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Late and Chronic Antibody-Mediated Rejection: Main Barrier to Long Term Graft Survival

Late and Chronic Antibody-Mediated Rejection: Main Barrier to Long Term Graft Survival Hindawi Publishing Corporation Clinical and Developmental Immunology Volume 2013, Article ID 859761, 7 pages http://dx.doi.org/10.1155/2013/859761 Review Article Late and Chronic Antibody-Mediated Rejection: Main Barrier to Long Term Graft Survival 1 2 Qiquan Sun and Yang Yang Department of Renal Transplantation, eTh ir Th d Alffi iated Hospital, Sun Yat-Sen University, 600 Tianhe Road, Guangzhou 510630, China Department of Liver Transplantation, eTh ir Th d Alffi iated Hospital, Sun Yat-Sen University, 600 Tianhe Road, Guangzhou 510630, China Correspondence should be addressed to Qiquan Sun; [email protected] and Yang Yang; [email protected] Received 27 June 2013; Accepted 3 September 2013 Academic Editor: Xian Li Copyright © 2013 Q. Sun and Y. Yang. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Antibody-mediated rejection (AMR) is an important cause of graft loss after organ transplantation. It is caused by anti-donor- specific antibodies especially anti-HLA antibodies. C4d had been regarded as a diagnosis marker for AMR. Although most early AMR episodes can be successfully controlled or reversed, late and chronic AMR remains the leading cause of late graft loss. The strategies which work in early AMR have limited eeff ct on late/chronic episodes. Here, we reviewed the lines of evidence that late/chronic AMR is the leading cause of late graft loss, characteristics of late AMR, and current strategies in managing late/chronic AMR. More effort should be put on the management of late/chronic AMR to make a better long term graft survival. 1. Introduction 2. Antibody-Mediated Rejection Organ transplantation now represents the treatment of choice AMR is caused by anti-donor-specific antibodies, mostly for patients developing end stage organ failure [1]. However, anti-HLA antibodies [8, 9]. Some non-HLA antibodies also despite the now routine nature of clinical transplantation, have been reported to induce AMRinrarecases.Thepheno- even well-matched transplants are recognized and eventually type of AMR ranges from hyperacute rejection, acute AMR, destroyed by the host immune system [2]. The emerging of and chronic AMR. The diagnosis of AMR depends on typical a new immunosuppressant has decreased the incidence of histological lesions, C4d staining, and serum DSA detection. earlygraftloss, andevenT-cell-mediatedrejection occurs; C4d, a protein from the classical complement activation it is usuallyeasilycontrolled. However, thelongtermgraft cascade that remains attached to the site of complement survival remains to be improved [3]. Although it was formerly activation, is regarded as a diagnosis marker for AMR. The held that alloreactive T cells are solely responsible for graft introduction of C4d as marker of AMR aroused an ever- injury, it is now well recognized that antidonor alloantibodies increasing interest in recognizing mechanisms of allograft are also an important barrier to long term graft survival rejection. However, C4d has several limitations in the diag- [4, 5]. More and more lines of evidence suggest that antibody- nosis of AMR. For instance, it can be found in the majority of mediated rejection (AMR) is predominance cause of late grasft with stable function in ABO-incompatible transplanta- term graft loss [ 6, 7], especially late occurring AMR and tions. On the other hand, a group of C4d-negative AMR has chronic AMR (CAMR). u Th s, strategies targeting alloanti- been recognized based on endothelial gene expression [10, 11]. body reactivity will be helpful in prolonging long term graft About 40% of patients with endothelial-associated transcripts survival. expression and chronic AMR features demonstrated no C4d 2 Clinical and Developmental Immunology Table 1: Early versus late AMR in renal transplant recipients. Early AMR Late AMR Withdrawal or reduction of immunosuppressants Positive panel reactivity antibody before Main risk factor Noncompliance with immunosuppressive therapy, young transplantation, including factors causing sensitization age Mostly de novo donor-specific antibodies, especially HLA Antibody Mostly pre-existing donor-specific antibodies class-II antibodies Very rapid graft dysfunction, significantly decreased Proteinuria, hypertension, progressive functional Clinical features urine output, and rapid graft dysfunction deterioration, and overt graft failure May have chronic tissue injury, such as glomerular double ATN-like minimal inflammation; capillary and or contours, peritubular capillary basement membrane Histology glomerular inflammation and/or thrombosis; multilayering, interstitial fibrosis/tubular atrophy, and/or arterial—v3 fibrous intimal thickening in arteries Outcome Good, mostly reversible Usually poor staining. Similarly, C4d staining is only positive in about clinical subentities [19–21]. They have different risk fac- half of patients with transplant glomerulopathy [12, 13], tors, different clinical manifestations, and different outcomes which is a special form of chronic AMR. C4d-positive and (Table 1). Early AMR are usually correlated with sensitization, -negative AMR share similar degrees of glomerulitis and pre-existing alloantibodies, and rapid graft dysfunction and peritubular capillaritis, similar frequencies of concurrent cell- are usually easy to be controlled; while late AMR mostly mediated rejection, and both may occur early or late after correlated with withdrawal or reduction of immunosup- transplantation, thus needing to be treated equally [14]. pressants, noncompliance with immunosuppressive therapy. Obviously, a new marker for AMR is