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Managing the highly sensitized transplant recipient and B cell tolerance
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Managing the highly sensitized transplant recipient and B cell tolerance Seema Baid, Susan L Saidman, Nina Tolkoff-Rubin, Winfred W Williams, Francis L Delmonico, A Benedict Cosimi and Manuel Pascual The detection of anti-donor-HLA antibodies in a renal allograft recipient’s serum, either at the time of or after transplantation, is usually associated with specific antibody-mediated clinical syndromes. These can be divided temporally into three categories: hyperacute rejection, acute humoral rejection and chronic humoral rejection. With the identification of new immunosuppressive drug combinations, more-effective control of alloantibody production has been recently achieved in humans. Thus, prevention and/or treatment of antibodymediated allograft injury are now possible. Ultimately, the induction of mixed hematopoietic chimerism may allow us to overcome the problem of allosensitization and accept an allograft without chronic immunosuppression. Addresses Renal and Transplantation Units, and Histocompatibility Laboratory, Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street, Boston, MA 02114, USA Correspondence: Manuel Pascual Current Opinion in Immunology 2001, 13:577–581 0952-7915/01/$ — see front matter © 2001 Elsevier Science Ltd. All rights reserved. Abbreviations CAN chronic allograft nephropathy CR chronic rejection HAR hyperacute rejection IVIg intravenous polyclonal immunoglobulin MMF mycophenolate mofetil PRA panel-reactive antibody TAC tacrolimus
Introduction In organ transplantation, the term ‘highly sensitized’ (or ‘hyperimmunized’) refers to individuals who have detectable circulating antibodies against HLA antigens (anti-HLA alloantibodies). These alloantibodies have generally been induced by previous transplantation, pregnancies or multiple blood transfusions [1]. The enhanced B cell alloresponses in potential allograft recipients can be assessed by various techniques. Testing for anti-HLA antibodies before and after transplantation is important, as their presence increases the likelihood and severity of rejection episodes and is a significant risk factor for allograft loss [2]. Anti-HLA antibodies have been reported to play an important pathogenic role in most solid organ transplants, including heart, lung, liver and pancreas [3–5]. However, because the vast majority of the literature published for more than thirty years regarding highly sensitized patients has originated from the field of renal transplantation, the focus of this review will be on the impact of anti-HLA antibodies on the renal transplant recipient.
Specific humoral syndromes in renal transplantation The level of ‘sensitization’ in a kidney transplant recipient can be monitored pre- and/or post-transplant by PRA (panel-reactive antibody) testing. Here, the patient’s serum is tested against a panel of cells or purified HLA molecules that includes a wide range of HLA antigens representing most antigens encountered in the general population [6,7]. The percentage of the panel that is killed (by cytotoxicity) or that binds antibody provides an estimate of the patient’s sensitization. Highly sensitized patients (e.g. with PRAs of 80–100%) frequently wait for many years before a suitable organ-transplant donor can be identified, as the recipients have preformed donor-specific antibodies against most available donors. The presence of donor-specific antibodies in the potential recipient’s serum has, until recently, precluded transplantation because, in that setting, a high risk of hyperacute rejection exists (see below). Post-transplant, most acuterejection episodes are due to cellular mechanisms of tissue injury (acute cellular rejection). The de novo demonstration of previously undetectable donor-specific antibodies after transplantation is associated with specific ‘humoral syndromes’ that are due, at least in part, to antibody-mediated mechanisms of tissue injury [8]. Hyperacute rejection
The rejection of an allograft within the first 24 hours following transplantation has been termed ‘hyperacute rejection (HAR)’ to emphasize the rapidity of the rejection process. HAR is generally considered to be mediated purely by humoral mechanisms. That is, the binding of donor-specific antibodies to the graft vasculature triggers complement activation by the classical pathway and results in severe tissue injury. The detrimental effect of preformed donor-specific antibodies first became apparent in the 1960s, as pre-existing donor-specific antibodies (i.e. a ‘positive cross-match’ at the time of renal transplantation) almost inevitably led to HAR of grafted kidneys [9,10]. Histopathologic examination of the failed allografts revealed interstitial hemorrhage, neutrophils and fibrin thrombi in capillaries. It became clear then that either preformed alloantibodies to HLA antigens or isohemagglutinins directed against incompatible major blood group antigens could result in HAR [9–12]. This experience stimulated the requirement for demonstration of a pre-transplant ‘negative’ cross-match (i.e. no alloantibodies) and ABO compatibility (i.e. no natural antiABO antibodies) in kidney transplantation [11,12]. Therefore, antibody-mediated HAR has become a very rare event. Of note, rarely, HAR can occur in the absence of detectable donorspecific antibodies, due to cellular immunity [13].
