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Editorials and Perspectives: Forum—The B Cell in Transplantation

“To B or Not to B?” B-Cells and Graft Rejection

Zarkhin, Valeriya; Li, Li; Sarwal, Minnie

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doi: 10.1097/TP.0b013e318177793e


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).

FIGURE 1. (A) Schema of B-cell development.
FIGURE 1. (A) Schema of B-cell development.:
B-cells develop throughout life from uncommitted precursors in bone marrow. Early B-cell maturation is characterized by high mitotic activity, stimulated mainly by IL-7, a cytokine produced by bone marrow stromal cells. After the developing B-cells express antigen receptors, these molecules take over the function of stimulating proliferation. In the absence of antigen receptor expression, developing B-cells undergoing apoptosis. Naïve B-cells migrate to lymphoid organs, specifically to lymph node follicles, using l-selectin and the CXCR5 chemokine receptor. Naïve B-cells recognize soluble antigen in the blood or lymph using their B-cell receptor or membrane bound-immunoglobulin, and bind major histocompatibility complex (MHC) class II. This antigen/MHC II complex can be recognized by compatible T-cells. Naïve B-cells become activated by antigen, T-cell co-stimulation and cytokines and form a germinal center where immunoglobulin isotype switching occurs. On activation, B-cells lose expression of CXCR5 and exit the follicles into the T-cell zones of the lymphoid organ using integrins. Activated B-cells differentiate into either memory B-cells or early plasmablasts. On the re-exposure to specific antigens, memory B-cells may differentiate to plasmablasts. Under the direction of specific chemokines (CXCL12, CCL25, CCL28), late plasmablasts can migrate to the bone marrow, gut, red pulp of spleen, or mucosal epithelium of tonsil and complete differentiation into long-lived plasma cells whose survival supported by such factors as CD40L, CD70, BAFF, IL-6 (79, 80). CD20 marker is specific for B-cells only, expressed during the mid stages of ontogeny but not found on stem cells, pro-B-cells or normal plasma cells. CD20 is not shed from the cell surface and does not internalize on antibody binding and free CD20 is not found in the circulation (81, 82). CD19 mirrors CD20 expression and has been used as a surrogate marker in patients treated by Rituximab. (B) B-cells are infiltrating rejecting renal allografts. Different B-cell infiltrates were found to populate renal allografts with acute rejection. This panel presents a hematoxylin-eosin picture showing graft rejection with infiltrating mononuclear cells (a), with staining for a CD20+ cluster in the same patient (b) and scattered CD138+/CD20− plasma B-cells (c) in a different patient. Magnification: 1×200 (courtesy of Dr. N. Kambham, Stanford Pathology Department).

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.

A review of the published literature on CD20+ intragraft cells and acute rejection

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).