extremely necessary. There is a relatively slow but progressive graft dysfunction; It is reported that microcirculating inflammation is strongly some patients have anemia and hypoalbuminemia. Late correlated with alloantibody reactivity; however, whether it AMR have little response to antirejection strategies and thus is canbeusedasmaker of AMRisstill of contradictory[15]. correlate with poor graft outcomes [ 19, 20]. The significantly T-box expressed in T cells (T-bet), transcription factor for poorer outcome of late AMR is also observed in simultaneous Th1, has been reported to be correlated with microcirculating pancreas-kidney transplantation [22], even under combined inflammation both in acute and chronic AMR [ 16, 17], and the treatment of steroids, intravenous immunoglobuin (IVIG), predominance of T-bet over GATA3 (transcription factor for and rituximab. Th2) is strongly correlated with AMR [ 16]. However, whether the ratio of T-bet/GATA3 can be used as a diagnosis maker 2.3. Late/Chronic AMR, Main Cause to Late Graft Loss. A for AMR needs further investigation. eliminated term, chronic allograft nephropathy, had been regarded as a main cause of late graft loss [ 23]. However, 2.1. Late/Chronic AMR. The importance of CAMR is increas- chronic allograft nephropathy is actually like a can, which ingly recognized. It has been known as a major cause of includs both immunological and nonimmunological param- late graft dysfunction in renal transplantation. Banff 07 eters caused graft damage; thus, this term has been eliminated consensus conference [18] described that the characteris- in Banff 2005 meeting [ 24]. Recent studies revealed that AMR tics of chronic AMR were C4d deposition in the capillary is theleading causeoflategrasft loss.In2009, researchers basement membrane, the presence of circulating anti-donor from Dr. Holloran’s group in Edmonton studied the pheno- antibodies, and morphologic evidence of chronic tissue type of late kidney graft failure [ 6]; they found that patients injury such as glomerular double contours compatible with with late index biopsies (>1 year) frequently displayed donor- transplant glomerulopathy, peritubular capillary basement specicfi HLA antibody (particularly class II) and micro- membrane multilayering, interstitial fibrosis/tubular atrophy, circulation changes, including glomerulitis, glomerulopathy, and b fi rous arterial intimal thickening. Late occurring AMR capillaritis, capillary multilayering, and C4d staining. T-cell- may manifest as CAMR; however, according to Banff 07 mediated rejection rarely leads to graft failure. However, meeting, the term “chronic” is not related to a certain time they found that 63% of late kidney failures aer ft biopsy were aer ft transplantation but indicates morphological changes of attributable to AMR. remodeling seen in the allograft due to antibody-mediated Further prospective study from the same group [7] injury [18], for example, double contours of glomerular investigated kidney transplants that progressed to failure after basement membranes. u Th s, it is not strange that late AMR a biopsy for clinical indications. Similarly, they found that canbeacute AMR. However, both CAMR andlateAMR have graft failure was rare after T-cell-mediated rejection and acute poor response to regular anti-AMR treatment, and they are kidney injury while was common aer ft AMR or glomeru- sometimes discussed together. lonephritis. The majority of graft loss had evidence of AMR by thetimeoffailure.Interestingly,pureT-cell-mediated 2.2. Late AMR, a Special Clinical Entity? AMR episodes rejection, acute kidney injury, and drug toxicity were not occurring at different time periods seem to be different causes of loss. es Th e ndin fi gs are interesting and, however, Clinical and Developmental Immunology 3 Table 2: Strategies to treat AMR. are not strange as they are consistant with an early study which reported that all chronic rejection failures of kidney Strategies Mechanisms transplants preceded by development of HLA antibodies Plasmapheresis [37], [25]. Recent study from Terasaki Foundation Laboratory Removal of donor-specific antibodies immunoadsorption [38] revealed that 11% of the patients without detectable DSA at Multiple mechanisms, basically transplantation will have detectable DSA at 1 year; and over IVIG [39, 40] pleiotropic immunomodulation the next 4 years, the incidence of de novo DSA will increase Chimeric anti-CD 20 monoclonal to 20%. After de novo DSA development, 24% of the patients Rituximab [41, 42] antibody, depleting B cells will fail within 3 years [26]. Given these n fi dings, de novo Proteasome inhibitor, may cause DSA, especially anti-HLA class II antibodies [27], have to be Bortezomib [43, 44] apoptosis of normal plasma cells which in considered as a primary risk factor for late allograft loss. turn decreases alloantibody production Humanized monoclonal antibody Eculizumab [45, 46] 2.4. Natural History of Chronic AMR. The development of anti-C5 chronic AMR, especially TG usually takes years, and there Mycophenolic acid, Inhibit production of DSA still lacks of a perfect animal model to mimic the lesions tacrolimus [34, 35] during chronic AMR; thus, the natural history of chronic Immediate reduction of the B-cell and Splenectomy [47, 48] AMRisstill notclear.RecentlyWiebe et al.