Humoral Theory of Transplantation: Mechanism, Prevention, and Treatment

Humoral Theory of Transplantation: Mechanism, Prevention, and Treatment Junchao Cai and Paul I. Terasaki ABSTRACT: We discuss the potential mechanisms of antibody-induced primary endothelium injury, which includes complement-dependent pathway (membrane attack complex formation, recruitment of inflammatory cells, and complement-complement receptor-mediated phagocytosis) and complement independent pathway antibody-dependent cell cytotoxicity. Secondary to endothelium injury, the following pathological reactions are found to be responsible for progressive tissue injury and final graft function loss: platelet activation and thrombosis, pathological smooth muscle and endothelial cell proliferation, and humoral and/or cellular infiltrate-mediated parenchyma damage after endothelium injury. We also introduce three categories of therapeutic strategy in the prevention and treatment of antibodymediated rejection: (1) inhibition and depletion of antibody producing cells (immunosuppressants, antilymphocyte antibodies, splenectomy); (2) removal or blockage of preexistABBREVIATIONS HLA human leukocyte antigen MIC major histocompatibility complex class I–related chain

ing or newly developed antibodies (immunoadsorption, plasmapheresis/plasma exchange, intravenous immunoglobulin); and (3) impediment or postponement of antibodymediated primary and secondary tissue injury (anticoagulation, glucosteroids). In conclusion, because alloantibodies have destructive effect on allografts, alloantibody monitoring becomes extremely important. It will help clinicians to determine a patient’s humoral responses against allograft and will therefore direct clinicians to optimize and/or minimize immunosuppressive drug therapy. Human Immunology 66, 334 –342 (2005). © American Society for Histocompatibility and Immunogenetics, 2005. Published by Elsevier Inc. KEYWORDS: HLA antibody; antibody monitoring; allograft; antibody-mediated rejection; chronic rejection

PE plasma exchange PPH plasmapheresis

INTRODUCTION We have reviewed accumulated evidence regarding the role of antibody in graft injury [1]. Antibodies are associated with hyperacute, acute, and chronic rejection [2]. In a prospective trial, it has already been found that by using antibody screening tests with flow cytometry or enzyme-linked immunosorbent assay, about 14%–23% of transplant recipients with functioning grafts have detectable human leukocyte antigen (HLA) antibodies [3]. Within a 1-year follow-up period, 21 (8.6%) of 244 antibody-positive patients experienced graft rejection, which is significantly higher than that found in the HLA antibody–negative patient group (43/1421 ⫻ 100% ⫽ 3%, p ⫽ 0.00003). These data suggest that some transplants may still function well in the presence of alloantibodies, which might be because

of the compensational reactions of the transplanted organ to tissue injury. However, the graft may finally be rejected when the tissue repair system can not fully compensate for the antibody-mediated injury. This damage-repair-damage process could take years to result in irreversible graft loss. This hypothesis has been supported by the study of Lee et al., who found that in some patients, it took many years for antibody-positive transplants to finally be rejected [4]. Why are some transplants rejected sooner and other transplants rejected later, after the presence of alloantibodies is found in the periphery blood? In this review, we discuss how antibody causes graft rejection after it binds to its target and how to prevent and treat antibodymediated rejection.

From the Terasaki Foundation Laboratory, Los Angeles, CA, USA. Address reprint requests to: Dr. Paul I. Terasaki, Terasaki Foundation Laboratory, 11570 W Olympic Blvd., Los Angeles, CA 90064; Tel: (310) 479-6101 ext 104; Fax: (310) 445-3381; E-mail: terasaki@ terasakilab.org. Received October 19, 2004; accepted January 19, 2005.

MECHANISM OF HUMORAL REJECTION Endothelial Cell—The Primary Target of Antibody Among cellular and humoral immunologists, there is limited debate that the endothelium of transplanted

Human Immunology 66, 334 –342 (2005) © American Society for Histocompatibility and Immunogenetics, 2005 Published by Elsevier Inc.