FIGURE 2. (A) Possible trafficking signals for the intragraft B-cells in acute rejection.
FIGURE 2. (A) Possible trafficking signals for the intragraft B-cells in acute rejection.:
We performed additional statistical analysis such as Spearman correlation coefficients calculations of previously published lymphochip gene expression data from 15 normal biopsies and 21 biopsies from pediatric (1–22 years of age) patients undergoing acute renal allograft rejection (1), and found strong association of intragraft CD20+ B-cells with CXCL10 (r=0.74, P<0.0001), CCR1 (r=0.67, P=0.0003), Figure 2. (Continued) CCL5 (r=0.76, P<0.0001) and CCL7 (r=−0.59, P=0.001) that confirmed previously discussed observations for possible role of these factors in B-cell migration in acute graft rejection (43–45, 48). Also, we found that gene expression level for CD20+ B-cells strongly correlates with additional chemokines/receptors and factors, such as STAT1, VEGF, VEGF-β, CXCL3, CXCL5, CXCL9, CCL2, CCL8, CCL18, CCL20, CCL21, CCL23, CX3CL1, CXCR4, CCR7, whose influence on the B-cells role in allograft rejection has not been previously studied. Further statistical analysis (SAS, SAS Institute Inc., Cary, NC) was performed to compare gene expression levels for all these chemokines/receptors between three groups: AR with CD20+ B-cell infiltrates (12 biopsies), AR without B-cell infiltrates (nine biopsies), and 15 normal biopsies. The individual biopsies are presented on the x-axis and the chemokines and their receptors are clustered on the y-axis of heatmap. As seen from this heatmap, the most possible predominant factors regulating migration of CD20+ B-cells into the rejecting kidney allograft are CCL2, CCL3, CCL5, CCL7, CCR1, CXCL10, TNF, STAT-1, CXCR5 (labeled in red, significantly increased in CD20+ vs. CD20− rejecting group) and CXCL9, CCR7, IFNGR1, VEGFB2, and VEGF (blue, significantly different between CD20+ vs. normal, but not different in CD20− group vs. normal). Little has been published to date on the correlations and downstream effects of CCL2, TNF, STAT-1, VEGF, VEGFB2, and IFNGR1 on B-cells in graft rejection. (B) Cartoon showing the possible role of B-cells in allograft rejection. B-cell may participate in both cellular and humoral allograft rejection because of their multiple immunological functions. In cellular rejection B-cells can modulate T-cells and dendritic cells function. B-cells can activate CD8+ T-cells either directly through cross-presentation or indirectly through CD4+ T-cell activation (34). After Ag presentation, B-cells may co-stimulate T-cells through CD40/CD40L or CD80/CD28 and CD86/CD28. B-cells also secrete cytokines and chemokines, including IL-16, MIP1α, and MIP1β, that can affect dendritic cells migration and function (83, 84). Memory B-cells and especially long lived plasma cells produce big amount of specific antibodies and may cause humoral rejection. Some cases can have “mixed” rejections with different degrees of cellular and humoral components on it. However, the optimal treatment schema for humoral and mixed rejections is not established yet. There are two possible approaches to manipulate the B-cell compartment: removal of alloantibodies with suppression of antibody production by B-cells (anti-CD20, CD22, and CD52 antibodies) and blockage of factors and signals (CD40/CD40L and BLyS/BR3 pathways) essential for B-cell activation and survival (34). Peripheral deletion of mature alloreactive B-cells by blocking CD154/CD40 interaction were observed in animal transplant model. Anti-CD154 treatment together with donor-specific transfusion results in the long-term survival of MHC-mismatched mouse heart grafts and inhibition of alloantibody production (85).

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.

Clinical experience with Rituximab treatment for AR in transplantation (single center, nonrandomized studies, case reports and case series)

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.