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Acute humoral rejection
In 1970, Jeannet et al. [14] reported that kidney transplant recipients who developed de novo donor-specific antibodies in the early post-transplant period also suffered severe allograft rejection leading to graft loss in most cases. These initial observations suggested that, in addition to evoked post-transplant cellular immune responses, de novo production of donor-specific antibodies could lead to severe graft injury, a condition that has come to be termed ‘acute humoral rejection’ [15]. In the early 1990s, Halloran et al. [16,17] proposed that acute rejection associated with the development of de novo donor-specific antibodies in recipient’s serum is a clinico-pathologic entity carrying a poor prognosis. Typical histopathologic features of acute humoral rejection include neutrophils in the peritubular capillaries, glomerulitis, fibrin thrombi, vasculitis and, sometimes, fribrinoid necrosis of vessel walls [15,18,19]. These findings are distinct from those of ‘classic’ cellmediated acute rejection, which is characterized predominantly by a mononuclear cellular infiltrate with tubulitis and/or endothelialitis [18]. In 1999, Collins et al. [20••] demonstrated that staining of peritubular capillaries in allograft biopsies for the complement fraction C4d, a split product of C4 in the classical pathway of complement, is a specific and reliable method for diagnosing acute humoral rejection. This observation provided further evidence for the pathogenic role of alloantibodies. Clinically, acute humoral rejection typically presents as early and severe allograft dysfunction that is resistant to steroid and antilymphocyte therapy [8,15]. The risk of allograft failure is approximately 50–80% [19,20••,21,22]. We have recently reviewed our four-year experience (1995–1999), during which an incidence of acute humoral rejection after renal transplantation of 7.7% was observed [23••]. Approximately half of the patients with acute humoral rejection had severe refractory rejection — a rejection episode resistant to both steroid and antilymphocyte therapy. New approaches to treat these patients are described below. A broader range of PRA specificities and a history of a previous failed allograft were found to be significant predictive factors for acute humoral rejection, suggesting that a specific anamnestic humoral response against donor antigens may play a role in the pathogenesis of this type of rejection [23••]. Alternatively, it may also indicate that an overall state of enhanced humoral alloreactivity in some individuals may facilitate an anti-donor-specific humoral response. It should be emphasized that, not uncommonly, histopathologic findings of acute cellular rejection are present in allograft biopsies with acute humoral rejection. The identification of C4d deposits in peritubular capillaries may be the only pathologic feature pointing toward the humoral component of the rejection process. Chronic humoral rejection
Both cellular and humoral immune mechanisms play key roles in the pathogenesis of chronic rejection (CR), a condition also
termed ‘chronic allograft nephropathy’ (CAN) [24]. The presence of serum alloantibodies to donor HLA class I or class II antigens has been associated with chronic rejection of various transplanted organs [25•,26,27•]. In renal recipients, posttransplant production of alloantibodies to HLA class II appears to be associated with CR/CAN, probably manifesting alloresponsiveness via the indirect pathway of allograft recognition [27•,28,29•]. Post-transplant production of alloantibodies often predates the clinical manifestations of CR/CAN, further implicating humoral mechanisms as a cause of CR/CAN [30]. Recent studies indicate that complement C4d deposits in peritubular capillaries are found not only in patients with acute humoral rejection but also in a subset of patients with CR/CAN [25•]. In this study, it was found that 61% of the patients with the typical histologic features of CR/CAN (i.e. transplant arteriopathy and/or chronic transplant glomerulopathy) had C4d deposits in peritubular capillaries. In most cases, this was accompanied by detectable donor-specific antibodies in the patient’s serum [25•]. To determine the relative contribution of humoral mechanisms of rejection to late allograft failure, we further studied the prevalence of chronic humoral rejection in patients with chronic renal allograft dysfunction of all causes. C4d deposits in peritubular capillaries were found in 13% of renal recipients who received an allograft biopsy for chronic allograft dysfunction [31]. In contrast with acute humoral rejection, it does not appear that pre-transplant sensitization is a risk factor for the development of chronic humoral rejection.
Therapeutic approaches to control humoral responses For almost two decades, induction immunosuppression in most centers has included cyclosporine and steroids, with or without azathioprine, for uncomplicated transplant procedures. Removal of alloantibodies immediately before renal transplantation, either by plasmapheresis or immunoadsorption, was attempted in a small number of highly sensitized recipients in order to allow transplantation without HAR [32,33]. In general, such efforts were combined with the administration of monoclonal (OKT3) or polyclonal antilymphocyte therapy, and with cyclophosphamide. Despite some isolated successful cases, the unreliable efficacy of such approaches became apparent as most of these allografts continued to fail due to HAR or acute humoral rejection. With the more recent advent of new immunosuppressive agents, namely tacrolimus (TAC), mycophenolate mofetil (MMF), sirolimus and the anti-IL2-receptor monoclonal antibodies [34•], there has been renewed optimism that more-effective control of antidonor humoral responses might now be feasible. In particular, MMF has been shown to inhibit in vitro antibody production by B cells and to reduce in vivo humoral responses in renal transplant recipients [8]. TAC is a powerful inhibitor of T cell function, which could reduce the T helper cell function required by plasma cells for optimal production of alloantibodies, at least in the initial stages [34•].
Managing highly sensitized transplant recipients Baid et al.
Recent studies using protocols that combine tacrolimus and mycophenolate mofetil Since 1995, we have evaluated a new therapeutic approach consisting of plasmapheresis combined with tacrolimus and mycophenolate rescue (PPh−TAC−MMF rescue) for renal recipients suffering from acute humoral rejection resistant to both steroid and antilymphocyte therapy [15,23••]. During a four-year period, 232 renal transplants were performed under cyclosporine-based immunosuppression. In 10 out of 232 (4.4%) consecutively studied patients with ‘refractory’ acute humoral rejection, the protocol of PPh−TAC−MMF rescue was initiated. Daily plasmapheresis (five sessions) followed by additional alternate-day plasmapheresis if necessary (when renal function did not improve) were combined with TAC and MMF. Significantly decreased circulating donorspecific antibody levels were observed over a period of 3−6 weeks with reversal of rejection in 9/10 patients. At the end of the plasmapheresis course of therapy, intravenous polyclonal immunoglobulin (IVIg) was administered. With a mean follow-up of 40 months, patient and graft survival are currently 100% and 80%, respectively, with persistently undetectable levels of donor-specific antibodies in all patients with functioning allografts [35]. These observations on the control of humoral responses in patients with refractory acute humoral rejection have been recently extended to the treatment of chronic humoral rejection, that is CR/CAN associated with donor-specific antibodies and C4d deposits in peritubular capillaries. In these recipients, we found that rescue therapy with TAC–MMF alone (i.e. without plasmapheresis or IVIg) resulted in a sustained decrease in donor-specific antibody titers and stabilization of renal allograft function. Donor-specific antibodies became undetectable after 6−9 months of therapy, and repeat biopsies performed at 12 months in two patients revealed a decrease or absence of C4d deposits in peritubular capillaries [27•]. These preliminary findings confirm that suppression of alloantibody production is possible with combination therapy such as TAC−MMF. This observation is relevant for the treatment of patients with CR/CAN, but may be even more important in developing strategies to prevent this condition. Similar therapeutic strategies may also be useful for allowing kidney transplantation in patients with high PRA levels or pre-transplant donor-specific antibodies. We recently evaluated low-dose pre-transplant TAC−MMF therapy in a highly sensitized patient (awaiting a second renal transplant), who had a positive T cell cross-match (titer 1:4) against her potential living unrelated donor. After six months of therapy, control of antidonor antibody production was achieved, allowing successful transplantation when the T cell cross-match became negative. Rabbit antithymocyte globulin was added to this patient’s peritransplant TAC, MMF and steroid induction therapy regimen. The patient has had no rejection episodes and has excellent allograft function 20 months after transplantation (M Pascual, unpublished data).
