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• W1603235615 abstract "Several studies have analyzed the phenotype of repopulated T-lymphocytes following alemtuzumab induction; however there has been less scrutiny of the reconstituted B-cell compartment. In the context of a randomized controlled trial (RCT) comparing alemtuzumab induction with tacrolimus monotherapy against basiliximab induction with tacrolimus and mycophenolate mofetil (MMF) therapy in renal transplantation, we analyzed the peripheral B- and T-lymphocyte phenotypes of patients at a mean of 25 +/− 2 months after transplantation. We examined the relationship between peripheral lymphocyte phenotype and graft function. Patients who received alemtuzumab had significantly higher numbers of B cells including naïve, transitional and regulatory subsets. In contrast, the CD4+ T-cell compartment was dominated by a memory cell phenotype. Following either basiliximab or alemtuzumab induction patients with lower numbers of B cells or B subsets had significantly worse graft function. For alemtuzumab there was also a correlation between these subsets the stability of graft function and the presence of HLA-specific antibodies. These results demonstrate that a significant expansion of regulatory type B cells is associated with superior graft function and that this pattern is more common after alemtuzumab induction. This phenomenon requires further prospective study to see whether this phenotype could be used to customize immunotherapy. Several studies have analyzed the phenotype of repopulated T-lymphocytes following alemtuzumab induction; however there has been less scrutiny of the reconstituted B-cell compartment. In the context of a randomized controlled trial (RCT) comparing alemtuzumab induction with tacrolimus monotherapy against basiliximab induction with tacrolimus and mycophenolate mofetil (MMF) therapy in renal transplantation, we analyzed the peripheral B- and T-lymphocyte phenotypes of patients at a mean of 25 +/− 2 months after transplantation. We examined the relationship between peripheral lymphocyte phenotype and graft function. Patients who received alemtuzumab had significantly higher numbers of B cells including naïve, transitional and regulatory subsets. In contrast, the CD4+ T-cell compartment was dominated by a memory cell phenotype. Following either basiliximab or alemtuzumab induction patients with lower numbers of B cells or B subsets had significantly worse graft function. For alemtuzumab there was also a correlation between these subsets the stability of graft function and the presence of HLA-specific antibodies. These results demonstrate that a significant expansion of regulatory type B cells is associated with superior graft function and that this pattern is more common after alemtuzumab induction. This phenomenon requires further prospective study to see whether this phenotype could be used to customize immunotherapy. Alemtuzumab causes profound T-cell depletion and has been used successfully as an induction agent in solid-organ transplantation (1Newell KA Cendales LC Kirk AD Finding the right job for the tool: Alemtuzumab and its role in renal transplantation.Am J Transplant. 2008; 8: 1363-1364Crossref PubMed Scopus (6) Google Scholar,2Weaver TA Kirk AD Alemtuzumab.Transplantation. 2007; 84: 1545-1547Crossref PubMed Scopus (31) Google Scholar). The experience in renal transplantation has generally been positive with good medium-term outcomes in published studies (3Cai J Terasaki PI Induction immunosuppression improves long-term graft and patient outcome in organ transplantation: An analysis of United Network for Organ Sharing registry data.Transplantation. 2010; 90: 1511-1515Crossref PubMed Scopus (118) Google Scholar, 4Clatworthy MR Friend PJ Calne RY et al.Alemtuzumab (CAMPATH-1H) for the treatment of acute rejection in kidney transplant recipients: Long-term follow-up.Transplantation. 2009; 87: 1092-1095Crossref PubMed Scopus (49) Google Scholar, 5Knechtle SJ Fernandez LA Pirsch JD et al.Campath-1H in renal transplantation: The University of Wisconsin experience.Surgery. 