0198-8859/05/$–see front matter doi:10.1016/j.humimm.2005.01.021

Humoral Theory of Transplantation

organs serve as the primary target of patient immune responses. In the humoral theory of organ transplantation, the endothelium of a donor organ is primarily targeted by alloantibody, either preexisting or developed de novo after transplant [5–15]. Primary Effects of Antibody-Antigen Interaction As proposed here and shown in Figure 1.1– 4, binding of antibodies to antigens on endothelial cells can finally cause endothelium damage via four distinct pathways. Damage of endothelium can be mediated directly by complement via forming membrane attack complex [16] (Figure 1.2) or inflammatory cells recruited by soluble complement fragments [17, 18] (Figure 1.1), or by phagocytes that recognize complement fragments deposited on endothelial cells via a complement receptor [19] (Figure 1.3). These three pathways are complement dependent. The finding of complement C4d in graft capillaries provided strong evidence to support this complement-dependent hypothesis [20]. However, it is also possible that after antibody binds to its target antigen on the surface of the endothelial cell, antibody-dependent cell cytotoxicity may play a role in mediating endothelium damage without the involvement of complement [21–24] (Figure 1.4). Secondary Effects After Endothelium Injury Secondary pathological changes after endothelium damage include platelet activation and thrombosis, endothelial and smooth muscle cell proliferation, and humoral and/or cellular infiltrates mediated direct organ/tissue damage (Figure 1A–D). Hyperacute rejection, the best documented example of antibody-mediated rejection, is mediated by preexisting antibodies (e.g., anti– blood group antigen A or B antibodies, or anti-HLA antibodies) that bind to endo-

FIGURE 1 Mechanisms of antibody-mediated transplant rejection.

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thelium and activate complement. Antibody binding and complement activation induce a series of pathological changes in the graft endothelium that promote intravascular thrombosis. Endothelial cells are stimulated to secrete von Willebrand factor that mediates platelet adhesion and aggregation. Complement activation leads to endothelial cell injury and exposure of subendothelial basement membrane proteins that activate platelets. These series processes contribute to thrombosis and vascular occlusion; therefore, the organ suffers irreversible ischemic damage (Figure 1A). We know that the rapid progress of antibody-mediated hyperacute rejection is related to a large amount of preexisting alloantibodies and it usually happens in ABO-incompatible or presensitized patients. However, in current transplant clinics, transplantation is performed primarily in ABO-compatible, low-sensitized patients; moreover, highly effective immunosuppressive drug therapies are widely used in transplant recipients. Therefore, unlike hyperacute rejection, acute or chronic graft function loss might not result mainly from thrombosis-related rapid vascular occlusion. Instead, they are most likely due to a progressive damage-repair-damage pathological process. As found in chronic rejection, which is manifested as atherosclerosis of the vessels of the transplanted organ, the intimal thickening is the result of the proliferative effects of anti-HLA antibodies (Figure 1B,C) [25]. It is also a possibility that after endothelium injury, humoral and/or cellular infiltrates can directly cause organ parenchyma damage (Figure 1D). This direct parenchyma injury also follows the law of “quantitative change to qualitative change.” The process speed of any potential pathological changes after endothelium injury depends on the following three major factors: the level of alloantibodies; the capability of transplanted organ tissue repair; and immunosuppressive and other supportive therapy. The first factor is the level of alloantibodies. In ABOcompatible transplantation, there was considerable variation in antibody titers against blood group antigens [26]. Recipients with higher antibody titers against blood group antigens had a much higher incidence of early graft failure [27, 28]. In ABO-compatible transplantation, there was a significant stepwise decrease in graft outcome with increasing levels of sensitization. Patients with less than 10% panel-reactive antibodies had a significantly longer half-life than patients with higher levels of sensitization [29]. These data suggested that graft outcome is strongly associated with the alloantibody level. High levels of antibodies result in more irreversible rejection. These data also implied that in lower sensitized patients, because of the lower levels of preexisting antibodies, the rejection process is slower, but the transplanted graft may finally be rejected when

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J. Cai and P.I. Terasaki

TABLE 1 Prevention and treatment of antibody-mediated rejection No.

Categorya

1

I

Cyclosporin A

2

I

Tacrolimus (FK506)

3

I

Rapamycin (sirolimus)

4 5 6 7 8

I I I I I

Azathioprine Cyclophosphamide Mycophenolate mofetil (MMF) Rituximab OKT3

9

I

10

I

Anti-thymocyte globulin (ATG) and antilymphocyte globulin (ALG) Campath-1H

11 12

I II

Splenectomy Immunoadsorption

13

II

Plasmapheresis (PPH) or plasma exchange (PE)

14

II

Intravenous immunoglobulin (IVIG)

