Progress in transplantation achieved the last decades has had little impact on chronic rejection, which remains a major cause of late allograft failure. A better comprehension of the pathophysiology of this condition therefore appears as a mandatory step in designing innovative therapies that would improve long-term allograft outcome.
Accumulating evidence indicates that most chronic rejection cases result from the inadequate control of the humoral arm of the recipient's immune system by currently available immunosuppressive drugs. Although the deleterious impact of antibodies is becoming increasingly acknowledged, the role of the B-cell clusters that have been recently observed within chronically rejected allografts remains a matter of controversy (1). Recent studies aiming at delineating their impact on the natural history of chronic rejection have indeed reached conflicting conclusions and it is therefore unclear whether they actively participate in the pathogenic process or simply represent an epiphenomenon. This article reviews the recent literature and proposes an integrative model that reconciles this apparently conflicting data.
THE “HUMORAL THEORY” OF CHRONIC REJECTION
Paul Russell was probably the first, in 1970, to suggest the association between de novo antidonor antibodies and the development of chronic renal allograft arteriosclerosis (2). Subsequently, the same team, using a murine model of heterotopic heart transplantation, demonstrated that the mere transfer of antiserum was sufficient to promote the development of transplant arteriosclerosis (3). Since the completion of these seminal works, accumulating clinical evidence has confirmed the central role of donor-specific anti-human leukocyte antigen (HLA) alloantibodies (DSA) in the pathogenesis of chronic rejection (4).
Highly polymorphic mismatched HLA molecules are indeed obvious targets for a recipient's immune system. Molecular bases of humoral allorecognition were clarified in the 80s by analyses of serological cross-reactivity, which demonstrated that each HLA molecule could be seen as a unique combination of multiple epitopes, namely short sequences involving polymorphic amino acid residues in antibody- accessible positions (5). The fact that distinct HLA antigens share some identical epitopes provides a likely explanation for the frequent detection of nondonor specific anti-HLA antibodies in the circulation of graft recipients (5).
Antibodies directed against polymorphic non-HLA alloantigens and nonpolymorphic autoantigens have also been detected in the serum of allograft recipients (6–9). Using integrative genomics analysis Li et al. (10) have recently demonstrated the uneven immunogenic potential of different graft compartments by showing that serological responses to non-HLA targets were mainly directed against compartment-specific antigens from the renal pelvis and cortex after renal transplantation. Although recent studies have suggested that these “non-HLA” antibodies could be potentially harmful for the graft (7), this issue currently remains a matter of debate. In the same line, recent studies have reported that anti-HLA II DSA could have a higher capability than anti-HLA I to trigger microvasculature injury and subsequent graft failure (11, 12), leading to the hypothesis that all DSA may not be “created equal” regarding their pathogenicity. In this regard, it is probable that, besides the specificity, the titer and the isotype of the heavy chain are also important parameters that influence the pathogenic potential of the antibodies directed against the graft (13, 14).
Binding of DSA to allogenic targets expressed by graft microvasculature activates the classical complement pathway, initiates antibody-dependent cell-mediated cytotoxicity and modulates the biology of vascular cells (15, 16). The lesions created by microcirculation inflammation gradually become irreversible and permanently compromise graft function (17).
The differentiation of B cells into alloantibody-producing plasma cells requires T-cell help and takes place during germinal center reaction, a complex process thought to occur only in canonical secondary lymphoid organs (i.e., spleen and lymph nodes). However, recent studies have reported the presence of B cells organized in clusters within chronically rejected grafts, raising questions regarding their role in the rejection process.
EVIDENCE FOR LYMPHOID NEOGENESIS IN EXPLANTED CHRONICALLY REJECTED GRAFTS
Although they represent only a minor fraction (∼5%–10%) of the infiltrate, B-cells have been recurrently observed at the site of chronic inflammation. Several groups have reported the progressive organization of chronic immune cell infiltrate into functional ectopic tertiary lymphoid tissues (TLT) that display the same microarchitecture as secondary lymphoid organs: a core of B cells intermingled with follicular dendritic cells, surrounded by T cells, mature dendritic cells, and specialized endothelial cells (Fig. 1). This process has been named lymphoid neogenesis (18).
Murine experimental studies have documented the presence of TLT in chronically rejected grafts (19, 20) and TLT have been observed in virtually all kinds of human grafts explanted for terminal failure due to chronic rejection (kidneys: [20, 21], lungs: , and hearts: [20, 23–25]). The analysis of these human explanted organs has revealed that the development of intragraft TLT depends on the recapitulation of the genetic program triggered in the embryo during the ontogeny of secondary lymphoid organs (26). An incomplete recapitulation results in the accumulation of naive B cells, whereas if the recapitulation is complete, TLT become functional, that is they harbor germinal center reactions leading to the local differentiation of anti-HLA producing plasma cells and memory B cells (Fig. 1) (26).