2004; 136: 754-760Abstract Full Text Full Text PDF PubMed Scopus (135) Google Scholar). Further interest in alemtuzumab induction was generated by the demonstration that the induction of tolerance in animal models was facilitated by profound T-cell depletion (6Wells AD Li XC Li Y Walsh MC et al.Requirement for T-cell apoptosis in the induction of peripheral transplantation tolerance.Nat Med. 1999; 5: 1303-1307Crossref PubMed Scopus (525) Google Scholar). Thus, clinical studies were carried out to examine its role in novel immunosuppression regimes consisting of minimal or calcineurin inhibitor-free maintenance treatment (7Kirk 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: 1051-1059Crossref PubMed Scopus (119) Google Scholar,8Knechtle SJ Pirsch JD Fechner Jr, J et al.Campath-1H induction plus rapamycin monotherapy for renal transplantation: Results of a pilot study.Am J Transplant. 2003; 3: 722-730Crossref PubMed Scopus (350) Google Scholar). These trials yielded unacceptably high rates of acute rejection; however other studies in which alemtuzumab induction was followed by long-term tacrolimus or ciclosporin monotherapy as maintenance treatment have yielded acceptable results with excellent graft function (9Margreiter R Klempnauer J Neuhaus P et al.Alemtuzumab (Campath-1H) and tacrolimus monotherapy after renal transplantation: Results of a prospective randomized trial.Am J Transplant. 2008; 8 (doi:10.1111/j.1600-6143.2008.02273.x.): 1480-1485Crossref PubMed Scopus (98) Google Scholar, 10Tan HP Donaldson J Basu A et al.Two hundred living donor kidney transplantations under alemtuzumab induction and tacrolimus monotherapy: 3-year follow-up.Am J Transplant. 2009; 9: 355-366Crossref PubMed Scopus (53) Google Scholar, 11Vathsala A Ona ET Tan SY et al.Randomized trial of alemtuzumab for prevention of graft rejection and preservation of renal function after kidney transplantation.Transplantation. 2005; 80: 765-774Crossref PubMed Scopus (101) Google Scholar). The first clinical studies in renal transplantation demonstrated that alemtuzumab caused profound and prolonged depletion of T lymphocytes (12Watson CJ Bradley JA Friend PJ et al.Alemtuzumab (CAMPATH 1H) induction therapy in cadaveric kidney transplantation—efficacy and safety at five years.Am J Transplant. 2005; 5: 1347-1353Crossref PubMed Scopus (212) Google Scholar). CD4+ T cells took the longest time to repopulate and the process was often incomplete more than 1 year after treatment. It has also been shown in human and animal models of both autoimmune and alloimmune disease that the reconstituted CD4+ T-cell pool consists of cells with a predominant memory phenotype (CD45RO+) (13Brett S Baxter G Cooper H et al.Repopulation of blood lymphocyte sub-populations in rheumatoid arthritis patients treated with the depleting humanized monoclonal antibody, CAMPATH-1H.Immunology. 1996; 88: 13-19Crossref PubMed Scopus (86) Google Scholar,14Trzonkowski P Zilvetti M Chapman S et al.Homeostatic repopulation by CD28-CD8+ T cells in alemtuzumab-depleted kidney transplant recipients treated with reduced immunosuppression.Am J Transplant. 2008; 8: 338-347Crossref PubMed Scopus (105) Google Scholar). Such CD4+ memory cells have also been identified in the biopsies of patients undergoing T-cell-mediated rejection of renal allografts after induction with alemtuzumab (15Gallon 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: 539-545Crossref PubMed Scopus (27) Google Scholar). Furthermore, a relative increase in the population of CD4+ CD25+ FoxP3+ T regulatory cells has been demonstrated in recipients of renal transplants following alemtuzumab induction (16Bloom DD Chang Z Fechner JH et al.CD4+ CD25+ FOXP3+ regulatory T cells increase de novo in kidney transplant patients after immunodepletion with Campath-1H.Am J Transplant. 