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A more rapid ‘desensitization’ protocol was evaluated by Montgomery et al. [36•]. Successful desensitization was achieved in four highly sensitized patients who had positive cross-matches against their potential living donors. Their protocol consisted of plasmapheresis and IVIg with concomitant administration of TAC−MMF−prednisone, initiated several days or weeks prior to transplantation. All four patients developed acute humoral rejection in the first month post-transplant, but this was reversed with additional plasmapheresis and IVIg. In another similar study, 11 out of 15 patients with a pretransplant positive cross-match against their living donors were successfully desensitized [37•]. Pre-transplant, the patients received plasmapheresis three times weekly over two consecutive weeks, in combination with IVIg and TAC−MMF−prednisone. All 11 patients underwent successful living-donor transplantation with OKT3 induction and continuation of TAC−MMF. In this study, relatively low initial donor-specific antibody titers (lower than 1:4) were predictive of attainment of a negative cross-match. The potential efficacy of high-dose IVIg alone for suppression of HLA-specific antibodies and desensitizing patients awaiting transplantation had been proposed earlier [38,39]. IVIg has well-known but poorly understood immunomodulatory properties and has also been shown to be beneficial in the treatment of acute humoral rejection in renal and cardiac allograft recipients [40]. Thus, further studies incorporating IVIg to both desensitization and therapeutic protocols, especially in combination with PPh–TAC–MMF, are warranted to determine its effect on donor-specific antibody synthesis. In ongoing studies, it is likely that the effects of other new immunosuppressive drugs on in vivo alloantibody synthesis will be further clarified. As an example, blockade of the IL-2receptor with daclizumab has been shown to reduce the formation of anti-HLA antibodies and the frequency of acute rejection in cardiac transplant patients [41]. Sirolimus has been shown to decrease acute rejection after renal transplantation and it also suppresses immunoglobulin synthesis in vitro [42]. Thus it might be speculated that combining TAC with sirolimus may offer a potentially effective alternative to the TAC−MMF regimen for controlling humoral responses [43]. Finally, the role of complement inhibitors also remains to be defined. Indeed, specific inhibition of the complement system could allow treatment of the deleterious consequences of donor-specific antibodies without the need for antibody removal [8].
B cell tolerance Elucidating the mechanisms leading to selective long-term suppression of donor-specific antibody production with the newer immunosuppressants may give important insights in the processes associated with tolerance to allografts. In our series, the combination of TAC and MMF was found to be highly effective in suppressing long-term donor-specific antibody production, whereas only a nonspecific and modest decrease in total immunoglobulin synthesis was observed
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[27•,35]. In addition, Montgomery et al. [36•] found that selective long-term inhibition of donor-specific antibody production was maintained despite the re-emergence of thirdparty alloantibody. Taken together, these observations suggest that an active process associated with the continuing presence of donor antigens (i.e. the kidney allograft) may be necessary to limit donor-specific antibody production in allograft recipients receiving TAC−MMF. Whether this reflects a state of B cell tolerance of selected specificities remains to be studied. Since the early 1950s, the induction of donor-specific immunologic tolerance has remained the ‘Holy Grail’ of clinical transplantation. At our Institution, the induction of ‘mixed hematopoietic chimerism’ has been used as an effective strategy to induce tolerance to kidney allografts in nonhuman primates [44•,45•]. In this approach, a nonmyeloablative conditioning regimen provides transient T cell depletion, which allows donor bone marrow engraftment and the induction of both T cell and B cell tolerance [45•]. In other approaches to tolerance induction currently being investigated in nonhuman primates (costimulatory blockade or severe T cell depletion by anti-CD3 immunotoxin), it was observed that some recipients may still develop chronic rejection associated with antidonor alloantibodies [44•]. Similarly, when recipient splenectomy was not performed in the mixed-chimerism approach, late production of antidonor alloantibodies has occurred [44•]. These observations emphasize that, to induce robust and stable long-term tolerance, both T and B cell tolerance need to be considered. The extension of the mixed-chimerism regimen to induce tolerance in humans was first reported in 1999 [46••]. Interestingly, induction of mixed allogeneic chimerism has been demonstrated to confer donor-specific tolerance both in previously nonsensitized recipients and in the setting of existing allosensitization [47]. In an experimental mouse model, acceptance of skin grafts and loss of circulating donor-specific antibodies suggested that allosensitization can be suppressed with the induction of stable mixed chimerism. Similarly, in xenotransplantation models, the ‘mixed chimerism’ approach has been used to induce B cell tolerance — to suppress natural anti-Gal antibody production [45•]. These recent data suggest that, when more clinically applicable strategies to induce allograft tolerance will become available, the problems associated with recipient’s allosensitization may be overcome.
Conclusions The role of humoral immunity in the pathogenesis of allograft rejection is progressively being clarified. Although the detrimental role of donor-specific antibodies in clinical transplantation was reported more than 30 years ago, it is only recently that effective control of antidonor antibody production has been demonstrated using new immunosuppresive drug combinations. This may have important implications for the management of highly sensitized recipients and to improve long-term results in solid organ transplantation.
The induction of mixed hematopoietic chimerism in transplant recipients has the potential to induce both T cell and B cell tolerance. In the future, strategies aiming at achieving mixed chimerism in the clinical setting may allow us to overcome the problem of allosensitization.
Acknowledgements This work was supported by grants from the Helen and George Burr Endowed Research and Educational Fund in Support of Transplantation (MP) and by the Yates Fund for Transplant Technology (MP). SB was supported by a Fellowship Training Award from the International Society of Nephrology (Cairo, Egypt). We are indebted to many staff members of the Massachusetts General Hospital Transplantation Unit, and of the Department of Pathology (RB Colvin) who contributed to the studies mentioned in this article.