1. Sarwal M, Chua MS, Kambham N, et al. Molecular heterogeneity in acute renal allograft rejection identified by DNA microarray profiling. N Engl J Med 2003; 349: 125.
2. Tsai EW, Rianthavorn P, Gjertson DW, et al. CD20+ lymphocytes in renal allografts are associated with poor graft survival in pediatric patients. Transplantation 2006; 82: 1769.
3. Hippen BE, DeMattos A, Cook WJ, et al. Association of CD20+ infiltrates with poorer clinical outcomes in acute cellular rejection of renal allografts. Am J Transplant 2005; 5: 2248.
4. Terasaki PI, Cai J. Humoral theory of transplantation: Further evidence. Curr Opin Immunol 2005; 17: 541.
5. Gartner V, Eigentler TK, Viebahn R. Plasma cell-rich rejection processes in renal transplantation: Morphology and prognostic relevance. Transplantation 2006; 81: 986.
6. Nickeleit V, Andreoni K. The classification and treatment of antibody- mediated renal allograft injury: Where do we stand? Kidney Int 2007; 71: 7.
7. Wehner J, Morrell CN, Reynolds T, et al. Antibody and complement in transplant vasculopathy. Circ Res 2007; 100: 191.
8. Michaels PJ, Kobashigawa J, Laks H, et al. Differential expression of RANTES chemokine, TGF-beta, and leukocyte phenotype in acute cellular rejection and quilty B lesions. J Heart Lung Transplant 2001; 20: 407.
9. Noorchashm H, Reed AJ, Rostami SY, et al. B cell-mediated antigen presentation is required for the pathogenesis of acute cardiac allograft rejection. J Immunol 2006; 177: 7715.
10. Krukemeyer MG, Moeller J, Morawietz L, et al. Description of B lymphocytes and plasma cells, complement, and chemokines/receptors in acute liver allograft rejection. Transplantation 2004; 78: 65.
11. Cosio FG, Pelletier RP, Falkenhain ME, et al. Impact of acute rejection and early allograft function on renal allograft survival. Transplantation 1997; 63: 1611.
12. Solez K, Colvin RB, Racusen LC, et al. Banff ’05 Meeting Report: Differential diagnosis of chronic allograft injury and elimination of chronic allograft nephropathy (‘CAN’). Am J Transplant 2007; 7: 518.
13. Alegre ML, Florquin S, Goldman M. Cellular mechanisms underlying acute graft rejection: Time for reassessment. Curr Opin Immunol 2007; 19: 563.
14. Terasaki PI. Humoral theory of transplantation. Am J Transplant 2003; 3: 665.
15. Nomi H, Tashiro-Yamaji J, Yamamoto Y, et al. Acute rejection of allografted CTL-susceptible leukemia cells from perforin/Fas ligand double-deficient mice. J Immunol 2007; 179: 2180.
16. Croker BP, Clapp WL, Abu Shamat AR, et al. Macrophages and chronic renal allograft nephropathy. Kidney Int Suppl 1996; 57: S42.
17. Matheson PJ, Dittmer ID, Beaumont BW, et al. The macrophage is the predominant inflammatory cell in renal allograft intimal arteritis. Transplantation 2005; 79: 1658.
18. Kirk AD, Hale DA, Mannon RB, et al. Results from a human renal allograft tolerance trial evaluating the humanized CD52-specific monoclonal antibody alemtuzumab (CAMPATH-1H). Transplantation 2003; 76: 120.
19. Wyburn KR, Jose MD, Wu H, et al. The role of macrophages in allograft rejection. Transplantation 2005; 80: 1641.
20. Blocher S, Wilker S, Sucke J, et al. Acute rejection of experimental lung allografts: Characterization of intravascular mononuclear leukocytes. Clin Immunol 2007; 124: 98.
21. Jezior D, Boratynska M, Halon A, et al. Biopsy eosinophilia as a predictor of renal graft dysfunction. Transplant Proc 2003; 35: 2182.
22. Jezior D, Boratynska M, Halon A, et al. [Biopsy eosinophilia as a predictor of renal graft dysfunction]. Pol Merkur Lekarski 2006; 21: 152.
23. Nagral A, Quaglia A, Sabin CA, et al. Blood and graft eosinophils in acute cellular rejection of liver allografts. Transplant Proc 2001; 33: 2588.
24. Nagral A, Ben-Ari Z, Dhillon AP, et al. Eosinophils in acute cellular rejection in liver allografts. Liver Transpl Surg 1998; 4: 355.
