De novo autoimmunity after organ transplantation: Targets and possible pathways

Human Immunology (2008) 69, 383–388

De novo autoimmunity after organ transplantation: Targets and possible pathways Peter Borosa,*, Jonathan S. Bromberga,b,c a b c

Recanati/Miller Transplantation Institute, Mount Sinai School of Medicine, New York, NY Department of Cell and Gene Medicine, Mount Sinai School of Medicine, New York, NY Center for Immunology, Mount Sinai School of Medicine, New York, NY

Received 17 March 2008; received in revised form 8 May 2008; accepted 14 May 2008

KEYWORDS Organ transplantation; Autoreactivity; Ischemia/reperfusion injury; Chronic rejection; Graft function

Summary The development of autoantibodies to different tissue-specific antigens in patients without existing history of autoimmune diseases suggests that autoimmunity may develop de novo after organ transplantation. In addition to allo-specific immune responses, tissue-specific autoimmunity also appears contribute to the host anti-graft response, and thus may affect long-term graft function. As graft failure caused by chronic rejection is a major challenge in clinical transplantation, understanding de novo autoreactivity after transplantation has important ramifications. This review investigates this emerging concept by discussing target antigens and possible pathways. © 2008 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.

Introduction Autoimmune diseases and organ transplantation have different pathologic characteristics and present different clinical and scientific challenges. The main focus of transplantation biology for decades has been the allospecific immune response. Understanding the cellular and molecular events associated with allograft rejection were of most significance and, along with improved surgical techniques and advanced graft procurement methods, paved the way to the success of clinical organ transplantation. Autoimmunity, on the other hand, has not traditionally been in the forefront of transplant biology. It has been approached as a pre-existing clinical condition: in patients

* Corresponding author. Fax: (212) 426-2233. E-mail address: [email protected] (P. Boros).

with autoimmune diseases. the new organs may be exposed to autoaggressive cells and antibodies as the underlying autoimmune disease persists or recurs. In recent years, a new aspect of autoreactivity after transplantation has been discovered. Post-transplantation de novo autoimmunity is suggested by clinical studies in which patients without previous history of autoimmune disorders display autoantibodies to tissue-specific antigens. These target molecules include cardiac myosin, phospholipids, ribosomal antigens, intercellular adhesion molecule–1, and vimentin. In addition to identifying the possible target molecules, several new immune regulatory pathways were also recognized. In general, de novo post-transplantation autoimmunity may occur in two basic ways. Immediately after transplantation, the host immunologic memory is activated. If the graft autoantigen mimics a previously encountered environmental antigen, the resulting response may be pathogenic.

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P. Boros and J.S. Bromberg

ABBREVIATIONS col(V) col(II) CR GCAD GSTT1 HSA mHAg I/R MMP PBMC ROS

collagen type V collagen type II chronic rejection graft coronary artery disease glutathione-S-transferase T1 human serum albumin minor histocompatibility antigen ischemia/reperfusion matrix metalloproteinases peripheral blood mononuclear cells reactive oxygen species

Later, autoimmunity results from primary activation of naive autoreactive T- and B-cells that have escaped negative selection. This usually depends on concomitant activation of host adaptive alloresponses. It is increasingly recognized that tissue-specific autoimmunity and allo-specific immune response both contribute to the host anti-graft response and, ultimately, to long-term graft function. Because late graft failure caused by chronic rejection (CR) is becoming a major challenge and concern in clinical transplantation, understanding de novo autoreactivity after transplantation is of growing significance. This review investigates this emerging concept by discussing target antigens and possible pathways.

Pathways: Role of autoreactivity in the development of CR and long-term graft function The mechanisms involved are multiple, and several possible pathways have been explored [1,2].

Role of early graft damage The “injury response” has been suggested as the common denominator in many of the factors influencing both shortand long-term graft survival. Both clinical and basic data imply that early injury initiates a “stereotyped” response as part of the innate response, which promotes immune recognition and immune responsiveness [3]. Early graft damage is detected in all transplantation settings. When gene expression after murine heterotopic heart transplantation was compared in recombinase activating gene-deficient (alymphoid) syngeneic and allogeneic recipients, upregulation of multiple pro-inflammatory genes, including chemokines, cytokines, and cytokine receptors, was observed, with no substantial differences in expression profiles among the three groups. Thus early inflammatory changes induced by tissue damage, ischemia, and surgical stress are integral part of all post-transplantation events [4]. Within the early injury response, ischemia/reperfusion (I/R) injury appears to be the foremost contributor. It leads to shedding of self-proteins, activation of autoreactive T cells, and production of antibodies by B cells as a result of local inflammation. In addition, I/R injury results in induc-

