B-cells are being increasingly recognized as important players in acute and chronic graft rejection. Acute rejection episodes are being described across organs that show infiltration of B-cells in kidneys (1–6), hearts (7–9), and livers (10) as potential effectors in different forms of acute and chronic graft injury. With the failure to significantly improve long-term graft survival, and the central role of acute rejection in graft life expectancy (11), delving deeper into rejection pathogenesis remains important. The Banff classification deals with the topographical categorization of immune injury (cellular or vascular), these changes being rated by their severity (borderline and differing grades of acute tubulointerstitial and vascular rejection) (12). This classification currently does not deal with the composition of cell infiltrates, which are mostly gauged to be T-cell based in cellular acute graft rejection. Nevertheless, the involvement and impact of other cell types may also impact the quality and quantity of the rejection response (13), such as CD20+ B-cells (1–3), plasma cells (4–6, 14), macrophages (15–20), eosinophils (21–27), and natural killer cells (28). The impact of these cells might become even more prominent when T-cell depleting protocols are employed (18, 27, 29). The immunological factors driving preponderance of different cell infiltrates in rejection, and their clinical interpretation, is still unclear. This review focuses on the more recent observations of B-cell dense graft rejections, the published literature on their clinical relevance, and a summary of the published literature on B-cell depleting therapies for treatment of graft rejection.
B-cells develop from stem cell precursors in bone marrow (Fig. 1A). Historically, the primary focus of research on B-cells in transplantation has been on the terminally differentiated plasma cells and their contributory role in antibody-mediated rejection, with the production of donor specific antibodies (DSA) (4). Recent studies showed that active solid organ rejection episodes can either be “pure” antibody or “pure” cellular mediated events or represent mixed rejection with varying degrees of humoral and cellular alloimmune injury (6).
An importance for the B-cell compartment and DSA in acute rejection has been elegantly demonstrated in transplant models using B-cell deficient mice. B-cells were shown to play a dominant role in allograft rejection when T-cells were depleted or suppressed, but depletion of B-cells could not prevent a T-cell driven rejection (9, 30–32). To confirm the pathogenic role of DSA in rejection, passive transfer of donor-specific immune serum to B-cell deficient recipients significantly accelerated allograft rejection.
Recent studies describe an antibody-independent role of B-cell because of the capacity of B-cells to secrete inflammatory cytokines and chemokines, participate in antigen presentation and T-cell and dendritic cells regulation as well as in lymphoid tissue development (33–36). Indirect alloantigen presentation by the recipients’ B-cells has been shown to play an important role in the efficient progression of acute vascularized allograft rejection in experimental models of cardiac rejection (9).
As supported by the Banff schema, the persistence of cellular infiltrates (on protocol biopsies) has been shown to be a key predictor of allograft function outcome (37, 38). Nevertheless, the composition and intensity of the infiltrate in rejection may drive its molecular heterogeneity and explain its different clinical outcomes, with regards to rejection severity, its treatment response and resultant outcome. Though the predominance of T-cell infiltration and T-cell transcripts lead the cellular repertoire, a predominance of B-cell transcripts on microarray and nodular infiltrates of CD20+ B-cells was found in renal interstitial infiltrates of ∼30% of pediatric patients with acute cellular rejection (Fig. 1B) with increased risk of future graft rejection (P<0.001) (1). They were found to populate 30% to 45% of renal allograft biopsies with acute cellular rejection. These findings were subsequently confirmed in adult renal transplant rejection, where 22% of patients (Banff grades 1A–1B) had dense B-cell infiltrates and associated with adverse graft outcomes (3). Another independent pediatric study confirmed the association of B-cell density with acute rejection and adverse outcomes (P=0.0001) (2). None of these studies showed an association of CD20+ B-cells with intragraft peritubular C4d or acute humoral rejection, though DSA data were not available to review in these studies. In addition, immunohistochemical analysis of another independent study of 38 adult renal allograft biopsy specimens showed that CD20+ intragraft infiltrates may present in nodular or scattered patterns in acute rejection and chronic allograft damage but only clustered B-cells were associated with higher level of serum creatinine (39).
Nevertheless, the complexity of the immunological processes in human translational studies cannot be underscored enough. Unlike the relative homogeneity of the immune response in inbred mice, transplant patients from different ethnic groups, different causes of end stage renal disease, different induction protocols (T-cell depleting vs. not), different immunosuppression maintenance protocols, time posttransplantation, number of previous rejections, and different causatives of rejection etiology (center effects, drug combination choices, economics, nonadherence, infections, so forth), may drive subtle or more overt immunological differences and their different downstream molecular and cellular responses. Some studies have shown that the presence of CD20+ B-cell nodules in renal allografts in all patient populations may not always portend glucocorticoid resistance or less favorable outcome in C4d-negative biopsies (40–42). In addition to the patient population differences, the exact phenotype of the CD20+ pathogenic B-cells in rejection, as yet remains to be fully defined, and may underlie the differences in causal associations observed. In addition, a lack of standardized criteria for defining “CD20-positive” versus “CD20-negative” biopsies may cause discrepancies among different studies. Some of the pertinent published studies involving B-cells and graft rejection are shown in Table 1.