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of renal transplants with anti-class I-like antibody. Transplantation 1992, 53:550-555. 18. Colvin RB: The renal allograft biopsy. Kidney Int 1996, 50:1069-1082. 19. Trpkov K, Campbell P, Pazderka F, Cockfield S, Solez K, Halloran PF: Pathologic features of acute renal allograft rejection associated with donor-specific antibody. Transplantation 1996, 61:1586-1592. 20. Collins AB, Schneeberger EE, Pascual MA, Saidman SL, •• Williams WW, Tolkoff-Rubin N, Cosimi AB, Colvin RB: Complement activation in acute humoral renal allograft rejection: diagnostic significance of C4d deposits in peritubular capillaries. J Am Soc Nephrol 1999, 10:2208-2214. This study demonstrated that the presence of complement C4d deposits in peritubular capillaries is a sensitive and specific marker for the diagnosis of acute humoral rejection. 21. Lobo PI, Spencer CE, Stevenson WC, Pruett TL: Evidence demonstrating poor kidney graft survival when acute rejections are associated with IgG donor-specific lymphocytotoxin. Transplantation 1995, 59:357-360. 22. Martin S, Dyer PA, Mallick NP, Gokal R, Harris R, Johnson RWG: Posttransplant antidonor lymphocytotoxic antibody production in relation to graft outcome. Transplantation 1987, 44:50-53. 23. Crespo M, Pascual M, Tolkoff-Rubin N, Mauiyyedi S, Collins AB, •• Fitzpatrick D, Delmonico FL, Cosimi AB, Colvin RB, Saidman S: Acute humoral rejection in renal allograft recipients: incidence, serology and clinical characteristics. Transplantation 2001, 71:652-658. In approximately 20% of acute rejection episodes, humoral mechanisms of tissue injury were demonstrated. Most (95%) of cases with donor-specific antibodies at the time of rejection had widespread C4d deposits in peritubular capillaries, suggesting a pathogenic role of donor-specific antibodies. 24. Pascual M, Swinford RD, Ingelfinger JR, Williams WW, Cosimi AB, Tolkoff-Rubin N: Chronic rejection and chronic cyclosporine toxicity in renal allografts. Immunol Today 1998, 19:514-519. 25. Mauiyyedi S, Pelle PD, Saidman S, Collins AB, Pascual M, • Tolkoff-Rubin NE, Williams WW, Cosimi AB, Schneeberger EE, Colvin RB: Chronic humoral rejection: identification of antibody mediated chronic renal allograft rejection by C4d deposits in peritubular capillaries. J Am Soc Nephrol 2001, 12:574-582. C4d deposits in peritubular capillaries were found to be present in 61% of allograft biopsies with CR, suggesting the presence of ongoing immunologic activity in a subset of cases with CR. 26. Suciu-Foca N, Reed E, D’Agati VD, Ho E, Cohen DJ, Benvenisty AI, McCabe R, Brensilver JM, King DW, Hardy MA: Soluble HLA antigens, anti-HLA antibodies, and anti-idiotype antibodies in the circulation of renal transplant recipients. Transplantation 1991, 51:593-601. 27. •
Theruvath TP, Saidman SL, Mauiyyedi S, Delmonico FL, Williams WW, Tolkoff-Rubin N, Collins AB, Colvin RB, Cosimi AB, Pascual M: Control of antidonor antibody production with tacrolimus and mycophenolate mofetil in renal allograft recipients with chronic rejection. Transplantation 2001, in press. In this preliminary study, it was demonstrated that control of donor-specific antibody production with TAC−MMF combination alone (with no plasmapheresis or IVIg) is possible in patients with chronic humoral rejection. This may have implications for the treatment or prevention of CR. 28. Abe M, Kawai T, Futatsuyama K, Tanabe K, Fuchinoue S, Teraoka S, Toma H, Ota K: Postoperative production of anti-donor antibody and chronic rejection in renal transplantation. Transplantation 1997, 63:1616-1619. 29. Sayegh MH: Why do we reject a graft? Role of indirect • allo-recognition in graft rejection. Kidney Int 1999, 56:1967-1979. An excellent review on the immunologic mechanisms of CR. 30. Davenport A, Younie ME, Parsons JE, Klouda PT: Development of cytotoxic antibodies following renal allograft transplantation is associated with reduced graft survival due to chronic vascular rejection. Nephrol Dial Transplant 1994, 9:1315-1319. 31. Theruvath TP, Saidman S, Mauiyyedi M, Rubin N, Williams WW, Collins B, Colvin RB, Delmonico F, Cosimi AB, Pascual M: Prevalence of chronic humoral rejection in chronic renal allograft dysfunction [abstract 896]. Am J Transplant 2001, 1(suppl 1):360. 32. Malik ST, Churcher P, Sweny P, Varghese Z, Fernando ON, Moorehead JF: Renal transplantation after removal of anti-HLA antibodies. Lancet 1984, 8387:1185.
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33. Higgins RM, Bevan DJ, Carey BS, Lea CK, Fallon M, Buhler R, Vaughan RW, O’Donnell PJ, Snowden SA, Bewick M, Hendry BM: Prevention of hyperacute rejection by removal of antibodies to HLA immediately before renal transplantation. Lancet 1996, 348:1208-1211. 34. Denton MD, Magee CC, Sayegh MH: Immunosuppressive • strategies in transplantation. Lancet 1999, 353:1083-1091. A comprehensive review on the newer immunosuppressive strategies in transplantation. 35. Theruvath TP, Delmonico FL, Saidman S, Rubin N, Williams WW, Mauiyyedi S, Farrell ML, Collins B, Colvin RB, Cosimi AB, Pascual M: Long-term outcome after treatment of early refractory acute humoral rejection in kidney transplantation [abstract 61]. Am J Transplant 2001, 1(suppl 1):151. 36. Montgomery RA, Zachary AA, Racusen LC, Leffell MS, King KE, • Burdick J, Maley WR, Ratner LE: Plasmapheresis and intravenous immune globulin provides effective rescue therapy for refractory humoral rejection and allows kidneys to be successfully transplanted into cross-match positive recipients. Transplantation 2000, 70:887-895. Successful desensitization was achieved in patients with low-titer positive cross-matches against their potential living donors, using plasmapheresis and IVIg with concomitant TAC−MMF to allow transplantation. 37. •
Schweitzer EJ, Wilson JS, Fernandez-Vina M, Fox M, Gutierrez M, Wiland A, Hunter J, Farney A, Philosophe B, Colonna J et al.: A high panel-reactive antibody rescue protocol for cross-match-positive live donor kidney transplants. Transplantation 2000, 70:1531-1536. Another study that showed successful desensitization and subsequent transplantation in patients with pre-transplant low-titer positive cross-matches, using plasmapheresis and IVIg in conjunction with a TAC−MMF protocol. 38. Glotz D, Hayman J, Naiudet P, Lang P, Druet P, Bairety J: Successful kidney transplantation of immunized patients after desensitization with normal human polyclonal immunoglobulins. Transplant Proc 1995, 27:1038-1039. 39. Tyan D, Li VA, Czer L, Trento A, Jordan SC: Intravenous immunoglobulin suppression of HLA antibody in highly sensitized transplant candidates and transplantation with a histoincompatible organ. Transplantation 1994, 57:553-562. 40. Jordan SC, Quartel AW, Czer LS, Adman D, Chen G, Fishbein MC, Schwieger J, Steiner RW, Davis C, Tyan DB: Posttransplant therapy using high-dose human immunoglobulin (intravenous gammaglobulin) to control acute humoral rejection in renal and cardiac allograft recipients and potential mechanism of action. Transplantation 1998, 66:800-805. 