tion of intragraft apoptosis [5–7]. Reactive oxygen species (ROS) and apoptosis proteases cause further modification of cellular proteins, changing their processing and presentation and thus creating an altered self-antigen repertoire. It is also evident that the inflammatory environment is associated with increased exposure of neoantigens [8]. The possible role of the altered antigenicity resulting from ROS in the development of autoreactivity has been demonstrated. For example, ROS-modified human serum albumin (HSA) was shown to be highly immunogenic compared with native HSA. Furthermore, induced antibodies against ROS modified HSA resembled the diverse antigen-binding characteristics of naturally occurring systemic lupus erythematosus anti-DNA autoantibodies [9]. Recently, enhanced recognition of ROSdamaged human albumin by circulating autoantibodies has been established, suggesting that this neoantigen may be involved in the generation of autoimmunity [10]. Additional possible pathways related to cellular damage may include autophagy, a physiologic cellular mechanism involved in cellular homeostasis, differentiation, tissue remodeling, and breakdown of tolerance and development of autoimmunity. Autophagy helps to degrade and recycle proteins to maintain an adequate amino acid level during nutritional starvation of the cell [11]. I/R injury–related hypoxia and elevated ROS level has been shown to increase autophagy in the tubular epithelial cells, both in vivo and in murine kidney ischemia models as well as in specimens from transplanted human kidneys. Inhibition of autophagy significantly inhibited ROS-induced cell death [12]. According to recent experimental data, autophagy contributes to autoimmunity by the promotion of MHC class II presentation of cytosolic antigens [13]. The indirect antigen recognition pathway is believed to be predominant in driving CR [14,15]. In human recipients of heart, kidney, and liver allografts, indirect response shows a strong correlation with episodes of clinical rejection. It is also clear that the indirect response to minor polymorphic antigens such as minor histocompatibility antigens (mHAg) can also cause tissue destruction [16,17]. Any protein that is polymorphic can become an mHAg, thus making the number of the possible mHAgs in transplantations performed between genetically unrelated, MHC-matched individuals very large [18]. The importance of the indirect pathway is suggested by studies demonstrating that immunization of animals with peptides of allogeneic MHC (which, by definition, are able to elicit only indirect responses) leads to rejection, whereas intrathymic injection of the same peptides downmodulates the indirect response, resulting in prolonged survival of allografts of the same MHC type [19]. In addition, autoantigens may also be recognized as part of the alloimmune response. Experimental studies have demonstrated that allotransplantation breaks tolerance to self-antigens [20,21]. Injection of recipient mice with allogeneic cells lead to in vivo T-cell response to donor MHC molecules, and resulted in the breakdown of immune tolerance to a recipient self-antigen [22].

Epitope spreading T-cell responses appear initially epitope specific. However determinant spreading is a common feature of a prolonged immune responses, and it may include different regions of

Autoreactivity after organ transplantation donor MHC class II peptides [23,24]. It has been demonstrated that, in primary acute rejection, recipient T-cell responses to donor alloantigens are limited to a single dominant determinant present on one of the disparate alloantigens and are restricted by one of the responder’s HLA-DR molecules. In allograft recipients with recurring episodes of rejection and/or at the onset of chronic rejection, recipient T-cell reactivity may spread to other epitopes within the allogeneic MHC molecule and may target other alloantigens expressed by graft tissue. Both quantitative and qualitative alterations in T-cell allopeptide reactivity are associated with increased risk of cellular and/or humoral rejection [25].