15 16

III III and I

Treatment

Anticoagulation therapy Glucocorticoid

Major mechanism Indirectly inhibit B cell proliferation secondary to reduced cytokine production by T cells Indirectly inhibit B cell proliferation secondary to reduced cytokine production by T cells Indirectly inhibit B cell proliferation secondary to reduced cytokine production by T cells Inhibit DNA synthesis in dividing cells (T,B and other dividing cells) Inhibit DNA synthesis in dividing cells (T,B and other dividing cells) Inhibit DNA synthesis in dividing cells (mainly T and B cells) Anti–CD-20 (B cell surface marker) mAb, deplete B cells Anti-CD3 (T-cell surface marker) antibody, indirectly inhibit B-cell proliferation Directly deplete or indirectly inhibit B cells Anti-CD52 (surface marker of thymocytes, T, B cells, etc.), direct deplete B cells Surgically remove lymphocyte-producing organ (both B and T) Remove antibody from periphery (blood group antigen-, protein A- or anti-human Ig antibody-coated columns) Remove antibodies and other humoral factors (complements, cytokines, etc.) from periphery Anti-idiotypic effects (blocking of the antigen-binding cites of antidonor antibodies) and others Inhibit the formation of clot (Figure 1A) Anti-inflammatory effects (Figure 1.1 and D), B-cell apoptosis

I ⫽ inhibition and depletion of antibody-producing cells; II ⫽ removal or blocking of preexisting or newly developed antibodies; III ⫽ impediment or postponement of antibody-mediated primary and secondary tissue injury.

a

a majority of parenchyma are affected and cannot be compensated by tissue repair. The second factor is the capability of transplanted organ tissue repair. This is the major mechanism to impede or postpone the development of rejection; but this regeneration capability is tissue dependent. Some tissue cells have the capacity to regenerate after injury (e.g., endothelial cells, renal tubular cells, hepatocytes), but other cells, such as myocardial cells, cannot regenerate and are usually replaced by scar tissue (typically fibrosis) after irreversible injury and cell loss. Also, there should be an awareness that uncontrolled tissue repair sometimes becomes a risk factor that accelerates the rejection process (Figure 1B,C) [25]. The third factor is immunosuppressive and other supportive therapy. Different immunosuppressants many have different effects on inhibition of antibody development [3]; therefore, they affect graft survival [30, 31]. For example, as previously discussed, the major characteristics of antibody-mediated hyperacute rejection are antibody/complement-mediated endothelium injury and activated plateletmediated thrombosis and vascular occlusion. On the basis of the hypothesis that preventing clot formation may postpone graft rejection, anticoagulation therapy was used in transplant clinics [32–35]. Recently, in combination with other antibody depletion or suppression treatments, anti-

coagulation therapy successfully reduced hyperacute/acute rejection episodes and enabled ABO-incompatible transplantation to become feasible and reach satisfying longterm graft survivals [36]. PREVENTION AND TREATMENT OF HUMORAL REJECTION Therapeutic strategies to prevent and treat antibodymediated rejection include: (1) inhibition and depletion of antibody producing cells; (2) removal or blockage of preexisting or newly developed antibodies; and (3) impediment or postponement of antibody-mediated primary and secondary tissue injury. Inhibition or Depletion of Antibody-Producing Cells This strategy is etiotropic. B cells, or more precisely, plasma cells, are the main antibody-secreting cells of the body. Therefore, to prevent and/or treat antibody-mediated humoral rejection, inhibition or depletion of antibody producing cells becomes extremely important (Table 1.1–11). Primary immunosuppressants. Generally speaking, almost all currently used immunosuppressive drugs have direct