[28]havemoni- plasma cell pool tored a group of renal allograft recipients with de novo DSA, they proposed that posttransplant de novo DSA is probably preceded by an antibody-free period. eTh n, inflammatory pound of cure [32]. As late AMR usually is caused by de novo events such as cellular rejection or graft infection might DSA, posttransplant HLA alloantibody monitoring is of great upregulate HLA expression on endothelial cells and stimulate importance for the prevention of antibody-mediated allograft B-cell allorecognition and subsequent long-lived plasma cells injury [33]. Prevention of nonadherence and insufficient producing de novo DSA. De novo DSA binding vascular immunosuppression are additional important issues in the endothelium could induce injury through the activation of prevention of antibody-mediated allograft injury, as these complement or recruitment of neutrophils, macrophage, or factors are risk factor for late AMR. A recent study based natural killer cells. Sustained microvascular inflammation on ABO-incompatible renal transplantation revealed that eventually leads to progressive tissue damage and graft B-cell depletion protocols, such as splenectomy or rituximab dysfunction. Cellular inflammation is oeft n concomitant of administration, could reduce chronic AMR after kidney AMR [29, 30]ineitherits acuteorchronic form.However, transplantation. Finally, the triple immunosuppressants the pathogenesis remains to be determined. protocol including mycophenolic acid, tacrolimus, and steroid can control antidonor antibody production in renal 2.5. Antibody-Mediated Vascular Rejection. Arecentpop- allograft recipients with chronic rejection [ 34]and seem to be superior to others in treating AMR [35, 36]; however, ulation based study [31] revealed a new type of kidney rejection not presently included in classifications, which is whether it can prevent the development of late AMR is not clear, see Table 2. an antibody-mediated vascular rejection. This study included 302 cases of acute biopsy-proven rejection. Four distinct pat- terns of kidney allograft rejection were identified, including 3.2. Rituximab/IVIG. Several single center studies showed T-cell-mediated vascular rejection (26 patients (9%)), anti- that the combination treatment with rituximab/IVIG may be bodymediated vascular rejection (64 (21%)), T-cell-mediated a useful strategy for the treatment of chronic AMR. In 2008, a rejection without vasculitis (139 (46%)), and AMR without German group [49] published their pilot study in six pediatric vasculitis (73 (24%)). The graft survival is very poor in renal transplant recipients with chronic AMR. Their treat- antibody-mediated vascular rejection, which has a 9 times ment regimen was four weekly doses of IVIG (1 g/kg body higher graft loss incidence compared with T-cell-mediated weight per dose), followed by a single dose of rituximab rejection without vasculitis. Unfortunately, the authors did (375 mg/m body surface area) 1 week aeft r the last IVIG not provide how many of the AMR episodes were late AMR. infusion.Fourofthe sixpatientshad good response to this treatment; they had improved or stabilized eGFR. Further prospective studies from the same group showed that under 3. Management of Late/Chronic AMR this treatment, in the means of eGFR, 70% patients responded 3.1. An Ounce of Prevention Is Worth a Pound of Cure. to treatment as measured 6 months aer ft intervention, and Chronic AMR is a B-cell-mediated production of this response persisted over a 24-month observation period. immunoglobulin (Ig) G antibody against a transplanted eTh rationale for the rituximab/IVIG treatment was to use organ. Based on this pathophysiologic condition, rituximab, IVIG for its immunomodulatory action and then rituximab IVIG, and bortezomib have been used as treatment for for prevention of further antibody production. chronic AMR recently. However, till now, there is no At the year 2009, Fehr et al. [50] published his work standardized treatment for late/chronic AMR. The strategies of using rituximab/IVIG treatment on four adult patients that caneeff ctivelyreverse earlyAMR do notworkaswellin with chronic AMR. eTh result showed that rituximab/IVIG late episodes; thus, an ounce of prevention is really worth a treatment improved kidney allograft function in all four 4 Clinical and Developmental Immunology patients, and donor-specific antibodies were reduced in 2 of hemolytic uremic syndrome aeft r renal transplantation [ 57]. 4 patients. The treatment regimen of this study was that on A prospective study showed that eculizumab can reduce the diagnosis of chronic AMR, all patients received intravenous incidence of AMR and transplant glomerulopathy in highly steroid pulses (500–1000 mg once daily for 3 to 5 days) sensitized individuals when administered immediately aer ft transplant [58]. Cases had been reported that eculizumab and rituximab (375 mg/m once on day 1), whereas IVIG reverse AMR is associated with thrombotic microangiopathy (0.4 g/kg once daily on day 2 to 5) was given only to 3 [59]; it can even reverse severe AMR episode refractory patients. About the treatment safety, 3 out of 4 patients to salvage splenectomy and daily plasmapheresis in ABO underwent therapy with rituximab/IVIG without side eeff cts. incompatible (ABOI) living donor kidney transplantation One patient had severe, possibly rituximab-associated lung [45]. However, there is no evidence that eculizumab can toxicity. eir Th study showed that rituximab/IVIG may be a be used for late AMR, and clinical trials are necessary to useful strategy for the treatment of chronic AMR. Another determine the optimal use of C5 inhibition. pilot study showed that rituximab/IVIG treatment took eeff ct in 3 out of 4 patients. Early stage of chronic AMR has better response than advanced stage [51]. Anyway, although ritux- 3.5. Splenectomy. The spleen acts as a repository for memory imab/IVIG treatment takes effects in some CAMR cases, it is B cells and plasma cells; thus, splenectomy is supposed to far from comparable to early AMR cases [22]. A retrospective be eecti ff ve in treating AMR. eTh re is data suggesting that study from Massachusetts General Hospital [52]studied splenectomy alone can lead to rapid diuresis and immediate