Targets: Tissue-specific antigens in post-transplantation alloreactivity Cardiac myosin Cardiac myosin (CM) is a heart-specific protein that has been identified as target antigen in murine autoimmune myocarditis. Several models of cardiac transplantation in mice and rats suggest that CM is recognized by T cells in the context of self-MHC class II molecules on the recipient antigen-presenting cells. CR models using anti-CD40 ligand antibody revealed a sustained high frequency of in CM-specific autoreactive T cells, without the presence of CD4-mediated direct alloimmunity. Thus CM-specific T cells are able to inflict damage to the graft in the absence of an allo-response [26,27]. The correlation and time distribution of the two types of host anti-graft response were futher explored in an immunosuppression-free murine model of post-transplantation graft coronary artery disease (GCAD), using minor histocompatibility antigen (mHAg)–mismatched animals. Grafts developed GCAD and survived for more than 100 days. In this model, in vitro tests suggested that basal donor mHC presentation is not sufficient to induce alloresponse. However inflammatory conditions associated with the transplantation procedure may upregulate mHC expression to a level required to trigger an alloresponse. Accordingly, at an early time point (8 days) post-transplantation, a limited anti-mHAg alloresponse was detected. Host autoimmunity against CM was indicated by early production of anti-myosin IgG1 autoantibodies, in the absence of activated CM-specific T lymphocytes. After 50 days, GCAD indices were significantly increased, accompanied by elevated numbers of mHC- and CM-reactive T cells, as well as high levels of circulating allo- and CM-specific antibodies. The allo-response was absent after 100 days [28]. The dynamics of the allo- and autoimmune response indicate that the various stages of GCAD have different underlying mechanisms. The initiation of the process is dependent on indirectly primed allospecific T cells that are required for the development of GCAD. Advanced stages, on the other hand, are alloantigen independent and self-propagating, and autoimmune responses against graft tissue antigens may drive the ongoing GCAD.

Heat shock proteins Heat shock proteins (Hsp) are biochemical chaperones, and their interaction with both innate and acquired responses are increasingly recognized. There is evidence that Hsp can

385 regulate chronic inflammation by inducing Treg lymphocytes with regulatory activity [29,30]. Although Hsp were primarily identified as cytoprotective proteins in transplant-related I/R, cellular response to these proteins after transplanation have also been suggested. Graft-infiltrating T lymphocytes reactive to mycobacterium Hsp65 and human Hsp70 have been detected both in rats and in human cardiac transplant patients. This response was associated with increased rejection of allografts. Different regions of Hsp60 molecules, however, may induce functionally distinct immune responses. The cytokine profile and specificity of cells recognizing self-Hsp60, as well as the kinetics of autoreactivity after transplantation, were investigated in renal transplant patients. Different Hsp peptides were used to stimulate peripheral blood mononuclear cells (PBMCs) and graft-infiltrating lymphocytes. Cytokine production analysis indicated a predominance of interleukin (IL)–10 during the late post-transplantation period, in response to intermediate and C-terminal peptides. Patients with CR demonstrated higher IL-10/interferon (IFN)–␥ ratios compared with patients who were clinically stable long term. In addition, graft-infiltrating T-cell lines, produced mainly IL-10 after Hsp60 stimulation. These results suggest that autoreactivity to Hsp60 in transplantation has a complex role, and in addition to its proinflammatory activity, may also have a regulatory function [31]. Vimentin is an intermediate filament found in leukocytes, endothelial cells, and proliferating smooth muscle cells. Autoantibodies to vimentin have been detected in autoimmune diseases including systemic lupus erythematosus and rheumatoid arthritis. Autoimmune responses to vimentin have been demonstrated after heart and kidney transplantation. Patients display an autoimmune response to vimentin demonstrated by both autoantibodies and selfrestricted vimentin-specific CD8⫹ T cells [32–34]. The autoantibody response appears to be pathogenic, as it is associated with development of cardiac graft vasculopathy. A recent study investigated the role of the anti-vimentin immune response on allogenic and isografted hearts in a minor mismatch murine transplantation model (129/sv– C57BL/6). Immunization of the recipient mice with murine vimentin in complete Freund’s adjuvant resulted in breaking tolerance to vimentin and established a pretransplantation autoimmune response. Both anti-vimentin antibodies and vimentin-reactive Th-1 cells were detected. Transplantation of 129/sv hearts into preimmunized C57BL/6 recipients resulted in accelerated rejection, whereas isografts survived beyond 90 days. Immunohistochemical analysis of the allografts demonstrated increased numbers of T cells, enhanced microvascular deposition of C3d, and increased expression of CD41 and P-selectin compared with those in controls. Antibodies were essential for accelerated rejection, as shown by the fact that vimentin-immunized, B-cell– deficient mice did not show accelerated rejection, and by the fact that rejection could be restored by adoptive transfer of serum containing anti-vimentin antibodies. Presence of anti-vimentin autoantibodies is not sufficient to cause graft rejection as isografts survived in recipients displaying high titers. These results suggest that autoantibodies to vimentin, in conjunction with the alloimmune response, have a pathogenic role in allograft rejection [35].