Humoral Theory of Transplantation

or indirect effects in inhibiting/depleting B cells. The most commonly used primary agents of maintenance immunosuppression, such as cyclosporine A, FK506 (tacrolimus), and rapamycin (sirolimus), are powerful immunosuppressants that interfere with T-cell signaling. The successful prolongation of graft survival by using these agents has misled many clinicians and some immunologists into thinking that T cell is the only player that causes graft rejection. However, because many alloantigens eliciting antibody responses are proteins (e.g., HLA, major histocompatibility complex class I–related chain [MIC]) and antibody responses to protein antigens require antigen-specific T-cell help, T-cell targeting agents not only prevent T-cell but also antibody (B cell)-mediated immune responses. This mechanism explains why these primary agents can be used alone or in combination with other therapies to treat antibody-mediated humoral rejection [37–39] (Table 1.1–3). Adjunct immunosuppressants. Unlike primary immunosuppressive agents, which block T-cell signaling and indirectly inhibit proliferation of B cell secondary to reduced cytokine production by T cell, adjunctive immunosuppressants interfere with DNA synthesis and have their major pharmacological action on dividing tissues [40 – 42]. Hence, these agents, including azathioprine, cyclophosphamide, mycophenolate mofetil (MMF), have direct inhibitory effects on B cell, an active dividing tissue cell. It is notable that because of its role in targeting the de novo purine biosynthesis pathway, mycophenolates can inhibit human lymphocytes (B and T cells) more specifically and efficiently than other cell types [40, 43]. Clinical observations demonstrated that immunosuppressive protocols with MMF-inhibited antibody production therefore reduces allograft rejection episodes [3, 44, 45]. UNOS data analysis also indicated its superiority over azathioprine [30, 31] (Table 1.4 – 6). Antilymphocyte antibodies. Antibodies against lymphocyte surface molecules act by removing specific lymphocyte subsets or inhibiting cell function [46 –55]. Among these antilymphocyte monoclonal or polyclonal antibodies listed in Table 1.7–10, rituximab is the only antibody specifically targeting B-cell surface marker CD20. Garrett and colleagues reported the first case of humoral rejection successfully treated with rituximab [46]. Recently, using a single dose of rituximab in addition to other therapies, a Wisconsin group successfully treated 27 patients who were diagnosed with biopsy-confirmed rejection manifested by thrombotic microangiopathy and/or endothelialitis between February 1999 and February 2002. Twenty-four received additional steroids, and 22 of 27 patients were also treated with plasmapheresis (PPH) and antithymocyte globulin. Only three

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patients experienced graft loss not associated with patient death during the follow-up period (605 ⫾ 335.3 days). In the 24 successfully treated patients, serum creatinine at the time of initiating rituximab therapy was 5.6 ⫾ 1.0 mg/dl and was decreased to 0.95 ⫾ 0.7 mg/dl at discharge. Authors predicted that the addition of rituximab may improve outcomes in severe, steroid-resistant or antibody-mediated rejection episodes after kidney transplantation [47] (Table 1.7–10). Splenectomy. The spleen is an organ that produces lymphocytes, filters the blood, stores blood cells, and destroys those that are aging. The rationale to perform splenectomy in transplant recipients is to remove a major source of lymphocytes, including antibody-secreting B cells. The benefits of splenectomy in prolonging graft and patient survival remain controversial. It has been reported that splenectomized patients had reduced incidences and intensity of rejection episodes and better graft and patient survival rates [56]; however, this beneficial effect was short-termed [57]. The long-term benefit from splenectomy was mainly compromised by increased chances of fatal infection and sepsis [56 –58]. Recently, in combination with other treatment, splenectomy seems to play an important role in preventing humoral rejection and prolonging graft survival in ABO-incompatible transplantation [36] (Table 1.11). Removal or Blockage of Preexisting or Newly Developed Antibodies This strategy is also etiotropic. It mainly focuses on reducing existing antibodies or blocking their detrimental effects (Table 1.12–14). Immunoadsorption. This is an in vitro approach that specifically removes immunoglobulins from patient periphery by using blood group antigen A or B, protein A, or antihuman Ig-coated columns. Originally, it was primarily used as a preemptive therapy for ABO-incompatible or presensitized patients [59 – 67]. But successful reversal of antibody-mediated rejection were also reported [68 – 71]. An ABO antigen-coated column was used to specifically remove anti-ABO antibodies [72]; however, HLA antigen column, specialized to remove HLA antibodies, is not yet commercially available (Table 1.12). PPH/plasma exchange (PE). Removal of antibodies and other plasma factors by PPH and PE is an effective antihumoral rejection treatments. They have been used as a preemptive strategy to prevent potential rejection episodes [36, 73–75]. They have also been used to reverse established antibody-mediated rejection [76 – 83]. Unlike immunoadsorption, PPH and PE remove not only antibodies but also many other humoral factors, such as