the effect of rituximab followed by standard maintenance restoration of renal function [47]. Rescue splenectomy is immunosuppression, they found that this protocol shows a currently regarded as last salvage option for AMR. er Th e is therapeutic eeff ct in 8 out of 14 CAMR. Response to rituximab acasethatreported[60] that splenectomy is effective for was defined as decline or stabilization of serum creatinine for treatment of CAMR aeft r renal transplantation. However, at least one year in this study. clinical trials are needed to prove this ndin fi g. 3.3. Bortezomib. Bortezomib is a proteosome inhibitor that 4. AMR in Liver Transplantation leads in vitro to apoptosis of alloantibody-producing plasma cells [53]. It has shown promising eeff ct in early AMR eTh liver allograft is generally regarded as relatively resistant cases [43]. Early reports of bortezomib-based AMR treat- to AMR. eTh resistance is attributed to a variety of charac- ment demonstrated the ability of bortezomib to deplete teristic features of liver which contribute to the clearing and plasma cells producing DSA, reduce DSA levels, provide dilution of antibodies or antigen-antibody complexes, such as histological improvement or resolution, and improve renal Kuper ff cell phagocytosis, large sinusoidal surface area, dual allograft function [ 54]. Initial results from a multicenter aeff rent hepatic blood supply, and secretion of soluble MHC study showed [55] that bortezomib-based regimen reversed class I antigen [61]. For many years, hyperacute rejection AMR in adult kidney, kidney/pancreas, and pediatric heart was thought not to occur, even when the ABO incompatible transplant recipients; a common bortezomib-based regimen graft was used. However, subsequent increasing studies have demonstrated substantial DSA reductions, with more than shown that liver transplantation across the ABO blood type half of the patients achieving a 45.0% reduction in DSA level. barrier (ABOi) is prone to AMR, which oen ft leads to a poor However, plasmapheresis has been performed every third day clinical outcome. Unlike a reliable tissue marker of AMR immediately before bortezomib therapy. In a chronic AMR in renal and cardiac allograsft , the diagnostic utility and rat cardiac transplant model, administration of bortezomib functional significance of C4d immunostaining in the liver 60 or 80 days after transplantation may reduce antidonor allograft are controversial and less clearly formed. eTh re are MHC classes I and II Abs. Histological improvements were reports that showed that extensive C4d deposition is associ- also observed with bortezomib administration, including ated with AMR and correlated with graft survival. However, reduction in C4d expression, interstitial fibrosis, and vas- C4d deposition in liver was also detected in several other culopathy [56]. Unfortunately, it is not as eeff ctive in late conditions, such as acute cellular rejection, chronic rejection, AMR cases. Walsh et al. treated 30 episodes of AMR, and and recurrent diseases including hepatitis B, hepatitis C, and they found that early AMR patients demonstrated greater autoimmune hepatitis, and even preservation injury [62–64]. reduction in DSA and histologic resolution/improvement. Therefore, the diagnosis of AMR in liver cannot be made They concluded that early and late AMR exhibit distinct on the basis of histological n fi ding alone and requires other immunologic characteristics and respond differently to pro- supportive features as well as the exclusion of other causes teosome inhibitor therapy. of graft dysfunction that can mimic the pathological changes occurring in AMR. However, thepresenceofdiffuseC4d 3.4. Eculizumab. As complement plays an important role immunostaining (involving endothelium or stroma in>50% in the pathogenesis of AMR, complement-blocking agents of portal tracts or sinusoids) provides supportive evidence for could be used for the treatment of AMR. Eculizumab is a a diagnosis of AMR. Similar to renal transplantation, conven- humanized monoclonal antibody against complement C5. It tional T-cell-based immunosuppression usually seems less can bind to the C5 protein and inhibit conversion of C5 to effective for cases with strictly defined AMR. Treatment with C5b, thus preventing formation of the membrane attack com- aggressive B-cell directed immunosuppression, including plex (C5b–9). Eculizumab has been used to rescue atypical IVIG, plasmapheresis, and rituximab, is recommended to be Clinical and Developmental Immunology 5 used [61]. In animal models, antibody-mediated responses Authors’ Contribution might play important roles in the development of chronic Qiquan Sun and Yang Yang contributed equally to this work. liver allograft rejection. However, the role of AMR in late liver graft loss is still underdetermined. Acknowledgments This study was supported by Grants from the General 5. AMR in Other Organ Transplantation Program of National Natural Science Foundation of China AMRisalsoinvolvedinother organtransplantation,espe- (no. 81070593 and no. 81270834), a grant from Fund for cially for heart transplantation. DSA binding to the heart Distinguished Young of Jiangsu Province, and a grant from allograft causes myocardial injury predominantly through 333 Talent Training Program of Jiangsu Province. immune complex activation of the classical pathway of the complement cascade [65], and thus is a significant risk for References allograft failure, cardiac allograft vasculopathy, and poor survival. C4d is accepted as a marker for AMR in car- [1] R. A. Wolfe, V. B. Ashby, E. L. Milford et al., “Comparison of diac allografts. 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Late and Chronic Antibody-Mediated Rejection: Main Barrier to Long Term Graft Survival

Sun, Qiquan; Yang, Yang