25. Barnes EJ, Abdel-Rehim MM, Goulis Y, et al. Applications and limitations of blood eosinophilia for the diagnosis of acute cellular rejection in liver transplantation. Am J Transplant 2003; 3: 432.
26. Surquin M, Le Moine A, Flamand V, et al. IL-4 deficiency prevents eosinophilic rejection and uncovers a role for neutrophils in the rejection of MHC class II disparate skin grafts. Transplantation 2005; 80: 1485.
27. Wu T, Bond G, Martin D, et al. Histopathologic characteristics of human intestine allograft acute rejection in patients pretreated with thymoglobulin or alemtuzumab. Am J Gastroenterol 2006; 101: 1617.
28. Kitchens WH, Uehara S, Chase CM, et al. The changing role of natural killer cells in solid organ rejection and tolerance. Transplantation 2006; 81: 811.
29. Gallon L, Gagliardini E, Benigni A, et al. Immunophenotypic analysis of cellular infiltrate of renal allograft biopsies in patients with acute rejection after induction with alemtuzumab (Campath-1H). Clin J Am Soc Nephrol 2006; 1: 539.
30. Xu H, Chilton PM, Tanner MK, et al. Humoral immunity is the dominant barrier for allogeneic bone marrow engraftment in sensitized recipients. Blood 2006; 108: 3611.
31. Horne PH, Lunsford KE, Eiring AM, et al. CD4+ T-cell-dependent immune damage of liver parenchymal cells is mediated by alloantibody. Transplantation 2005; 80: 514.
32. Brandle D, Joergensen J, Zenke G, et al. Contribution of donor-specific antibodies to acute allograft rejection: Evidence from B cell-deficient mice. Transplantation 1998; 65: 1489.
33. Martin F, Chan AC. Pathogenic roles of B cells in human autoimmunity; insights from the clinic. Immunity 2004; 20: 517.
34. Martin F, Chan AC. B cell immunobiology in disease: Evolving concepts from the clinic. Annu Rev Immunol 2006; 24: 467.
35. Kerjaschki D, Regele HM, Moosberger I, et al. Lymphatic neoangiogenesis in human kidney transplants is associated with immunologically active lymphocytic infiltrates. J Am Soc Nephrol 2004; 15: 603.
36. Thaunat O, Field AC, Dai J, et al. Lymphoid neogenesis in chronic rejection: evidence for a local humoral alloimmune response. Proc Natl Acad Sci USA 2005; 102: 14723.
37. Mengel M, Gwinner W, Schwarz A, et al. Infiltrates in protocol biopsies from renal allografts. Am J Transplant 2007; 7: 356.
38. Mengel M, Chapman JR, Cosio FG, et al. Protocol biopsies in renal transplantation: Insights into patient management and pathogenesis. Am J Transplant 2007; 7: 512.
39. Martins HL, Silva C, Martini D, et al. Detection of B lymphocytes (CD20+) in renal allograft biopsy specimens. Transplant Proc 2007; 39: 432.
40. Doria C, di Francesco F, Ramirez CB, et al. The presence of B-cell nodules does not necessarily portend a less favorable outcome to therapy in patients with acute cellular rejection of a renal allograft. Transplant Proc 2006; 38: 3441.
41. Bagnasco SM, Tsai W, Rahman MH, et al. CD20-Positive infiltrates in renal allograft biopsies with acute cellular rejection are not associated with worse graft survival. Am J Transplant 2007; 7: 1968.
42. Kayler LK, Lakkis FG, Morgan C, et al. Acute cellular rejection with CD20-positive lymphoid clusters in kidney transplant patients following lymphocyte depletion. Am J Transplant 2007; 7: 949.
43. Lazzeri E, Rotondi M, Mazzinghi B, et al. High CXCL10 expression in rejected kidneys and predictive role of pretransplant serum CXCL10 for acute rejection and chronic allograft nephropathy. Transplantation 2005; 79: 1215.
44. Hancock WW, Wang L, Ye Q, et al. Chemokines and their receptors as markers of allograft rejection and targets for immunosuppression. Curr Opin Immunol 2003; 15: 479.
45. Muehlinghaus G, Cigliano L, Huehn S, et al. Regulation of CXCR3 and CXCR4 expression during terminal differentiation of memory B cells into plasma cells. Blood 2005; 105: 3965.
46. Steinmetz OM, Panzer U, Kneissler U, et al. BCA-1/CXCL13 expression is associated with CXCR5-positive B-cell cluster formation in acute renal transplant rejection. Kidney Int 2005; 67: 1616.
