process could take years to re-sult in irreversible graft loss. This hypothesis has beensupported by the study of Lee  et al.,  who found that insome patients, it took many years for antibody-positivetransplants to finally be rejected [4].Why are some transplants rejected sooner and othertransplants rejected later, after the presence of alloanti-bodies is found in the periphery blood? In this review, wediscuss how antibody causes graft rejection after it bindsto its target and how to prevent and treat antibody-mediated rejection. MECHANISM OF HUMORAL REJECTIONEndothelial Cell—The Primary Target of Antibody Among cellular and humoral immunologists, there islimited debate that the endothelium of transplanted From the Terasaki Foundation Laboratory, Los Angeles, CA, USA. Address reprint requests to: Dr. Paul I. Terasaki, Terasaki Foundation Laboratory, 11570 W Olympic Blvd., Los Angeles, CA 90064; Tel: (310)479-6101 ext 104; Fax: (310) 445-3381; E-mail: terasaki@terasakilab.org. Received October 19, 2004; accepted January 19, 2005. Human Immunology  66,  334–342 (2005)© American Society for Histocompatibility and Immunogenetics, 2005 0198-8859/05/$–see front matterPublished by Elsevier Inc. doi:10.1016/j.humimm.2005.01.021  organs serve as the primary target of patient immuneresponses. In the humoral theory of organ transplanta-tion, the endothelium of a donor organ is primarilytargeted by alloantibody, either preexisting or developed de novo  after transplant [5–15]. Primary Effects of Antibody-Antigen Interaction As proposed here and shown in Figure 1.1–4, binding of  antibodies to antigens on endothelial cells can finallycause endothelium damage via four distinct pathways.Damage of endothelium can be mediated directly bycomplement via forming membrane attack complex [16] (Figure 1.2) or inflammatory cells recruited by soluble complement fragments [17, 18] (Figure 1.1), or by phagocytes that recognize complement fragments depos-ited on endothelial cells via a complement receptor [19] (Figure 1.3). These three pathways are complement de- pendent. The finding of complement C4d in graft cap-illaries provided strong evidence to support this comple-ment-dependent hypothesis [20]. However, it is also possible that after antibody binds to its target antigen onthe surface of the endothelial cell, antibody-dependentcell cytotoxicity may play a role in mediating endothe-lium damage without the involvement of complement [21–24] (Figure 1.4). Secondary Effects After Endothelium Injury Secondary pathological changes after endothelium damageinclude platelet activation and thrombosis, endothelial andsmooth muscle cell proliferation, and humoral and/or cel-lular infiltrates mediated direct organ/tissue damage (Fig-ure 1A–D). Hyperacute rejection, the best documentedexample of antibody-mediated rejection, is mediated bypreexisting antibodies ( e.g.,  anti–blood group antigen A orB antibodies, or anti-HLA antibodies) that bind to endo-thelium and activate complement. Antibody binding andcomplement activation induce a series of pathologicalchanges in the graft endothelium that promote intravas-cular thrombosis. Endothelial cells are stimulated to se-crete von Willebrand factor that mediates platelet adhe-sion and aggregation. Complement activation leads toendothelial cell injury and exposure of subendothelial base-ment membrane proteins that activate platelets. Theseseries processes contribute to thrombosis and vascular oc-clusion; therefore, the organ suffers irreversible ischemicdamage (Figure 1A).We know that the rapid progress of antibody-mediatedhyperacute rejection is related to a large amount of preex-isting alloantibodies and it usually happens in ABO-in-compatible or presensitized patients. However, in currenttransplant clinics, transplantation is performed primarilyin ABO-compatible, low-sensitized patients; moreover,highly effective immunosuppressive drug therapies arewidely used in transplant recipients. Therefore, unlikehyperacute rejection, acute or chronic graft function lossmight not result mainly from thrombosis-related rapidvascular occlusion. Instead, they are most likely due to aprogressive damage-repair-damage pathological process.As found in chronic rejection, which is manifested asatherosclerosis of the vessels of the transplanted organ, theintimal thickening is the result of the proliferative effectsof anti-HLA antibodies (Figure 1B,C) [25]. It is also a possibility that after endothelium injury, humoral and/orcellular infiltrates can directly cause organ parenchymadamage (Figure 1D). This direct parenchyma injury also follows the law of “quantitative change to qualitativechange.” The process speed of any potential pathologicalchanges after endothelium injury depends on the followingthree major factors: the level of alloantibodies; the capa-bility of transplanted organ tissue repair; and immunosup-pressive and other supportive therapy.The first factor is the level of alloantibodies. In ABO-compatible transplantation, there was considerable vari-ation in antibody titers against blood group antigens[26]. Recipients with higher antibody titers againstblood group antigens had a much higher incidence of early graft failure [27, 28]. In ABO-compatible trans- plantation, there was a significant stepwise decrease ingraft outcome with increasing levels of sensitization.Patients with less than 10% panel-reactive antibodieshad a significantly longer half-life than patients withhigher levels of sensitization [29]. These data suggested that graft outcome is strongly associated with the alloan-tibody level. High levels of antibodies result in moreirreversible rejection. These data also implied that inlower sensitized patients, because of the lower levels of preexisting antibodies, the rejection process is slower,but the transplanted graft may finally be rejected when FIGURE 1  Mechanisms of antibody-mediated transplantrejection. 