Journal of Immunology Research , Volume 2013 – Oct 8, 2013
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Copyright © 2013 Qiquan Sun and Yang Yang. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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10.1155/2013/859761
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Hindawi Publishing Corporation Clinical and Developmental Immunology Volume 2013, Article ID 859761, 7 pages http://dx.doi.org/10.1155/2013/859761 Review Article Late and Chronic Antibody-Mediated Rejection: Main Barrier to Long Term Graft Survival 1 2 Qiquan Sun and Yang Yang Department of Renal Transplantation, eTh ir Th d Alffi iated Hospital, Sun Yat-Sen University, 600 Tianhe Road, Guangzhou 510630, China Department of Liver Transplantation, eTh ir Th d Alffi iated Hospital, Sun Yat-Sen University, 600 Tianhe Road, Guangzhou 510630, China Correspondence should be addressed to Qiquan Sun; [email protected] and Yang Yang; [email protected] Received 27 June 2013; Accepted 3 September 2013 Academic Editor: Xian Li Copyright © 2013 Q. Sun and Y. Yang. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Antibody-mediated rejection (AMR) is an important cause of graft loss after organ transplantation. It is caused by anti-donor- specific antibodies especially anti-HLA antibodies. C4d had been regarded as a diagnosis marker for AMR. Although most early AMR episodes can be successfully controlled or reversed, late and chronic AMR remains the leading cause of late graft loss. The strategies which work in early AMR have limited eeff ct on late/chronic episodes. Here, we reviewed the lines of evidence that late/chronic AMR is the leading cause of late graft loss, characteristics of late AMR, and current strategies in managing late/chronic AMR. More effort should be put on the management of late/chronic AMR to make a better long term graft survival. 1. Introduction 2. Antibody-Mediated Rejection Organ transplantation now represents the treatment of choice AMR is caused by anti-donor-specific antibodies, mostly for patients developing end stage organ failure [1]. However, anti-HLA antibodies [8, 9]. Some non-HLA antibodies also despite the now routine nature of clinical transplantation, have been reported to induce AMRinrarecases.Thepheno- even well-matched transplants are recognized and eventually type of AMR ranges from hyperacute rejection, acute AMR, destroyed by the host immune system [2]. The emerging of and chronic AMR. The diagnosis of AMR depends on typical a new immunosuppressant has decreased the incidence of histological lesions, C4d staining, and serum DSA detection. earlygraftloss, andevenT-cell-mediatedrejection occurs; C4d, a protein from the classical complement activation it is usuallyeasilycontrolled. However, thelongtermgraft cascade that remains attached to the site of complement survival remains to be improved [3]. Although it was formerly activation, is regarded as a diagnosis marker for AMR. The held that alloreactive T cells are solely responsible for graft introduction of C4d as marker of AMR aroused an ever- injury, it is now well recognized that antidonor alloantibodies increasing interest in recognizing mechanisms of allograft are also an important barrier to long term graft survival rejection. However, C4d has several limitations in the diag- [4, 5]. More and more lines of evidence suggest that antibody- nosis of AMR. For instance, it can be found in the majority of mediated rejection (AMR) is predominance cause of late grasft with stable function in ABO-incompatible transplanta- term graft loss [ 6, 7], especially late occurring AMR and tions. On the other hand, a group of C4d-negative AMR has chronic AMR (CAMR). u Th s, strategies targeting alloanti- been recognized based on endothelial gene expression [10, 11]. body reactivity will be helpful in prolonging long term graft About 40% of patients with endothelial-associated transcripts survival. expression and chronic AMR features demonstrated no C4d 2 Clinical and Developmental Immunology Table 1: Early versus late AMR in renal transplant recipients. Early AMR Late AMR Withdrawal or reduction of immunosuppressants Positive panel reactivity antibody before Main risk factor Noncompliance with immunosuppressive therapy, young transplantation, including factors causing sensitization age Mostly de novo donor-specific antibodies, especially HLA Antibody Mostly pre-existing donor-specific antibodies class-II antibodies Very rapid graft dysfunction, significantly decreased Proteinuria, hypertension, progressive functional Clinical features urine output, and rapid graft dysfunction deterioration, and overt graft failure May have chronic tissue injury, such as glomerular double ATN-like minimal inflammation; capillary and or contours, peritubular capillary basement membrane Histology glomerular inflammation and/or thrombosis; multilayering, interstitial fibrosis/tubular atrophy, and/or arterial—v3 fibrous intimal thickening in arteries Outcome Good, mostly reversible Usually poor staining. Similarly, C4d staining is only positive in about clinical subentities [19–21]. They have different risk fac- half of patients with transplant glomerulopathy [12, 13], tors, different clinical manifestations, and different outcomes which is a special form of chronic AMR. C4d-positive and (Table 1). Early AMR are usually correlated with sensitization, -negative AMR share similar degrees of glomerulitis and pre-existing alloantibodies, and rapid graft dysfunction and peritubular capillaritis, similar frequencies of concurrent cell- are usually easy to be controlled; while late AMR mostly mediated rejection, and both may occur early or late after correlated with withdrawal or reduction of immunosup- transplantation, thus needing to be treated