47. Heller F, Lindenmeyer MT, Cohen CD, et al. The contribution of B cells to renal interstitial inflammation. Am J Pathol 2007; 170: 457.
48. Mayer V, Hudkins KL, Heller F, et al. Expression of the chemokine receptor CCR1 in human renal allografts. Nephrol Dial Transplant 2007; 22: 1720.
49. Kirk AD, Mannon RB, Kleiner DE, et al. Results from a human renal allograft tolerance trial evaluating T-cell depletion with alemtuzumab combined with deoxyspergualin. Transplantation 2005; 80: 1051.
50. Stuht S, Gwinner W, Franz I, et al. Lymphatic neoangiogenesis in human renal allografts: Results from sequential protocol biopsies. Am J Transplant 2007; 7: 377.
51. Venetz JP, Pascual M. New treatments for acute humoral rejection of kidney allografts. Expert Opin Investig Drugs 2007; 16: 625.
52. Agarwal A, Vieira CA, Book BK, et al. Rituximab, anti-CD20, induces in vivo cytokine release but does not impair ex vivo T-cell responses. Am J Transplant 2004; 4: 1357.
53. Sidner RA, Book BK, Agarwal A, et al. In vivo human B-cell subset recovery after in vivo depletion with rituximab, anti-human CD20 monoclonal antibody. Hum Antibodies 2004; 13: 55.
54. Vieira CA, Agarwal A, Book BK, et al. Rituximab for reduction of anti-HLA antibodies in patients awaiting renal transplantation: 1. Safety, pharmacodynamics, and pharmacokinetics. Transplantation 2004; 77: 542.
55. Sonnenday CJ, Warren DS, Cooper M, et al. Plasmapheresis, CMV hyperimmune globulin, and anti-CD20 allow ABO-incompatible renal transplantation without splenectomy. Am J Transplant 2004; 4: 1315.
56. Tyden G, Kumlien G, Genberg H, et al. ABO-incompatible kidney transplantation and rituximab. Transplant Proc 2005; 37: 3286.
57. Tyden G, Kumlien G, Fehrman I. Successful ABO-incompatible kidney transplantations without splenectomy using antigen-specific immunoadsorption and rituximab. Transplantation 2003; 76: 730.
58. Ravichandran P, Natrajan T, Jaganathan R. Combination treatment of low dose Anti-Thymocyte Globulin (ATG), Rituximab and high dose Sirolimus as induction agents in immune-conditioned recipients. Int Immunopharmacol 2006; 6: 1973.
59. Balfour IC, Fiore A, Graff RJ, et al. Use of rituximab to decrease panel-reactive antibodies. J Heart Lung Transplant 2005; 24: 628.
60. Yamada Y, Hoshino K, Morikawa Y, et al. Successful liver transplantation across the ABO incompatibility barrier in 6 cases of biliary atresia. J Pediatr Surg 2006; 41: 1976.
61. Skogsberg U, Breimer ME, Friman S, et al. Successful ABO-incompatible liver transplantation using A2 donors. Transplant Proc 2006; 38: 2667.
62. Skogsberg U, Breimer ME, Friman S, et al. Adult ABO-incompatible liver transplantation, using A and B donors. Xenotransplantation 2006; 13: 154.
63. Boberg KM, Foss A, Midtvedt K, et al. ABO-incompatible deceased donor liver transplantation with the use of antigen-specific immunoadsorption and anti-CD20 monoclonal antibody. Clin Transplant 2006; 20: 265.
64. Yoshizawa A, Sakamoto S, Ogawa K, et al. New protocol of immunosuppression for liver transplantation across ABO barrier: The use of Rituximab, hepatic arterial infusion, and preservation of spleen. Transplant Proc 2005; 37: 1718.
65. Kawagishi N, Satoh K, Enomoto Y, et al. New strategy for ABO- incompatible living donor liver transplantation with anti-CD20 antibody (rituximab) and plasma exchange. Transplant Proc 2005; 37: 1205.
66. Monteiro I, McLoughlin LM, Fisher A, et al. Rituximab with plasmapheresis and splenectomy in ABO-incompatible liver transplantation. Transplantation 2003; 76: 1648.
67. Garrett HE Jr, Groshart K, Duvall-Seaman D, et al. Treatment of humoral rejection with rituximab. Ann Thorac Surg 2002; 74: 1240.
68. Aranda JM Jr, Scornik JC, Normann SJ, et al. Anti-CD20 monoclonal antibody (rituximab) therapy for acute cardiac humoral rejection: A case report. Transplantation 2002; 73: 907.