2008; 8 (doi: 10.1111/j.1600-6143.2007.02134.x.): 793-802Crossref PubMed Scopus (152) Google Scholar). It has also been shown that CD8+ T cells reestablish themselves more rapidly than CD4+ cells and that some of these cells possess a regulatory phenotype (14Trzonkowski P Zilvetti M Chapman S et al.Homeostatic repopulation by CD28-CD8+ T cells in alemtuzumab-depleted kidney transplant recipients treated with reduced immunosuppression.Am J Transplant. 2008; 8: 338-347Crossref PubMed Scopus (105) Google Scholar). Human B cells also express CD52 and they are profoundly depleted following alemtuzumab induction. The reconstitution of B-cell subsets has not previously been studied in human renal transplantation. In the autoimmune field it has been demonstrated that B cells reconstitute within 3 months of treatment with a predominance of the mature naïve phenotype and that this is associated with a sustained increase in levels of B-cell activating factor (BAFF) (17Thompson SA Jones JL Cox AL Compston DA Coles AJ B-cell reconstitution and BAFF after alemtuzumab (Campath-1H) treatment of multiple sclerosis.J Clin Immunol. 2010; 30 (doi: 10.1007/s10875-009-9327-3.): 99-105Crossref PubMed Scopus (188) Google Scholar). The recent association of certain B-cell phenotypes with operational tolerance in renal allografts and the demonstration of immune regulation by human B cells encouraged us to study the reconstitution of B cells following alemtuzumab induction and compare this with standard basiliximab induction, in the context of a clinical trial (18Pallier A Hillion S Danger R et al.Patients with drug-free long-term graft function display increased numbers of peripheral B cells with a memory and inhibitory phenotype.Kidney Int. 2010; 78 (doi: 10.1038/ki.2010.162.): 503-513Abstract Full Text Full Text PDF PubMed Scopus (221) Google Scholar, 19Lund FE Randall TD Effector and regulatory B cells: Modulators of CD4(+) T cell immunity.Nat Rev Immunol. 2010; 10: 236-247Crossref PubMed Scopus (492) Google Scholar, 20Mauri C Blair PA Regulation of immunity and autoimmunity by B cells regulatory B cells in autoimmunity: Developments and controversies.Curr Opin Immunol. 2010; 22: 761-767Crossref PubMed Scopus (102) Google Scholar, 21Sagoo P Perucha E Sawitzki B et al.Development of a cross-platform biomarker signature to detect renal transplant tolerance in humans.J Clin Invest. 2010; 120 (doi: 10.1172/JCI39922.): 1848-1861Crossref PubMed Scopus (443) Google Scholar, 22Newell KA Asare A Kirk AD et al.Identification of a B cell signature associated with renal transplant tolerance in humans.J Clin Invest. 2010; 120 (doi: 10.1172/JCI39933.): 1836-1847Crossref PubMed Scopus (565) Google Scholar). We have recently completed a randomized controlled study comparing two steroid avoidance regimes. The control arm received basiliximab induction followed by maintenance with MMF and tacrolimus. The study arm received alemtuzumab induction followed by tacrolimus monotherapy. Here we present the results of lymphocyte subset analysis at a mean of 25 +/− 2 months following transplantation and show how this correlates with clinical outcomes including graft function and HLA-specific antibody production. Samples were obtained from participants in a randomized control study (European clinical trials database number: 2006-000830-11) comparing alemtuzumab induction and maintenance tacrolimus monotherapy with basiliximab induction and maintenance tacrolimus and MMF therapy. The study was approved by the local ethics committee (Research ethics reference: 06/Q1206/64). All adult low to medium immunological risk patients (defined by the absence of: preformed donor-specific antibodies; previous early (less than 3 months) immunological graft loss; and 2 HLA-DR mismatch) were eligible and informed consent was obtained to participate. Venous blood samples for serum and peripheral blood mononuclear cells (PBMCs) were collected from consented renal transplant recipients at a mean of 25 (95% CI 23–27) months following transplantation. Blood samples were obtained from both healthy controls (n = 12), and patients undergoing dialysis treatment (n = 12) as a representation of the peripheral lymphocyte repertoire immediately prior to transplantation. Patients