equally [14]. pressants, noncompliance with immunosuppressive therapy. Obviously, a new marker for AMR is extremely necessary. There is a relatively slow but progressive graft dysfunction; It is reported that microcirculating inflammation is strongly some patients have anemia and hypoalbuminemia. Late correlated with alloantibody reactivity; however, whether it AMR have little response to antirejection strategies and thus is canbeusedasmaker of AMRisstill of contradictory[15]. correlate with poor graft outcomes [ 19, 20]. The significantly T-box expressed in T cells (T-bet), transcription factor for poorer outcome of late AMR is also observed in simultaneous Th1, has been reported to be correlated with microcirculating pancreas-kidney transplantation [22], even under combined inflammation both in acute and chronic AMR [ 16, 17], and the treatment of steroids, intravenous immunoglobuin (IVIG), predominance of T-bet over GATA3 (transcription factor for and rituximab. Th2) is strongly correlated with AMR [ 16]. However, whether the ratio of T-bet/GATA3 can be used as a diagnosis maker 2.3. Late/Chronic AMR, Main Cause to Late Graft Loss. A for AMR needs further investigation. eliminated term, chronic allograft nephropathy, had been regarded as a main cause of late graft loss [ 23]. However, 2.1. Late/Chronic AMR. The importance of CAMR is increas- chronic allograft nephropathy is actually like a can, which ingly recognized. It has been known as a major cause of includs both immunological and nonimmunological param- late graft dysfunction in renal transplantation. Banff 07 eters caused graft damage; thus, this term has been eliminated consensus conference [18] described that the characteris- in Banff 2005 meeting [ 24]. Recent studies revealed that AMR tics of chronic AMR were C4d deposition in the capillary is theleading causeoflategrasft loss.In2009, researchers basement membrane, the presence of circulating anti-donor from Dr. Holloran’s group in Edmonton studied the pheno- antibodies, and morphologic evidence of chronic tissue type of late kidney graft failure [ 6]; they found that patients injury such as glomerular double contours compatible with with late index biopsies (>1 year) frequently displayed donor- transplant glomerulopathy, peritubular capillary basement specicfi HLA antibody (particularly class II) and micro- membrane multilayering, interstitial fibrosis/tubular atrophy, circulation changes, including glomerulitis, glomerulopathy, and b fi rous arterial intimal thickening. Late occurring AMR capillaritis, capillary multilayering, and C4d staining. T-cell- may manifest as CAMR; however, according to Banff 07 mediated rejection rarely leads to graft failure. However, meeting, the term “chronic” is not related to a certain time they found that 63% of late kidney failures aer ft biopsy were aer ft transplantation but indicates morphological changes of attributable to AMR. remodeling seen in the allograft due to antibody-mediated Further prospective study from the same group [7] injury [18], for example, double contours of glomerular investigated kidney transplants that progressed to failure after basement membranes. u Th s, it is not strange that late AMR a biopsy for clinical indications. Similarly, they found that canbeacute AMR. However, both CAMR andlateAMR have graft failure was rare after T-cell-mediated rejection and acute poor response to regular anti-AMR treatment, and they are kidney injury while was common aer ft AMR or glomeru- sometimes discussed together. lonephritis. The majority of graft loss had evidence of AMR by thetimeoffailure.Interestingly,pureT-cell-mediated 2.2. Late AMR, a Special Clinical Entity? AMR episodes rejection, acute kidney injury, and drug toxicity were not occurring at different time periods seem to be different causes of loss. es Th e ndin fi gs are interesting and, however, Clinical and Developmental Immunology 3 Table 2: Strategies to treat AMR. are not strange as they are consistant with an early study which reported that all chronic rejection failures of kidney Strategies Mechanisms transplants preceded by development of HLA antibodies Plasmapheresis [37], [25]. Recent study from Terasaki Foundation Laboratory Removal of donor-specific antibodies immunoadsorption [38] revealed that 11% of the patients without detectable DSA at Multiple mechanisms, basically transplantation will have detectable DSA at 1 year; and over IVIG [39, 40] pleiotropic immunomodulation the next 4 years, the incidence of de novo DSA will increase Chimeric anti-CD 20 monoclonal to 20%. After de novo DSA development, 24% of the patients Rituximab [41, 42] antibody, depleting B cells will fail within 3 years [26]. Given these n fi dings, de novo Proteasome inhibitor, may cause DSA, especially anti-HLA class II antibodies [27], have to be Bortezomib [43, 44] apoptosis of normal plasma cells which in considered as a primary risk factor for late allograft loss. turn decreases alloantibody production Humanized monoclonal antibody Eculizumab [45, 46] 2.4. Natural History of Chronic AMR. The development of anti-C5 chronic AMR, especially TG usually takes years, and there Mycophenolic acid, Inhibit production of DSA still lacks of a perfect animal model to mimic the lesions tacrolimus [34, 35] during chronic AMR; thus, the natural history of chronic Immediate reduction of the B-cell and Splenectomy [47, 48] AMRisstill notclear.RecentlyWiebe et al.