69. Garrett HE Jr, Duvall-Seaman D, Helsley B, et al. Treatment of vascular rejection with rituximab in cardiac transplantation. J Heart Lung Transplant 2005; 24: 1337.
70. Kaczmarek I, Deutsch MA, Sadoni S, et al. Successful management of antibody-mediated cardiac allograft rejection with combined immunoadsorption and anti-CD20 monoclonal antibody treatment: Case report and literature review. J Heart Lung Transplant 2007; 26: 511.
71. Melcher ML, Olson JL, Baxter-Lowe LA, et al. Antibody-mediated rejection of a pancreas allograft. Am J Transplant 2006; 6: 423.
72. Lehnhardt A, Mengel M, Pape L, et al. Nodular B-cell aggregates associated with treatment refractory renal transplant rejection resolved by rituximab. Am J Transplant 2006; 6: 847.
73. Alausa M, Almagro U, Siddiqi N, et al. Refractory acute kidney transplant rejection with CD20 graft infiltrates and successful therapy with rituximab. Clin Transpl 2005; 19: 137.
74. Faguer S, Kamar N, Guilbeaud-Frugier C, et al. Rituximab therapy for acute humoral rejection after kidney transplantation. Transplantation 2007; 83: 1277.
75. Becker YT, Becker BN, Pirsch JD, et al. Rituximab as treatment for refractory kidney transplant rejection. Am J Transplant 2004; 4: 996.
76. Genberg H, Hansson A, Wernerson A, et al. Pharmacodynamics of rituximab in kidney allotransplantation. Am J Transplant 2006; 6: 2418.
77. Saville MW, Benyunes MC, Multani PS. No clinical evidence for CD4+ cell depletion caused by rituximab. Blood 2003; 102: 408.
78. Pescovitz MD. Rituximab, an anti-cd20 monoclonal antibody: History and mechanism of action. Am J Transplant 2006; 6(5 pt 1): 859.
79. Cyster JG. Homing of antibody secreting cells. Immunol Rev 2003; 194: 48.
80. Avery DT, Ellyard JI, Mackay F, et al. Increased expression of CD27 on activated human memory B cells correlates with their commitment to the plasma cell lineage. J Immunol 2005; 174: 4034.
81. Einfeld DA, Brown JP, Valentine MA, et al. Molecular cloning of the human B cell CD20 receptor predicts a hydrophobic protein with multiple transmembrane domains. EMBO J 1988; 7: 711.
82. Maloney DG, Liles TM, Czerwinski DK, et al. Phase I clinical trial using escalating single-dose infusion of chimeric anti-CD20 monoclonal antibody (IDEC-C2B8) in patients with recurrent B-cell lymphoma. Blood 1994; 84: 2457.
83. Kaser A, Dunzendorfer S, Offner FA, et al. B lymphocyte-derived IL-16 attracts dendritic cells and Th cells. J Immunol 2000; 165: 2474.
84. Krzysiek R, Lefevre EA, Zou W, et al. Antigen receptor engagement selectively induces macrophage inflammatory protein-1 alpha (MIP-1 alpha) and MIP-1 beta chemokine production in human B cells. J Immunol 1999; 162: 4455.
85. Li Y, Ma L, Shen J, et al. Peripheral deletion of mature alloreactive B cells induced by costimulation blockade. Proc Natl Acad Sci USA 2007; 104: 12093.
86. Schwarz A, Mengel M, Gwinner W, et al. Risk factors for chronic allograft nephropathy after renal transplantation: A protocol biopsy study. Kidney Int 2005; 67: 341.
87. Baran DA, Lubitz S, Alvi S, et al. Refractory humoral cardiac allograft rejection successfully treated with a single dose of rituximab. Transplant Proc 2004; 36: 3164.
88. Keren A, Hayes HM, O’Driscoll G. Late humoral rejection in a cardiac transplant recipient treated with the anti-CD20 monoclonal antibody rituximab. Transplant Proc 2006; 38: 1520.
89. Watson R, Kozlowski T, Nickeleit V, et al. Isolated donor specific alloantibody-mediated rejection after ABO compatible liver transplantation. Am J Transplant 2006; 6: 3022.
90. Usuda M, Fujimori K, Koyamada N, et al. Successful use of anti-CD20 monoclonal antibody (rituximab) for ABO-incompatible living- related liver transplantation. Transplantation 2005; 79: 12.

B-cells; Acute rejection; Graft survival; Transplantation

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