TLT, however, differs from canonical secondary lymphoid organs inasmuch as they develop in an inflammatory milieu (27), enriched in neoantigens released from injured tissue, and trapped by defective lymphatic drainage (28). This permissive unregulated microenvironment favors the spreading of local immune response. Indeed, the humoral alloimmune response that develops in intragraft TLT is uncoupled from the response elicited in canonical secondary lymphoid organs and the repertoires of anti-HLA antibodies produced in functional TLT appear to be wider (26, 29). Because grafts in which TLT are the most functional have a shorter life expectancy, it has been proposed that lymphoid neogenesis could play a detrimental role during chronic rejection (26, 27). However, the validity of this conclusion is limited by the fact that only explanted grafts have been analyzed, that is, organs displaying extreme rejection damages that are sometimes (notably in the case of renal grafts) removed after immunosuppressive therapy withdrawal.
CONFLICTING CONCLUSIONS OF BIOPSY-BASED STUDIES
The definitive demonstration that TLT are involved in the pathophysiology of chronic rejection would require selectively impairing the development of intragraft TLT while leaving the rest of the recipient immune system unaffected. Addressing this issue is not trivial because, as discussed earlier, TLT share many biological pathways with canonical lymphoid tissue, and hence an adequate experimental model is not currently available.
Therefore, most of the attempts to validate the data obtained in murine experimental models and in human explanted grafts have relied on graft biopsies. The identification of TLT within the graft before the development of chronic rejection lesions would indeed be good indirect evidence that TLT are involved in graft destruction. This implies the study of protocol biopsies, which has long been introduced as standard follow-up in heart transplantation. Interestingly, the presence of lymphoid nodules in allografts, named “Quilty effect,” was reported by Billingham and coworkers (30) in heart protocol biopsies 15 years ago. Unfortunately, the numerous studies aiming at evaluating the correlation between the presence of Quilty lesions in protocol biopsies and the later development of transplant vasculopathy have reached conflicting conclusions (Table 1).
In renal transplantation (Table 1), where protocol biopsies are less performed (31), the situation is even less clear because: (i) almost all the studies addressing this issue are based on histological specimens collected to confirm the diagnosis of acute rejection; (ii) there is a lack of consistency in the design of these studies, in particular in the definition of TLT (number of CD20+ cells per field, microanatomy of the infiltrate, localization, etc.) and the endpoints (response to therapy, graft survival, etc.) (32–42).
The absence of an unequivocal deleterious role for B-cell clusters in biopsy-based studies has led to the conclusion that these structure could be like “fish in a sunken ship,” that is, although they are frequently seen in sunken boat, fish do not play a role in the process responsible for the shipwreck. In line with this hypothesis is the recent report that B-cell–associated transcripts increase in renal allograft biopsies with time posttransplantation and inflammation, and are no longer related to graft function after correction for time (43).
We believe, however, that several nonmutually exclusive explanations could reconcile this apparently conflicting data.
LIMITS OF GRAFT BIOPSY
Graft biopsy is of limited value for the quantification of TLT. Indeed, lymphoid neogenesis is, by essence, a patchy process that can take place everywhere in the rejected graft (24, 25). In contrast, biopsies only screen a tiny fraction of the graft and do not allow for the assessment of all compartments of transplanted organs (31). In the case of renal biopsy for instance, the tissue sampled is less than or equal to 20 mm3, which represents ≈1/10,000 of the total volume of the graft, and is located almost exclusively in the cortex (while analysis of explanted grafts have shown that TLT can be found in the medulla, the renal pelvis and the adventitia of the large arteries ).
Besides sampling issues, one should remember that B-cell clusters are a heterogeneous collection, that is, not all B-cell clusters are functional ectopic germinal centers (26). Interestingly, we have recently shown that (i) the proportion of B cells that infiltrate chronically rejected kidneys does not correlate with the functionality of TLT, and (ii) only the functionality of TLT (not their numbers) correlates with graft outcome (26). In our experience, identification of chronically rejected grafts with functional ectopic germinal centers could only be achieved using functional assays, which require a greater amount of tissue.
Consequently, because graft biopsy does not allow for reliable quantification of TLT and provides no information regarding their functionality, this technique is of limited usefulness in deciphering the role of lymphoid neogenesis during chronic rejection. Instead, quantification of lymphoid neogenesis genes in urine might be a promising noninvasive tool to achieve this objective, at least in the setting of renal transplantation (44).
B CELLS: MORE THAN PLASMA CELL PRECURSORS
Besides their role in antibody production following their differentiation in plasma cells, B cells are also endowed with critical, yet overlooked, antibody-independent functions. It is thus conceivable that intragraft B cells can promote chronic rejection even in the absence of ectopic germinal centers (45).