386 Anti-vimentin immunity has also been described after nonhuman primate cardiac transplantation. Both IgM and IgG antibodies to vimentin were detected in the sera as well as in the native hearts and cardiac allografts from cynomolgus monkeys. This study also provided insight into how immunosuppression and tolerogenic protocols may influence the development of de novo autoimmunity. Untreated animals and cyclosporine- and anti-CD154 antibody–treated animals were investigated. Anti-vimentin antibodies and vascular complement deposition were found in rejected hearts. Cyclosporine had no effect on anti-vimentin antibody production, whereas anti-CD154 delayed the production of antivimentin IgG antibodies. These data suggest that acute and chronic events related to alloimmunity modulate autoreactivity to vimentin through pathways resistant to CsA, but they may be partially regulated by CD154 [36]. Type V collagen– directed autoimmunity has been linked to chronic lung allograft rejection. CR to lung allografts occurs more often than any other type of solid organ as a result of bronchiolitis obliterans, and newer immunosuppressive regimens have not improved survival. Studies suggest that the highly conserved native collagen, type V collagen [col(V)], is a target of the rejection response; col(V) is a 116-kDa heterodimer composed of ␣1 and ␣2 chains. Intrapulmonary instillation of allogenic lung macrophages and dendritic cells leads to progressive deposits in perivascular and peribronchiolar tissues of IgG2a antibody specific for col(V). In addition, matrix metalloproteinases (MMPs) such as MMP-2 and MMP-9 are capable of degrading col(V), and increased activity of MMP-2 and MMP-9 in lungs of human transplant recipients as well as rat during rejection have been reported. The inflammatory responses and architectural remodeling that occur during the rejection response may expose graft-infiltrating lymphocytes to fragments of col(V). The exposure of these rare self-antigens may result in the development of autoreactive T cells. T cells isolated from the lungs of mice that received instillations of allogeneic antigen-presenting cells proliferated in response to col(V), but not col(II), a collagen found only in cartilage [37,38]. A clinical study further supports that de novo autoimmunity causes CR. This work analyzed the role of cell-mediated immunity to col(V) in lung transplant recipients over an extended period of time. PBMC responses to different types of collagens, namely, col(II) and col(V), were monitored prospectively. High frequencies of col(V)-reactive PBMCs were identified in lung transplant patients but not in healthy controls. The col(V)-specific responses were mediated by both CD4⫹ T cells and monocytes and required IL-17, TNF-␣, and IL-1␣. Strong col(V)-specific responses were associated more significantly with increased incidence and severity of CR compared with incidence of acute rejection, HLA-DR mismatched grafts, and induction of HLA-specific antibodies [39].

Targets in de novo post-transplantation autoimmune hepatitis This clinical entity develops as a form of late graft dysfunction in patients with no previous history of autoimmune hepatitis [40,41]. The underlying mechanism is not clear, but a broad

P. Boros and J.S. Bromberg variety of autoantibodies have been described in numerous studies. The panel includes anti-nuclear antibody, anti– smooth-muscle antibody, anti-gastric parietal cell antibodies, serum anti-CK8/18 antibodies, and atypical anti-liver/ kidney cytosolic antibodies, which, however, do not appear to be specific for the onset of de novo autoimmune hepatitis AIH [42– 44]. Post-liver transplantation development of autoantibodies to soluble liver antigen is thought to predict the later appearance of de novo AIH [45]. Glutathione-S-transferase T1 (GSTT1)–specific antibodies were also associated with de novo post-transplantation AIH. These may, however, be part of an anti-graft reaction in individuals lacking the GSTT1 phenotype. As the GSTT1 enzyme is the product of a single polymorphic gene that was observed to be absent from 20% of Caucasian individuals, the graft dysfunction could be a consequence of an allo-reactive immune reaction [46].

Summary and perspectives Studies conducted in transplantation models lacking alloimmune reaction revealed that tissue-specific autoimmune anti-graft response is an important mechanism in the development of chronic rejection and graft failure. The target molecules vary according to organs. Breaking tolerance to autoantigens by the transplantation process, tissue damage, and remodeling associated with I/R injury and alloreaction are essential to the initiation of the autoimmune anti-graft response. The pathways are not well understood, but the significance of an inflammatory environment is of importance. These findings further emphasize the central role of graft quality, I/R injury, and early innate response in long-term graft function. In addition to the important role in the development of CR, there are additional areas in which further research on de novo post-transplantation autoimmunity might be of particular interest. To achieve tolerance in clinical transplantation, it will be necessary to explore how tolerogenic protocols might affect the pathways of post-transplantation autoreactivity. Correlating de novo and pre-existing or recurrent autoimmune phenomena in transplant patients may also further our understanding of both clinical problems. Finally, because CR has no specific treatment, applying knowledge accumulated from clinical experience with new treatment modalities and drugs in autoimmune diseases may provide novel approaches to CR treatment.

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