41. Beniaminovitz A, Itescu S, Lietz K, Donovan M, Burke EM, Groff BD, Edwards N, Mancini DM: Prevention of rejection in cardiac transplantation by blockade of the interleukin-2 receptor with a monoclonal antibody. New Engl J Med 2000, 342:613-619. 42. Sunders RN, Matcalfe MS, Nicholsan ML: Rapamycin in transplantation: a review of the evidence. Kidney Int 2001, 59:3-16. 43. McDonald AS, McAlister VC: Sirolimus-tacrolimus combination. Graft 2000, 3:245-247. 44. Kawai T, Sachs DH, Cosimi AB: Tolerance to vascularized organ • allografts in large-animal models. Curr Opin Immunol 1999, 11:516-520. A comprehensive review of protocols for tolerance induction in largeanimal models. 45. Wekerle T, Sykes M: Mixed chimerism as an approach for the • induction of transplantation tolerance. Annu Rev Med 2001, 52:353-370. An excellent review of the mixed-chimerism strategy to induce tolerance in the field of transplantation. 46. Spitzer TR, Delmonico F, Tolkoff-Rubin N, McAfee S, Sackstein R, •• Saidman S, Colby C, Sykes M, Sachs DH, Cosimi AB: Combined histocompatibility leukocyte antigen-matched donor bone marrow and renal transplantation for multiple myeloma with end stage renal disease: the induction of allograft tolerance through mixed lymphohematopeietic chimerism. Transplantation 1999, 68:480-484. This is the first report of the deliberate induction of allograft tolerance using the mixed-chimerism approach in humans. 47.
Colson YL, Schuchert MJ, Ildstad ST: The abrogation of allosensitization following the induction of mixed allogeneic chimerism. J Immunol 2000, 165:637-644.
Managing the highly sensitized transplant recipient and B cell tolerance Seema Baid, Susan L Saidman, Nina Tolkoff-Rubin, Winfred W Williams, Francis L Delmonico, A Benedict Cosimi and Manuel Pascual The detection of anti-donor-HLA antibodies in a renal allograft recipient’s serum, either at the time of or after transplantation, is usually associated with specific antibody-mediated clinical syndromes. These can be divided temporally into three categories: hyperacute rejection, acute humoral rejection and chronic humoral rejection. With the identification of new immunosuppressive drug combinations, more-effective control of alloantibody production has been recently achieved in humans. Thus, prevention and/or treatment of antibodymediated allograft injury are now possible. Ultimately, the induction of mixed hematopoietic chimerism may allow us to overcome the problem of allosensitization and accept an allograft without chronic immunosuppression. Addresses Renal and Transplantation Units, and Histocompatibility Laboratory, Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street, Boston, MA 02114, USA Correspondence: Manuel Pascual Current Opinion in Immunology 2001, 13:577–581 0952-7915/01/$ — see front matter © 2001 Elsevier Science Ltd. All rights reserved. Abbreviations CAN chronic allograft nephropathy CR chronic rejection HAR hyperacute rejection IVIg intravenous polyclonal immunoglobulin MMF mycophenolate mofetil PRA panel-reactive antibody TAC tacrolimus
Introduction In organ transplantation, the term ‘highly sensitized’ (or ‘hyperimmunized’) refers to individuals who have detectable circulating antibodies against HLA antigens (anti-HLA alloantibodies). These alloantibodies have generally been induced by previous transplantation, pregnancies or multiple blood transfusions [1]. The enhanced B cell alloresponses in potential allograft recipients can be assessed by various techniques. Testing for anti-HLA antibodies before and after transplantation is important, as their presence increases the likelihood and severity of rejection episodes and is a significant risk factor for allograft loss [2]. Anti-HLA antibodies have been reported to play an important pathogenic role in most solid organ transplants, including heart, lung, liver and pancreas [3–5]. However, because the vast majority of the literature published for more than thirty years regarding highly sensitized patients has originated from the field of renal transplantation, the focus of this review will be on the impact of anti-HLA antibodies on the renal transplant recipient.
Specific humoral syndromes in renal transplantation The level of ‘sensitization’ in a kidney transplant recipient can be monitored pre- and/or post-transplant by PRA (panel-reactive antibody) testing. Here, the patient’s serum is tested against a panel of cells or purified HLA molecules that includes a wide range of HLA antigens representing most antigens encountered in the general population [6,7]. The percentage of the panel that is killed (by cytotoxicity) or that binds antibody provides an estimate of the patient’s sensitization. Highly sensitized patients (e.g. with PRAs of 80–100%) frequently wait for many years before a suitable organ-transplant donor can be identified, as the recipients have preformed donor-specific antibodies against most available donors. The presence of donor-specific antibodies in the potential recipient’s serum has, until recently, precluded transplantation because, in that setting, a high risk of hyperacute rejection exists (see below). Post-transplant, most acuterejection episodes are due to cellular mechanisms of tissue injury (acute cellular rejection). The de novo demonstration of previously undetectable donor-specific antibodies after transplantation is associated with specific ‘humoral syndromes’ that are due, at least in part, to antibody-mediated mechanisms of tissue injury [8]. Hyperacute rejection
The rejection of an allograft within the first 24 hours following transplantation has been termed ‘hyperacute rejection (HAR)’ to emphasize the rapidity of the rejection process. HAR is generally considered to be mediated purely by humoral mechanisms. That is, the binding of donor-specific antibodies to the graft vasculature triggers complement activation by the classical pathway and results in severe tissue injury. The detrimental effect of preformed donor-specific antibodies first became apparent in the 1960s, as pre-existing donor-specific antibodies (i.e. a ‘positive cross-match’ at the time of renal transplantation) almost inevitably led to HAR of grafted kidneys [9,10]. Histopathologic examination of the failed allografts revealed interstitial hemorrhage, neutrophils and fibrin thrombi in capillaries. It became clear then that either preformed alloantibodies to HLA antigens or isohemagglutinins directed against incompatible major blood group antigens could result in HAR [9–12]. This experience stimulated the requirement for demonstration of a pre-transplant ‘negative’ cross-match (i.e. no alloantibodies) and ABO compatibility (i.e. no natural antiABO antibodies) in kidney transplantation [11,12]. Therefore, antibody-mediated HAR has become a very rare event. Of note, rarely, HAR can occur in the absence of detectable donorspecific antibodies, due to cellular immunity [13].