335 Humoral Theory of Transplantation  a majority of parenchyma are affected and cannot becompensated by tissue repair.The second factor is the capability of transplantedorgan tissue repair. This is the major mechanism toimpede or postpone the development of rejection; butthis regeneration capability is tissue dependent. Sometissue cells have the capacity to regenerate after injury( e.g.,  endothelial cells, renal tubular cells, hepatocytes),but other cells, such as myocardial cells, cannot regen-erate and are usually replaced by scar tissue (typicallyfibrosis) after irreversible injury and cell loss. Also, thereshould be an awareness that uncontrolled tissue repairsometimes becomes a risk factor that accelerates the rejection process (Figure 1B,C) [25]. The third factor is immunosuppressive and other sup-portive therapy. Different immunosuppressants many havedifferent effects on inhibition of antibody development [3]; therefore, they affect graft survival [30, 31]. For example, as previously discussed, the major characteristics of anti-body-mediated hyperacute rejection are antibody/comple-ment-mediated endothelium injury and activated platelet-mediated thrombosis and vascular occlusion. On the basisof the hypothesis that preventing clot formation may post-pone graft rejection, anticoagulation therapy was used intransplant clinics [32–35]. Recently, in combination with other antibody depletion or suppression treatments, anti-coagulation therapy successfully reduced hyperacute/acuterejection episodes and enabled ABO-incompatible trans-plantation to become feasible and reach satisfying long-term graft survivals [36]. PREVENTION AND TREATMENT OFHUMORAL REJECTION Therapeutic strategies to prevent and treat antibody-mediated rejection include: (1) inhibition and depletionof antibody producing cells; (2) removal or blockage of preexisting or newly developed antibodies; and (3) im-pediment or postponement of antibody-mediated pri-mary and secondary tissue injury. Inhibition or Depletion of Antibody-Producing Cells This strategy is etiotropic. B cells, or more precisely,plasma cells, are the main antibody-secreting cells of thebody. Therefore, to prevent and/or treat antibody-medi-ated humoral rejection, inhibition or depletion of anti-body producing cells becomes extremely important (Ta-ble 1.1–11).  Primary immunosuppressants.  Generally speaking, almostall currently used immunosuppressive drugs have direct TABLE 1  Prevention and treatment of antibody-mediated rejection No. Category a Treatment Major mechanism1 I Cyclosporin A Indirectly inhibit B cell proliferation secondary to reduced cytokineproduction by T cells2 I Tacrolimus (FK506) Indirectly inhibit B cell proliferation secondary to reduced cytokineproduction by T cells3 I Rapamycin (sirolimus) Indirectly inhibit B cell proliferation secondary to reduced cytokineproduction by T cells4 I Azathioprine Inhibit DNA synthesis in dividing cells (T,B and other dividing cells)5 I Cyclophosphamide Inhibit DNA synthesis in dividing cells (T,B and other dividing cells)6 I Mycophenolate mofetil (MMF) Inhibit DNA synthesis in dividing cells (mainly T and B cells)7 I Rituximab Anti–CD-20 (B cell surface marker) mAb, deplete B cells8 I OKT3 Anti-CD3 (T-cell surface marker) antibody, indirectly inhibit B-cellproliferation9 I Anti-thymocyte globulin (ATG) and anti-lymphocyte globulin (ALG)Directly deplete or indirectly inhibit B cells10 I Campath-1H Anti-CD52 (surface marker of thymocytes, T, B cells, etc.), directdeplete B cells11 I Splenectomy Surgically remove lymphocyte-producing organ (both B and T)12 II Immunoadsorption Remove antibody from periphery (blood group antigen-, protein A- oranti-human Ig antibody-coated columns)13 II Plasmapheresis (PPH) or plasma exchange (PE) Remove antibodies and other humoral factors (complements,cytokines, etc.) from periphery14 II Intravenous immunoglobulin (IVIG) Anti-idiotypic effects (blocking of the antigen-binding cites of anti-donor antibodies) and others15 III Anticoagulation therapy Inhibit the formation of clot (Figure 1A) 16 III and I Glucocorticoid Anti-inflammatory effects (Figure 1.1 and D), B-cell apoptosis a I    inhibition and depletion of antibody-producing cells; II    removal or blocking of preexisting or newly developed antibodies; III    impediment orpostponement of antibody-mediated primary and secondary tissue injury. 