Chemokines and chemokine receptors are critical in leukocyte recruitment, activation, and differentiation in rejection. It has been shown, that CXCL10 ligand and its receptors CCR5 and CXCR3 (43–45) as well as CXCL13 and CXCR5 (46, 47) and chemokine receptor CCR1 (48) might be involved in the recruitment of B-cells into the rejecting allograft or inflammation sites. In a study of renal allograft rejection biopsies by polymeras chain reaction, transcripts for CCL3, CCL5, CCL19, CCL21, CXCL9, CXCL11, CCR1, CCR5, CCR7, and CXCR3 chemokines were higher during renal rejection than in patients with stable allograft function on immunosuppression and CCL19 and CCL21 chemokines were persistently transcribed posttransplantation even in the absence of infiltrating mononuclear cells (49). In addition to the previous published data related to B-cell migratory signals reported here, we performed supervised statistical analysis on gene expression levels of chemokines and their receptors with CD20 expression, from previously published microarray biopsy rejection expression data (1). Suggestive migratory signals for CD20+ B-cells in graft rejection are shown in the heat map (Fig. 2A).
Newly formed graft lymphatics seem a suggested route for entry and egress of B-cells in rejection. A 50-fold increase of lymphatic vessel density was demonstrated by Kerjaschki et al. (35) in human renal grafts with nodular mononuclear infiltrates over normal kidneys. Nodular infiltrates were constantly associated with newly formed, Ki-67—expressing lymphatic vessels and contain the entire repertoire of T- and B- lymphocytes. Further investigation detected that lymphangiogenesis not only shows a clear association with cellular infiltrates but might also have an impact on the pathogenicity of these cellular infiltrates (50). Lymph vessel density was significantly higher in areas with cellular infiltrates than in areas without. Graft function at 1 year after transplantation was better in cases with lymph vessels in their infiltrates compared with cases with lymph vessel-free infiltrates.
B-cells in rejection thus seem to contribute to both humoral and cellular allograft rejection (Fig. 2B), and may be poorly targeted by current T-cell directed therapies. Given the prevalence of allosensitization and B-cell infiltration, several pilot studies have investigated the use of Rituximab, a monoclonal humanized antibody against the target CD20, currently approved for the treatment of D20+ B-cell lymphoma and posttransplant lymphoproliferative disorders. Despite some small efficacy reports, demonstration of efficacy and safety of Rituximab for graft rejection will require a randomized postpositive clinical trial in acute transplant rejection. Selected T-cell and B-cell suppression treatment may be required for mixed cellular and antibody-mediated graft rejections. Therapeutic regimens that allow the removal or neutralization of pathogenic antibodies and the blockage of B-cell proliferation and differentiation are the use of intravenous immunoglobulins, removal of donor-specific antibodies by immunoadsorption and plasmapheresis, and Rituximab therapy (51).
Rituximab has been clinically used as induction therapy to reduce panel reactive alloantibodies/antihuman leukocyte antigen antibodies/anti-ABO antibodies (52–66) before transplantation and antirejection therapy aiming at depleting B-cells and suppressing DSA production in renal, cardiac, and pancreatic transplantation. The first documented use of Rituximab for the treatment of vascular rejection was reported in 2002 when a patient with cardiac rejection refractory to plasmapharesis was successfully treated (67). Later, other case reports and a first study suggested the efficacy of Rituximab in treatment of humoral and vascular cardiac and pancreatic rejections (68–71). Currently, small cohort studies have indicated that Rituximab could successfully treat aggressive renal allograft rejections. There are only couple case reports (72, 73) and pilot studies (74–76) showing the efficacy of Rituximab in treatment of kidney allograft rejection refractory to high doses of steroids (72, 75) and thymoglobulin (73). Rituximab has been shown to deplete DSA (74) in renal allograft rejection and eliminate B-cells with improved graft survival (74–76). After Rituximab therapy, reconstitution of peripheral B-cells occurs between 6 and 9 months, though a persisting depletion is down for CD27+ memory B-cell subset (53). Although, the dynamic of peripheral blood B-cells depletion after Rituximab treatment is reported, little data exist regarding intragraft B-cells depletion and repopulation, though a significant reduction of CD20+ cells have been reported in renal allografts after Rituximab treatment, comparing with conventional immunosuppression (72, 76). Rituximab has little effect on circulating T-cells or ex vivo T-cell reactivity (52, 54, 77, 78). The current clinical experience with Rituximab treatment in transplantation is summarized in Table 2.
In summary, B-cells can abound in many cases of solid organ transplant rejection. The homing and migratory pathways for these B-cells to the graft, their origin, and their entry/exit routes are being uncovered. Once recruited to the alloinjured graft, early lineage CD20+ B-cells may expand into dense nodular aggregates and function as antigen presenting capacity for supporting a robust T-cell mediated rejection that is poorly responsive to conventional treatment with steroids. The identification of these cells has not found them to associate with vascular rejection, or the deposition of intragraft C4d. More mature plasma cells, CD20− and CD138+, are the prime producers of alloantibody directed against donor and drive the axis of vascular rejection. Given the increasing awareness of B-cells in transplant rejection, their impact on graft survival, and the potential impact to harness newer therapies for effective rejection resolution, the participation of B-cells in multilineage cellular responses in acute and chronic graft injury are warranted.
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