received 30 mg of alemtuzumab and 1 g of methylprednisolone prior to implantation on day −0. Maintenance immunosuppression consisted of tacrolimus with trough levels of 9–14 ng/mL for the first 3 months post-transplantation and 4–9 ng/mL thereafter. No routine maintenance steroids were given. Patients received 20 mg of basiliximab along with 1 g of methylprednisolone on day −0. A further 20 mg dose of basiliximab was administered on day −4. Maintenance immunosuppression consisted of tacrolimus (target levels as for the alemtuzumab group) and MMF at a dose of 1.5 g/day. Mycophenolic acid levels were not measured. Serum samples were analyzed for the presence of HLA-specific antibodies by luminex technology. A total of 10 μL of serum was mixed with 2.5 μL of HLA-single antigen luminex beads (One Lambda Inc., Los Angeles, CA, USA) in a 96-well plate and incubated for 30 min. After washing, 50 μL of diluted PE-conjugated goat antihuman IgG (1:100) was added to each well followed by 30 min incubation and three further washes. The beads were suspended in 80 μL of PBS and analyzed on a luminex platform. Serum reactivity was determined by the fluorescent signal for each HLA-coated bead after correction for nonspecific binding to the negative control bead. A normalized median fluorescent intensity (MFI) of >1000 was considered positive on the basis of local validation. Absolute lymphocyte numbers were analyzed using Beckton Dickinson trucount beads. Fifteen microliters each of the Multitest reagents CD3/CD8/CD45/CD4 and CD3/CD16+CD56/CD45/CD19 were added to two trucount tubes. A total of 50 μL of undiluted blood was added to each tube and incubated at room temperature for 15 min in darkness. A total of 450 μL of red cell lysis solution was added to each tube followed by further 15 min incubation before flow cytometric analysis. Peripheral blood mononuclear cells (PBMC) were isolated by ficoll density gradient centrifugation. The following antibodies were used for flow cytometry; CD4-PerCP (clone SK3), CD3-FITC (clone SK7), CD45RA-APC (clone AH9), CD45RO-PE (clone UCHL1), CD19-PerCP (clone 4G7), CD27-APC (clone M-T271), IgD-PE (clone IA6-2), CD24-PE (clone ML5), CD38-APC (clone HIT2), CD5-FITC (clone UCHT2) and CD1d-PE (clone CD1d42). A total of 500 000 PBMC were mixed with the antibodies and incubated in darkness at 4°C for 30 min. After three washes with ice cold 1% PBS-BSA, the cells were suspended in 0.5% PBS formaldehyde and analyzed on a Beckton Dickinson-FACS calibur flow cytometer. Isotype-matched negative controls were used appropriately. The T- and B-cell subsets were defined by the surface markers as summarized in Table 1.Table 1:Identification of various lymphocyte subsets by the surface markersCell typeSurface CD markersReferencesT cellsCD45+CD3+B cellsCD45+CD19+NK cellsCD45+CD56+CD16+Naïve T cellsCD4+/CD8+ and CD45RA+CD45RO−13Brett S Baxter G Cooper H et al.Repopulation of blood lymphocyte sub-populations in rheumatoid arthritis patients treated with the depleting humanized monoclonal antibody, CAMPATH-1H.Immunology. 1996; 88: 13-19Crossref PubMed Scopus (86) Google Scholar,15Gallon 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: 539-545Crossref PubMed Scopus (27) Google Scholar,27Weigel G Griesmacher A Karimi A et al.Effect of mycophenolate mofetil therapy on lymphocyte activation in heart transplant recipients.J Heart Lung Transplant. 2002; 21: 1074-1079Abstract Full Text Full Text PDF PubMed Scopus (48) Google ScholarMemory T cellsCD4+/CD8+ and CD45RA−CD45RO+13Brett S Baxter G Cooper H et al.Repopulation of blood lymphocyte sub-populations in rheumatoid arthritis patients treated with the depleting humanized monoclonal antibody, CAMPATH-1H.Immunology. 1996; 88: 13-19Crossref PubMed Scopus (86) Google Scholar,15Gallon 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: 539-545Crossref PubMed Scopus (27) Google Scholar,27Weigel G Griesmacher A Karimi A et al.Effect of mycophenolate mofetil therapy on lymphocyte activation in heart transplant recipients.J Heart Lung Transplant. 