[28]havemoni- plasma cell pool tored a group of renal allograft recipients with de novo DSA, they proposed that posttransplant de novo DSA is probably preceded by an antibody-free period. eTh n, inflammatory pound of cure [32]. As late AMR usually is caused by de novo events such as cellular rejection or graft infection might DSA, posttransplant HLA alloantibody monitoring is of great upregulate HLA expression on endothelial cells and stimulate importance for the prevention of antibody-mediated allograft B-cell allorecognition and subsequent long-lived plasma cells injury [33]. Prevention of nonadherence and insufficient producing de novo DSA. De novo DSA binding vascular immunosuppression are additional important issues in the endothelium could induce injury through the activation of prevention of antibody-mediated allograft injury, as these complement or recruitment of neutrophils, macrophage, or factors are risk factor for late AMR. A recent study based natural killer cells. Sustained microvascular inflammation on ABO-incompatible renal transplantation revealed that eventually leads to progressive tissue damage and graft B-cell depletion protocols, such as splenectomy or rituximab dysfunction. Cellular inflammation is oeft n concomitant of administration, could reduce chronic AMR after kidney AMR [29, 30]ineitherits acuteorchronic form.However, transplantation. Finally, the triple immunosuppressants the pathogenesis remains to be determined. protocol including mycophenolic acid, tacrolimus, and steroid can control antidonor antibody production in renal 2.5. Antibody-Mediated Vascular Rejection. Arecentpop- allograft recipients with chronic rejection [ 34]and seem to be superior to others in treating AMR [35, 36]; however, ulation based study [31] revealed a new type of kidney rejection not presently included in classifications, which is whether it can prevent the development of late AMR is not clear, see Table 2. an antibody-mediated vascular rejection. This study included 302 cases of acute biopsy-proven rejection. Four distinct pat- terns of kidney allograft rejection were identified, including 3.2. Rituximab/IVIG. Several single center studies showed T-cell-mediated vascular rejection (26 patients (9%)), anti- that the combination treatment with rituximab/IVIG may be bodymediated vascular rejection (64 (21%)), T-cell-mediated a useful strategy for the treatment of chronic AMR. In 2008, a rejection without vasculitis (139 (46%)), and AMR without German group [49] published their pilot study in six pediatric vasculitis (73 (24%)). The graft survival is very poor in renal transplant recipients with chronic AMR. Their treat- antibody-mediated vascular rejection, which has a 9 times ment regimen was four weekly doses of IVIG (1 g/kg body higher graft loss incidence compared with T-cell-mediated weight per dose), followed by a single dose of rituximab rejection without vasculitis. Unfortunately, the authors did (375 mg/m body surface area) 1 week aeft r the last IVIG not provide how many of the AMR episodes were late AMR. infusion.Fourofthe sixpatientshad good response to this treatment; they had improved or stabilized eGFR. Further prospective studies from the same group showed that under 3. Management of Late/Chronic AMR this treatment, in the means of eGFR, 70% patients responded 3.1. An Ounce of Prevention Is Worth a Pound of Cure. to treatment as measured 6 months aer ft intervention, and Chronic AMR is a B-cell-mediated production of this response persisted over a 24-month observation period. immunoglobulin (Ig) G antibody against a transplanted eTh rationale for the rituximab/IVIG treatment was to use organ. Based on this pathophysiologic condition, rituximab, IVIG for its immunomodulatory action and then rituximab IVIG, and bortezomib have been used as treatment for for prevention of further antibody production. chronic AMR recently. However, till now, there is no At the year 2009, Fehr et al. [50] published his work standardized treatment for late/chronic AMR. The strategies of using rituximab/IVIG treatment on four adult patients that caneeff ctivelyreverse earlyAMR do notworkaswellin with chronic AMR. eTh result showed that rituximab/IVIG late episodes; thus, an ounce of prevention is really worth a treatment improved kidney allograft function in all four 4 Clinical and Developmental Immunology patients, and donor-specific antibodies were reduced in 2 of hemolytic uremic syndrome aeft r renal transplantation [ 57]. 4 patients. The treatment regimen of this study was that on A prospective study showed that eculizumab can reduce the diagnosis of chronic AMR, all patients received intravenous incidence of AMR and transplant glomerulopathy in highly steroid pulses (500–1000 mg once daily for 3 to 5 days) sensitized individuals when administered immediately aer ft transplant [58]. Cases had been reported that eculizumab and rituximab (375 mg/m once on day 1), whereas IVIG reverse AMR is associated with thrombotic microangiopathy (0.4 g/kg once daily on day 2 to 5) was given only to 3 [59]; it can even reverse severe AMR episode refractory patients. About the treatment safety, 3 out of 4 patients to salvage splenectomy and daily plasmapheresis in ABO underwent therapy with rituximab/IVIG without side eeff cts. incompatible (ABOI) living donor kidney transplantation One patient had severe, possibly rituximab-associated lung [45]. However, there is no evidence that eculizumab can toxicity. eir Th study showed that rituximab/IVIG may be a be used for late AMR, and clinical trials are necessary to useful strategy for the treatment of chronic AMR. Another determine the optimal use of C5 inhibition. pilot study showed that rituximab/IVIG treatment took eeff ct in 3 out of 4 patients. Early stage of chronic AMR has better response than advanced stage [51]. Anyway, although ritux- 3.5. Splenectomy. The spleen acts as a repository for memory imab/IVIG treatment takes effects in some CAMR cases, it is B cells and plasma cells; thus, splenectomy is supposed to far from comparable to early AMR cases [22]. A retrospective be eecti ff ve in treating AMR. eTh re is data suggesting that study