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Acute humoral rejection
In 1970, Jeannet et al. [14] reported that kidney transplant recipients who developed de novo donor-specific antibodies in the early post-transplant period also suffered severe allograft rejection leading to graft loss in most cases. These initial observations suggested that, in addition to evoked post-transplant cellular immune responses, de novo production of donor-specific antibodies could lead to severe graft injury, a condition that has come to be termed ‘acute humoral rejection’ [15]. In the early 1990s, Halloran et al. [16,17] proposed that acute rejection associated with the development of de novo donor-specific antibodies in recipient’s serum is a clinico-pathologic entity carrying a poor prognosis. Typical histopathologic features of acute humoral rejection include neutrophils in the peritubular capillaries, glomerulitis, fibrin thrombi, vasculitis and, sometimes, fribrinoid necrosis of vessel walls [15,18,19]. These findings are distinct from those of ‘classic’ cellmediated acute rejection, which is characterized predominantly by a mononuclear cellular infiltrate with tubulitis and/or endothelialitis [18]. In 1999, Collins et al. [20••] demonstrated that staining of peritubular capillaries in allograft biopsies for the complement fraction C4d, a split product of C4 in the classical pathway of complement, is a specific and reliable method for diagnosing acute humoral rejection. This observation provided further evidence for the pathogenic role of alloantibodies. Clinically, acute humoral rejection typically presents as early and severe allograft dysfunction that is resistant to steroid and antilymphocyte therapy [8,15]. The risk of allograft failure is approximately 50–80% [19,20••,21,22]. We have recently reviewed our four-year experience (1995–1999), during which an incidence of acute humoral rejection after renal transplantation of 7.7% was observed [23••]. Approximately half of the patients with acute humoral rejection had severe refractory rejection — a rejection episode resistant to both steroid and antilymphocyte therapy. New approaches to treat these patients are described below. A broader range of PRA specificities and a history of a previous failed allograft were found to be significant predictive factors for acute humoral rejection, suggesting that a specific anamnestic humoral response against donor antigens may play a role in the pathogenesis of this type of rejection [23••]. Alternatively, it may also indicate that an overall state of enhanced humoral alloreactivity in some individuals may facilitate an anti-donor-specific humoral response. It should be emphasized that, not uncommonly, histopathologic findings of acute cellular rejection are present in allograft biopsies with acute humoral rejection. The identification of C4d deposits in peritubular capillaries may be the only pathologic feature pointing toward the humoral component of the rejection process. Chronic humoral rejection
Both cellular and humoral immune mechanisms play key roles in the pathogenesis of chronic rejection (CR), a condition also
termed ‘chronic allograft nephropathy’ (CAN) [24]. The presence of serum alloantibodies to donor HLA class I or class II antigens has been associated with chronic rejection of various transplanted organs [25•,26,27•]. In renal recipients, posttransplant production of alloantibodies to HLA class II appears to be associated with CR/CAN, probably manifesting alloresponsiveness via the indirect pathway of allograft recognition [27•,28,29•]. Post-transplant production of alloantibodies often predates the clinical manifestations of CR/CAN, further implicating humoral mechanisms as a cause of CR/CAN [30]. Recent studies indicate that complement C4d deposits in peritubular capillaries are found not only in patients with acute humoral rejection but also in a subset of patients with CR/CAN [25•]. In this study, it was found that 61% of the patients with the typical histologic features of CR/CAN (i.e. transplant arteriopathy and/or chronic transplant glomerulopathy) had C4d deposits in peritubular capillaries. In most cases, this was accompanied by detectable donor-specific antibodies in the patient’s serum [25•]. To determine the relative contribution of humoral mechanisms of rejection to late allograft failure, we further studied the prevalence of chronic humoral rejection in patients with chronic renal allograft dysfunction of all causes. C4d deposits in peritubular capillaries were found in 13% of renal recipients who received an allograft biopsy for chronic allograft dysfunction [31]. In contrast with acute humoral rejection, it does not appear that pre-transplant sensitization is a risk factor for the development of chronic humoral rejection.
Therapeutic approaches to control humoral responses For almost two decades, induction immunosuppression in most centers has included cyclosporine and steroids, with or without azathioprine, for uncomplicated transplant procedures. Removal of alloantibodies immediately before renal transplantation, either by plasmapheresis or immunoadsorption, was attempted in a small number of highly sensitized recipients in order to allow transplantation without HAR [32,33]. In general, such efforts were combined with the administration of monoclonal (OKT3) or polyclonal antilymphocyte therapy, and with cyclophosphamide. Despite some isolated successful cases, the unreliable efficacy of such approaches became apparent as most of these allografts continued to fail due to HAR or acute humoral rejection. With the more recent advent of new immunosuppressive agents, namely tacrolimus (TAC), mycophenolate mofetil (MMF), sirolimus and the anti-IL2-receptor monoclonal antibodies [34•], there has been renewed optimism that more-effective control of antidonor humoral responses might now be feasible. In particular, MMF has been shown to inhibit in vitro antibody production by B cells and to reduce in vivo humoral responses in renal transplant recipients [8]. TAC is a powerful inhibitor of T cell function, which could reduce the T helper cell function required by plasma cells for optimal production of alloantibodies, at least in the initial stages [34•].
Managing highly sensitized transplant recipients Baid et al.