B cells are unique antigen-presenting cells because (i) they have an antigen-specific receptor, allowing for extraction and antigen presentation, even if it is membrane-tethered or present in limiting quantities, and (ii) B cells have the capacity to clonally expand, thereby becoming the numerically dominant antigen-presenting cells (46). Interestingly, it has been recently reported that the presence of B-cell clusters within the graft during rejection was associated with reduced graft survival and resistance to steroid therapy, independently of C4d deposition or alloantibody detection (36). Zarkhin et al. (47) have recently proposed that this could be due to the local presentation of antigen to effector T cells by intragraft B cells. This hypothesis is supported by experimental data from Nasr et al. (48), who showed, in a murine skin graft model, that TLT perpetuate the rejection process by supporting naïve T-cell activation within the graft. Strikingly, the same authors also demonstrated that TLT generate T-cell memory immune responses (48), a finding in line with basic immunological works, which have established that B-cell antigen presentation to T cells is critical for the establishment and recall of antigen-specific memory CD4+ T cells (49, 50).
In addition to presenting antigen, B cells can also enhance T-cell mediated immune responses through the secretion of cytokines and chemokines (51). Like T cells, B cells can be functionally subdivided based on their cytokine profile: B effector 1 cells (Be1 cells) secrete interferon-γ and interleukin (IL)-12 while in contrast Be2 cells secrete IL-2, IL-4, and IL-13 (51). The importance of B-cell cytokines in promoting T-cell responses in vivo has been recently illustrated in mice models (52), but remains to be evaluated in the setting of chronic rejection.
CAN INTRAGRAFT B CELLS PLAY A REGULATORY ROLE?
Another layer of complexity has recently been brought into the picture by experimental evidence that B cells are also endowed with immune regulatory properties (53, 54). Dissection of the underlying mechanisms revealed that B cells control immune response by providing IL-10 (55–57) that, in turn, directly suppresses the differentiation of pathogenic T cells, promotes the development of regulatory T cells, and constrains dendritic cell functions (53, 54). The recent demonstration that IL-10–producing B cells exist in humans, and that B cells from patients with multiple sclerosis (58) and lupus (59) produce decreased amounts of IL-10, suggests a general role of B cells in clinical immune homeostasis. In transplantation, a role for B-cell regulation has been indirectly suggested by the reports that (i) in naive individuals, induction therapy with rituximab (a B-cell depleting monoclonal antibody) seems to greatly enhance acute T-cell– mediated rejection (60), and (ii) operational tolerance to renal allograft is strongly associated with a B-cell signature (61–63). It is therefore conceivable that in certain conditions intragraft B cells, instead of being deleterious, could actually promote graft survival. Consistent with this hypothesis, Brown et al. (64) have reported the presence of tertiary lymphoid organs within tolerated allografts in a mouse kidney allograft model. These findings have recently been validated in another murine model of long-term cardiac allograft tolerance by the Nantes group (65), who observed that tolerated allografts were infiltrated by numerous B-cells organized in clusters. B cells from tolerant animals exhibited an inhibited profile and were able to transfer allograft tolerance to a secondary irradiated host.
The study of B cells in transplantation tolerance is currently in its infancy and definitive evidence is still lacking. However, if such a local protective response exists, then not only would such samples having “tolerogenic” TLT be absent from the studies based on the analysis of explanted grafts, but it could also explain the difficulty of reaching an unequivocal conclusion in biopsy-based studies.
The demonstration of the central role of alloantibodies in late transplant failure has brought B cells back to the center of transplant immunologists' attention. Interestingly, while the prevailing immunologic dogma predicts that B cells exert their pathological role remotely in secondary lymphoid organs, several authors have reported their presence within rejected grafts as part of TLT. Because biopsy-based studies have reached conflicting conclusions regarding the pathological significance of these B-cell clusters, it has been proposed that B-cell infiltration in rejected grafts is a nonspecific response to local inflammation-induced production of chemokine. Although that can indeed sometimes be the case, it should not be forgotten that under appropriate conditions, lymphoid neogenesis turns nonfunctional B-cell clusters into ectopic germinal centers, in which a local aggressive humoral immune response can be elicited. It is also likely that intragraft B cells can present the antigen to effector T cells and modify the TLT cytokinic microenvironment, thereby locally amplifying antigraft immunity. Alternatively, recent findings suggest that TLT B cells could also regulate immune responses and thus slow down the destruction process. Therefore, rather than view them as passive witnesses, we propose to consider TLT as active players which can modulate the kinetics of the natural history of chronic rejection and therefore “Tune the Loss of Transplant.”
Future works will determine whether the versatility of TLT B cells can be manipulated to design innovative therapeutic intervention that would improve graft life expectancy.
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