from Massachusetts General Hospital [52]studied splenectomy alone can lead to rapid diuresis and immediate the effect of rituximab followed by standard maintenance restoration of renal function [47]. Rescue splenectomy is immunosuppression, they found that this protocol shows a currently regarded as last salvage option for AMR. er Th e is therapeutic eeff ct in 8 out of 14 CAMR. Response to rituximab acasethatreported[60] that splenectomy is effective for was defined as decline or stabilization of serum creatinine for treatment of CAMR aeft r renal transplantation. However, at least one year in this study. clinical trials are needed to prove this ndin fi g. 3.3. Bortezomib. Bortezomib is a proteosome inhibitor that 4. AMR in Liver Transplantation leads in vitro to apoptosis of alloantibody-producing plasma cells [53]. It has shown promising eeff ct in early AMR eTh liver allograft is generally regarded as relatively resistant cases [43]. Early reports of bortezomib-based AMR treat- to AMR. eTh resistance is attributed to a variety of charac- ment demonstrated the ability of bortezomib to deplete teristic features of liver which contribute to the clearing and plasma cells producing DSA, reduce DSA levels, provide dilution of antibodies or antigen-antibody complexes, such as histological improvement or resolution, and improve renal Kuper ff cell phagocytosis, large sinusoidal surface area, dual allograft function [ 54]. Initial results from a multicenter aeff rent hepatic blood supply, and secretion of soluble MHC study showed [55] that bortezomib-based regimen reversed class I antigen [61]. For many years, hyperacute rejection AMR in adult kidney, kidney/pancreas, and pediatric heart was thought not to occur, even when the ABO incompatible transplant recipients; a common bortezomib-based regimen graft was used. However, subsequent increasing studies have demonstrated substantial DSA reductions, with more than shown that liver transplantation across the ABO blood type half of the patients achieving a 45.0% reduction in DSA level. barrier (ABOi) is prone to AMR, which oen ft leads to a poor However, plasmapheresis has been performed every third day clinical outcome. Unlike a reliable tissue marker of AMR immediately before bortezomib therapy. In a chronic AMR in renal and cardiac allograsft , the diagnostic utility and rat cardiac transplant model, administration of bortezomib functional significance of C4d immunostaining in the liver 60 or 80 days after transplantation may reduce antidonor allograft are controversial and less clearly formed. eTh re are MHC classes I and II Abs. Histological improvements were reports that showed that extensive C4d deposition is associ- also observed with bortezomib administration, including ated with AMR and correlated with graft survival. However, reduction in C4d expression, interstitial fibrosis, and vas- C4d deposition in liver was also detected in several other culopathy [56]. Unfortunately, it is not as eeff ctive in late conditions, such as acute cellular rejection, chronic rejection, AMR cases. Walsh et al. treated 30 episodes of AMR, and and recurrent diseases including hepatitis B, hepatitis C, and they found that early AMR patients demonstrated greater autoimmune hepatitis, and even preservation injury [62–64]. reduction in DSA and histologic resolution/improvement. Therefore, the diagnosis of AMR in liver cannot be made They concluded that early and late AMR exhibit distinct on the basis of histological n fi ding alone and requires other immunologic characteristics and respond differently to pro- supportive features as well as the exclusion of other causes teosome inhibitor therapy. of graft dysfunction that can mimic the pathological changes occurring in AMR. However, thepresenceofdiffuseC4d 3.4. Eculizumab. As complement plays an important role immunostaining (involving endothelium or stroma in>50% in the pathogenesis of AMR, complement-blocking agents of portal tracts or sinusoids) provides supportive evidence for could be used for the treatment of AMR. Eculizumab is a a diagnosis of AMR. Similar to renal transplantation, conven- humanized monoclonal antibody against complement C5. It tional T-cell-based immunosuppression usually seems less can bind to the C5 protein and inhibit conversion of C5 to effective for cases with strictly defined AMR. Treatment with C5b, thus preventing formation of the membrane attack com- aggressive B-cell directed immunosuppression, including plex (C5b–9). Eculizumab has been used to rescue atypical IVIG, plasmapheresis, and rituximab, is recommended to be Clinical and Developmental Immunology 5 used [61]. In animal models, antibody-mediated responses Authors’ Contribution might play important roles in the development of chronic Qiquan Sun and Yang Yang contributed equally to this work. liver allograft rejection. However, the role of AMR in late liver graft loss is still underdetermined. Acknowledgments This study was supported by Grants from the General 5. AMR in Other Organ Transplantation Program of National Natural Science Foundation of China AMRisalsoinvolvedinother organtransplantation,espe- (no. 81070593 and no. 81270834), a grant from Fund for cially for heart transplantation. DSA binding to the heart Distinguished Young of Jiangsu Province, and a grant from allograft causes myocardial injury predominantly through 333 Talent Training Program of Jiangsu Province. immune complex activation of the classical pathway of the complement cascade [65], and thus is a significant risk for References allograft failure, cardiac allograft vasculopathy, and poor survival. C4d is accepted as a marker for AMR in car- [1] R. A. Wolfe, V. B. Ashby, E. L. Milford et al., “Comparison of diac allografts. 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