Recent studies using protocols that combine tacrolimus and mycophenolate mofetil Since 1995, we have evaluated a new therapeutic approach consisting of plasmapheresis combined with tacrolimus and mycophenolate rescue (PPh−TAC−MMF rescue) for renal recipients suffering from acute humoral rejection resistant to both steroid and antilymphocyte therapy [15,23••]. During a four-year period, 232 renal transplants were performed under cyclosporine-based immunosuppression. In 10 out of 232 (4.4%) consecutively studied patients with ‘refractory’ acute humoral rejection, the protocol of PPh−TAC−MMF rescue was initiated. Daily plasmapheresis (five sessions) followed by additional alternate-day plasmapheresis if necessary (when renal function did not improve) were combined with TAC and MMF. Significantly decreased circulating donorspecific antibody levels were observed over a period of 3−6 weeks with reversal of rejection in 9/10 patients. At the end of the plasmapheresis course of therapy, intravenous polyclonal immunoglobulin (IVIg) was administered. With a mean follow-up of 40 months, patient and graft survival are currently 100% and 80%, respectively, with persistently undetectable levels of donor-specific antibodies in all patients with functioning allografts [35]. These observations on the control of humoral responses in patients with refractory acute humoral rejection have been recently extended to the treatment of chronic humoral rejection, that is CR/CAN associated with donor-specific antibodies and C4d deposits in peritubular capillaries. In these recipients, we found that rescue therapy with TAC–MMF alone (i.e. without plasmapheresis or IVIg) resulted in a sustained decrease in donor-specific antibody titers and stabilization of renal allograft function. Donor-specific antibodies became undetectable after 6−9 months of therapy, and repeat biopsies performed at 12 months in two patients revealed a decrease or absence of C4d deposits in peritubular capillaries [27•]. These preliminary findings confirm that suppression of alloantibody production is possible with combination therapy such as TAC−MMF. This observation is relevant for the treatment of patients with CR/CAN, but may be even more important in developing strategies to prevent this condition. Similar therapeutic strategies may also be useful for allowing kidney transplantation in patients with high PRA levels or pre-transplant donor-specific antibodies. We recently evaluated low-dose pre-transplant TAC−MMF therapy in a highly sensitized patient (awaiting a second renal transplant), who had a positive T cell cross-match (titer 1:4) against her potential living unrelated donor. After six months of therapy, control of antidonor antibody production was achieved, allowing successful transplantation when the T cell cross-match became negative. Rabbit antithymocyte globulin was added to this patient’s peritransplant TAC, MMF and steroid induction therapy regimen. The patient has had no rejection episodes and has excellent allograft function 20 months after transplantation (M Pascual, unpublished data).
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A more rapid ‘desensitization’ protocol was evaluated by Montgomery et al. [36•]. Successful desensitization was achieved in four highly sensitized patients who had positive cross-matches against their potential living donors. Their protocol consisted of plasmapheresis and IVIg with concomitant administration of TAC−MMF−prednisone, initiated several days or weeks prior to transplantation. All four patients developed acute humoral rejection in the first month post-transplant, but this was reversed with additional plasmapheresis and IVIg. In another similar study, 11 out of 15 patients with a pretransplant positive cross-match against their living donors were successfully desensitized [37•]. Pre-transplant, the patients received plasmapheresis three times weekly over two consecutive weeks, in combination with IVIg and TAC−MMF−prednisone. All 11 patients underwent successful living-donor transplantation with OKT3 induction and continuation of TAC−MMF. In this study, relatively low initial donor-specific antibody titers (lower than 1:4) were predictive of attainment of a negative cross-match. The potential efficacy of high-dose IVIg alone for suppression of HLA-specific antibodies and desensitizing patients awaiting transplantation had been proposed earlier [38,39]. IVIg has well-known but poorly understood immunomodulatory properties and has also been shown to be beneficial in the treatment of acute humoral rejection in renal and cardiac allograft recipients [40]. Thus, further studies incorporating IVIg to both desensitization and therapeutic protocols, especially in combination with PPh–TAC–MMF, are warranted to determine its effect on donor-specific antibody synthesis. In ongoing studies, it is likely that the effects of other new immunosuppressive drugs on in vivo alloantibody synthesis will be further clarified. As an example, blockade of the IL-2receptor with daclizumab has been shown to reduce the formation of anti-HLA antibodies and the frequency of acute rejection in cardiac transplant patients [41]. Sirolimus has been shown to decrease acute rejection after renal transplantation and it also suppresses immunoglobulin synthesis in vitro [42]. Thus it might be speculated that combining TAC with sirolimus may offer a potentially effective alternative to the TAC−MMF regimen for controlling humoral responses [43]. Finally, the role of complement inhibitors also remains to be defined. Indeed, specific inhibition of the complement system could allow treatment of the deleterious consequences of donor-specific antibodies without the need for antibody removal [8].
B cell tolerance Elucidating the mechanisms leading to selective long-term suppression of donor-specific antibody production with the newer immunosuppressants may give important insights in the processes associated with tolerance to allografts. In our series, the combination of TAC and MMF was found to be highly effective in suppressing long-term donor-specific antibody production, whereas only a nonspecific and modest decrease in total immunoglobulin synthesis was observed
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[27•,35]. In addition, Montgomery et al. [36•] found that selective long-term inhibition of donor-specific antibody production was maintained despite the re-emergence of thirdparty alloantibody. Taken together, these observations suggest that an active process associated with the continuing presence of donor antigens (i.e. the kidney allograft) may be necessary to limit donor-specific antibody production in allograft recipients receiving TAC−MMF. Whether this reflects a state of B cell tolerance of selected specificities remains to be studied. Since the early 1950s, the induction of donor-specific immunologic tolerance has remained the ‘Holy Grail’ of clinical transplantation. At our Institution, the induction of ‘mixed hematopoietic chimerism’ has been used as an effective strategy to induce tolerance to kidney allografts in nonhuman primates [44•,45•]. In this approach, a nonmyeloablative conditioning regimen provides transient T cell depletion, which allows donor bone marrow engraftment and the induction of both T cell and B cell tolerance [45•]. In other approaches to tolerance induction currently being investigated in nonhuman primates (costimulatory blockade or severe T cell depletion by anti-CD3 immunotoxin), it was observed that some recipients may still develop chronic rejection associated with antidonor alloantibodies [44•]. Similarly, when recipient splenectomy was not performed in the mixed-chimerism approach, late production of antidonor alloantibodies has occurred [44•]. These observations emphasize that, to induce robust and stable long-term tolerance, both T and B cell tolerance need to be considered. The extension of the mixed-chimerism regimen to induce tolerance in humans was first reported in 1999 [46••]. Interestingly, induction of mixed allogeneic chimerism has been demonstrated to confer donor-specific tolerance both in previously nonsensitized recipients and in the setting of existing allosensitization [47]. In an experimental mouse model, acceptance of skin grafts and loss of circulating donor-specific antibodies suggested that allosensitization can be suppressed with the induction of stable mixed chimerism. Similarly, in xenotransplantation models, the ‘mixed chimerism’ approach has been used to induce B cell tolerance — to suppress natural anti-Gal antibody production [45•]. These recent data suggest that, when more clinically applicable strategies to induce allograft tolerance will become available, the problems associated with recipient’s allosensitization may be overcome.