336  J. Cai and P.I. Terasaki  or indirect effects in inhibiting/depleting B cells. Themost commonly used primary agents of maintenanceimmunosuppression, such as cyclosporine A, FK506 (ta-crolimus), and rapamycin (sirolimus), are powerful im-munosuppressants that interfere with T-cell signaling.The successful prolongation of graft survival by usingthese agents has misled many clinicians and some im-munologists into thinking that T cell is the only playerthat causes graft rejection. However, because many al-loantigens eliciting antibody responses are proteins ( e.g., HLA, major histocompatibility complex class I–relatedchain [MIC]) and antibody responses to protein antigensrequire antigen-specific T-cell help, T-cell targetingagents not only prevent T-cell but also antibody (Bcell)-mediated immune responses. This mechanism ex-plains why these primary agents can be used alone or incombination with other therapies to treat antibody-me-diated humoral rejection [37–39] (Table 1.1–3).  Adjunct immunosuppressants.  Unlike primary immunosup-pressive agents, which block T-cell signaling and indi-rectly inhibit proliferation of B cell secondary to reducedcytokine production by T cell, adjunctive immunosup-pressants interfere with DNA synthesis and have theirmajor pharmacological action on dividing tissues [40–42]. Hence, these agents, including azathioprine, cyclo-phosphamide, mycophenolate mofetil (MMF), have di-rect inhibitory effects on B cell, an active dividing tissuecell. It is notable that because of its role in targeting the de novo  purine biosynthesis pathway, mycophenolates caninhibit human lymphocytes (B and T cells) more specif-ically and efficiently than other cell types [40, 43]. Clinical observations demonstrated that immunosup-pressive protocols with MMF-inhibited antibody produc-tion therefore reduces allograft rejection episodes [3, 44, 45]. UNOS data analysis also indicated its superiority over azathioprine [30, 31] (Table 1.4–6).  Antilymphocyte antibodies.  Antibodies against lymphocytesurface molecules act by removing specific lymphocytesubsets or inhibiting cell function [46–55]. Among these antilymphocyte monoclonal or polyclonal antibod-ies listed in Table 1.7–10, rituximab is the only antibody specifically targeting B-cell surface marker CD20.Garrett and colleagues reported the first case of humoralrejection successfully treated with rituximab [46]. Re-cently, using a single dose of rituximab in addition toother therapies, a Wisconsin group successfully treated27 patients who were diagnosed with biopsy-confirmedrejection manifested by thrombotic microangiopathyand/or endothelialitis between February 1999 and Feb-ruary 2002. Twenty-four received additional steroids,and 22 of 27 patients were also treated with plasma-pheresis (PPH) and antithymocyte globulin. Only threepatients experienced graft loss not associated with pa-tient death during the follow-up period (605    335.3days). In the 24 successfully treated patients, serumcreatinine at the time of initiating rituximab therapy was5.6  1.0 mg/dl and was decreased to 0.95  0.7 mg/dlat discharge. Authors predicted that the addition of rituximab may improve outcomes in severe, steroid-re-sistant or antibody-mediated rejection episodes after kid- ney transplantation [47] (Table 1.7–10).  Splenectomy.  The spleen is an organ that produces lym-phocytes, filters the blood, stores blood cells, and de-stroys those that are aging. The rationale to performsplenectomy in transplant recipients is to remove a majorsource of lymphocytes, including antibody-secreting Bcells. The benefits of splenectomy in prolonging graftand patient survival remain controversial. It has beenreported that splenectomized patients had reduced inci-dences and intensity of rejection episodes and better graftand patient survival rates [56]; however, this beneficial effect was short-termed [57]. The long-term benefit from splenectomy was mainly compromised by increasedchances of fatal infection and sepsis [56–58]. Recently, in combination with other treatment, splenectomy seemsto play an important role in preventing humoral rejec-tion and prolonging graft survival in ABO-incompatible transplantation [36] (Table 1.11). Removal or Blockage of Preexisting or NewlyDeveloped Antibodies This strategy is also etiotropic. It mainly focuses onreducing existing antibodies or blocking their detrimen-tal effects (Table 1.12–14). Immunoadsorption.  This is an  in vitro  approach that spe-cifically removes immunoglobulins from patient periph-ery by using blood group antigen A or B, protein A, orantihuman Ig-coated columns. Originally, it was primar-ily used as a preemptive therapy for ABO-incompatibleor presensitized patients [59–67]. But successful reversal of antibody-mediated rejection were also reported [68–71]. An ABO antigen-coated column was used to spe- cifically remove anti-ABO antibodies [72]; however, HLA antigen column, specialized to remove HLA anti-bodies, is not yet commercially available (Table 1.12).  PPH/plasma exchange (PE).  Removal of antibodies andother plasma factors by PPH and PE is an effectiveantihumoral rejection treatments. They have been usedas a preemptive strategy to prevent potential rejectionepisodes [36, 73–75]. They have also been used to reverse established antibody-mediated rejection [76–83]. Un- like immunoadsorption, PPH and PE remove not onlyantibodies but also many other humoral factors, such as 337 Humoral Theory of Transplantation
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