338

complements and cytokine. Therefore, PPH and PE might theoretically be more efficient in preventing and/or reversing humoral rejection. However, the currently available, uncontrolled studies seemed to end in controversy [84], suggesting that further controlled clinical investigations are imperative (Table 1.13). Intravenous immunoglobulin. Given the fact that intravenous immunoglobulin preparations are isolated from plasma pools of several thousand healthy blood donors, it is assumed that an almost unlimited spectrum of antibody specificities is present therein. It is reported that the mechanism of suppression of panel-reactive antibodies in patients awaiting transplantation appear to be related to antiidiotypic antibodies presented [85]. However, many other potential mechanisms have already been proposed that include inhibition of complement activation [86, 87], blockade and downregulation of Fc receptors [88, 89], and modulation of T- and B-cell activation and differentiation [88]. Detailed discussion of its mechanisms is available in other reviews in this issue (Table 1.14). Impediment or Postponement of Antibody-Mediated Primary and Secondary Tissue Injury Unlike the two strategies discussed above, this strategy is an absolute allopathy. It is used to impede or postpone antibody-caused tissue damages in order to prolong graft survival (Table 1.15 and 1.16). Anticoagulation therapy. As we discussed in the mechanism section, antibody-mediated transplant rejection is characterized by primary endothelium injury, followed by some harmful secondary effects after endothelium damage. Posttransplant thrombosis is a major pathological characteristic of hyperacute or acute rejection (Figure 1A) [90 –96]. Depending on the level of antidonor antibodies, antibody-mediated posttransplant thrombosis may result in vascular narrowing or occlusion. On the basis of the hypothesis that preventing clot formation may postpone graft rejection, anticoagulation therapy was used in transplant clinics [32–35]. Recently, in combination with other antibody depletion or suppression treatment, anticoagulation therapy successfully reduced hyperacute/acute rejection episodes and enabled ABO-incompatible transplantation to become feasible and reach satisfying long-term graft survivals [36] (Table 1.15). Glucocorticoids. Glucocorticoid drugs are by far the most powerful agents used widely in transplantation to inhibit detrimental effects of immune responses induced by graft rejection. Although glucocorticoids can directly induce the apoptosis of B cells [97–99] and inhibit the produc-

J. Cai and P.I. Terasaki

tion of alloantibodies, the major purpose of using glucocorticoid to treat antibody-mediated rejection is its strong antiinflammatory effects. As shown in Figure 1, recruited inflammatory cells can directly cause endothelial cell damage (Figure 1.1). In addition, after endothelium injury, inflammatory cells can infiltrate into parenchyma and therefore affect its physiological function (Figure 1D). The pharmacological effects of corticosteroid drugs on rejection result mainly from inhibition of cytokine production [100, 101]. Because of its strong immunosuppressive and antiinflammatory effects, glucosteroid is currently the first-line therapeutic drug for transplant rejection. It is also a major component of maintenance immunosuppressive regimens. However, steroid therapy has many side effects, including fluid retention, weight gain, diabetes, and bone mineral loss. The benefits of continued rejection therapy with steroids must be balanced against the potential for serious, sometimes fatal, adverse effects (Table 1.16). PREVENTION IS BETTER THAN CURE—IMPORTANCE OF ANTIBODY MONITORING In current transplant clinics, the principal universal method of monitoring is periodical laboratory examination and/or protocol biopsy. However, in light of the recent evidence in renal transplantation that HLA antibodies appear before rise in serum creatinine [3, 4, 102], we can now suggest that testing for HLA antibodies is added to the routine monitoring of patients. At any given time after transplantation, approximately 20% of patients can be expected to have HLA antibodies [3]. Evidence from the prospective study [3] suggests that it is these patients with HLA antibodies who will eventually have grafts that fail as a result of humoral rejection. Ongoing humoral rejection is not apparent by laboratory indexes until the organ parenchyma is injured to some critical level, after which no amount of immunosuppression can reverse the changes. If this concept of antibody caused humoral injury is correct, then antibody testing will be the key to monitoring before irreversible damage has occurred. Various strategies for eliminating antibody have already been used, although in most instances, for acute humoral rejection. Whether PPH is practical—for example, for treatment of chronic rejection—remains to be seen. How effective treatment with monoclonal antibodies, such as rituximab would be, requires testing. A drug treatment regimen that reduces antibodies would be the method of choice. An example is the use of FK and MMF, as described by Theruvath et al. [103]. Drugs specifically aimed at reduction of antibodies will require development. An important consequence of the humoral theory of

Humoral Theory of Transplantation

chronic rejection is that if antibodies are not found, then immunosuppression might be reduced until production of antibodies begins. That is, many patients may be currently overimmunosuppressed, but we have no way of knowing which patients can be safely weaned from their current levels. If we can depend on circulating HLA antibodies to be a good test of responsiveness, decisions on drug levels can be based on it. It should be mentioned, however, that monitoring for HLA antibodies is likely not to be comprehensive because other antibodies, such as the MIC system, may also be involved. Assays for MIC antibodies are just now being developed and becoming widely available. Interestingly, the blood group A and B antigens seem to be different from HLAs because ABO-incompatible patients have slightly, but not significantly, lower long-term graft survival compared with those with ABO-compatible grafts [36].

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10.

11.

12.

13.

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