Conclusions The role of humoral immunity in the pathogenesis of allograft rejection is progressively being clarified. Although the detrimental role of donor-specific antibodies in clinical transplantation was reported more than 30 years ago, it is only recently that effective control of antidonor antibody production has been demonstrated using new immunosuppresive drug combinations. This may have important implications for the management of highly sensitized recipients and to improve long-term results in solid organ transplantation.
The induction of mixed hematopoietic chimerism in transplant recipients has the potential to induce both T cell and B cell tolerance. In the future, strategies aiming at achieving mixed chimerism in the clinical setting may allow us to overcome the problem of allosensitization.
Acknowledgements This work was supported by grants from the Helen and George Burr Endowed Research and Educational Fund in Support of Transplantation (MP) and by the Yates Fund for Transplant Technology (MP). SB was supported by a Fellowship Training Award from the International Society of Nephrology (Cairo, Egypt). We are indebted to many staff members of the Massachusetts General Hospital Transplantation Unit, and of the Department of Pathology (RB Colvin) who contributed to the studies mentioned in this article.
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Theruvath TP, Saidman SL, Mauiyyedi S, Delmonico FL, Williams WW, Tolkoff-Rubin N, Collins AB, Colvin RB, Cosimi AB, Pascual M: Control of antidonor antibody production with tacrolimus and mycophenolate mofetil in renal allograft recipients with chronic rejection. Transplantation 2001, in press. In this preliminary study, it was demonstrated that control of donor-specific antibody production with TAC−MMF combination alone (with no plasmapheresis or IVIg) is possible in patients with chronic humoral rejection. This may have implications for the treatment or prevention of CR. 28. Abe M, Kawai T, Futatsuyama K, Tanabe K, Fuchinoue S, Teraoka S, Toma H, Ota K: Postoperative production of anti-donor antibody and chronic rejection in renal transplantation. Transplantation 1997, 63:1616-1619. 29. Sayegh MH: Why do we reject a graft? Role of indirect • allo-recognition in graft rejection. Kidney Int 1999, 56:1967-1979. An excellent review on the immunologic mechanisms of CR. 30. Davenport A, Younie ME, Parsons JE, Klouda PT: Development of cytotoxic antibodies following renal allograft transplantation is associated with reduced graft survival due to chronic vascular rejection. Nephrol Dial Transplant 1994, 9:1315-1319. 31. Theruvath TP, Saidman S, Mauiyyedi M, Rubin N, Williams WW, Collins B, Colvin RB, Delmonico F, Cosimi AB, Pascual M: Prevalence of chronic humoral rejection in chronic renal allograft dysfunction [abstract 896]. Am J Transplant 2001, 1(suppl 1):360. 32. Malik ST, Churcher P, Sweny P, Varghese Z, Fernando ON, Moorehead JF: Renal transplantation after removal of anti-HLA antibodies. Lancet 1984, 8387:1185.
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Schweitzer EJ, Wilson JS, Fernandez-Vina M, Fox M, Gutierrez M, Wiland A, Hunter J, Farney A, Philosophe B, Colonna J et al.: A high panel-reactive antibody rescue protocol for cross-match-positive live donor kidney transplants. Transplantation 2000, 70:1531-1536. Another study that showed successful desensitization and subsequent transplantation in patients with pre-transplant low-titer positive cross-matches, using plasmapheresis and IVIg in conjunction with a TAC−MMF protocol. 38. Glotz D, Hayman J, Naiudet P, Lang P, Druet P, Bairety J: Successful kidney transplantation of immunized patients after desensitization with normal human polyclonal immunoglobulins. Transplant Proc 1995, 27:1038-1039. 39. Tyan D, Li VA, Czer L, Trento A, Jordan SC: Intravenous immunoglobulin suppression of HLA antibody in highly sensitized transplant candidates and transplantation with a histoincompatible organ. Transplantation 1994, 57:553-562. 40. Jordan SC, Quartel AW, Czer LS, Adman D, Chen G, Fishbein MC, Schwieger J, Steiner RW, Davis C, Tyan DB: Posttransplant therapy using high-dose human immunoglobulin (intravenous gammaglobulin) to control acute humoral rejection in renal and cardiac allograft recipients and potential mechanism of action. Transplantation 1998, 66:800-805. 41. Beniaminovitz A, Itescu S, Lietz K, Donovan M, Burke EM, Groff BD, Edwards N, Mancini DM: Prevention of rejection in cardiac transplantation by blockade of the interleukin-2 receptor with a monoclonal antibody. New Engl J Med 2000, 342:613-619. 42. Sunders RN, Matcalfe MS, Nicholsan ML: Rapamycin in transplantation: a review of the evidence. Kidney Int 2001, 59:3-16. 43. McDonald AS, McAlister VC: Sirolimus-tacrolimus combination. Graft 2000, 3:245-247. 44. Kawai T, Sachs DH, Cosimi AB: Tolerance to vascularized organ • allografts in large-animal models. Curr Opin Immunol 1999, 11:516-520. A comprehensive review of protocols for tolerance induction in largeanimal models. 45. Wekerle T, Sykes M: Mixed chimerism as an approach for the • induction of transplantation tolerance. Annu Rev Med 2001, 52:353-370. An excellent review of the mixed-chimerism strategy to induce tolerance in the field of transplantation. 46. Spitzer TR, Delmonico F, Tolkoff-Rubin N, McAfee S, Sackstein R, •• Saidman S, Colby C, Sykes M, Sachs DH, Cosimi AB: Combined histocompatibility leukocyte antigen-matched donor bone marrow and renal transplantation for multiple myeloma with end stage renal disease: the induction of allograft tolerance through mixed lymphohematopeietic chimerism. Transplantation 1999, 68:480-484. This is the first report of the deliberate induction of allograft tolerance using the mixed-chimerism approach in humans. 47.
Colson YL, Schuchert MJ, Ildstad ST: The abrogation of allosensitization following the induction of mixed allogeneic chimerism. J Immunol 2000, 165:637-644.