2002; 21: 1074-1079Abstract Full Text Full Text PDF PubMed Scopus (48) Google ScholarNaïve B cellsCD19+CD27−IgD+22Newell KA Asare A Kirk AD et al.Identification of a B cell signature associated with renal transplant tolerance in humans.J Clin Invest. 2010; 120 (doi: 10.1172/JCI39933.): 1836-1847Crossref PubMed Scopus (565) Google ScholarClass unswitched (marginal) memory B cellsCD19+CD27+IgD+22Newell KA Asare A Kirk AD et al.Identification of a B cell signature associated with renal transplant tolerance in humans.J Clin Invest. 2010; 120 (doi: 10.1172/JCI39933.): 1836-1847Crossref PubMed Scopus (565) Google ScholarClass switched memory B cellsCD19+CD27+IgD−22Newell KA Asare A Kirk AD et al.Identification of a B cell signature associated with renal transplant tolerance in humans.J Clin Invest. 2010; 120 (doi: 10.1172/JCI39933.): 1836-1847Crossref PubMed Scopus (565) Google ScholarTransitional B cellsCD19+CD24hi CD38hi33Toso C Edgar R Pawlick R et al.Effect of different induction strategies on effector, regulatory and memory lymphocyte sub-populations in clinical islet transplantation.Transpl Int. 2009; 22: 182-191Crossref PubMed Scopus (44) Google Scholar,35Sutter JA Kwan-Morley J Dunham J et al.A longitudinal analysis of SLE patients treated with rituximab (anti-CD20): Factors associated with B lymphocyte recovery.Clin Immunol. 2008; 126 (doi: 10.1016/j.clim.2007.11.012.): 282-290Crossref PubMed Scopus (54) Google Scholar,36Palanichamy A Barnard J Zheng B et al.Novel human transitional B cell populations revealed by B cell depletion therapy.J Immunol. 2009; 182 (doi: 10.4049/jimmunol.0801859.): 5982-5993Crossref PubMed Scopus (211) Google ScholarRegulatory B cellsCD19+CD5+CD1dhi18Pallier A Hillion S Danger R et al.Patients with drug-free long-term graft function display increased numbers of peripheral B cells with a memory and inhibitory phenotype.Kidney Int. 2010; 78 (doi: 10.1038/ki.2010.162.): 503-513Abstract Full Text Full Text PDF PubMed Scopus (221) Google Scholar, 27Weigel G Griesmacher A Karimi A et al.Effect of mycophenolate mofetil therapy on lymphocyte activation in heart transplant recipients.J Heart Lung Transplant. 2002; 21: 1074-1079Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar Open table in a new tab For the purpose of this analysis, graft function was assessed using creatinine measurements and applying the four-variable MDRD equation (23Klahr S Levey AS Beck GJ et al.The effects of dietary protein restriction and blood-pressure control on the progression of chronic renal disease. Modification of Diet in Renal Disease Study Group.N Engl J Med. 1994; 330: 877-884Crossref PubMed Scopus (2079) Google Scholar). eGFR was estimated at 6 months after transplantation and at the time of sampling. ΔeGFR was defined as the difference between the eGFR at 6 months and eGFR at the time of sampling, and was used as a measure of allograft function stability. Statistical analysis was performed by SPSS version 17 and Graphpad Prism version 5 for Windows. Categorical variables were compared using Fisher’s exact test and continuous variables using the Mann–Whitney U test for data with skewed distribution and independent sample Student’s t-test for normally distributed data. The absolute numbers of various lymphocytes were related to graft function by the nonparametric Spearman’s correlation. A p-value of <0.05 was considered significant. A total of 96 out of 116 patients enrolled in this RCT (51 alemtuzumab and 45 basiliximab) had peripheral blood lymphocyte phenotype analysis and serum detection of HLA-specific antibodies. Excluded patients consisted of 4 deaths, 2 primary graft nonfunctions, 3 patients lost to follow-up and 11 who declined to give blood samples. Baseline demographics of the two groups were similar and the primary outcome, isotopic GFR measurement at 12 months, was not significantly different (manuscript in preparation). Even though graft and patient survival were similar, patients in the alemtuzumab group had less biopsy proven acute rejection (alemtuzumab group 10.3% (n = 6), basiliximab group 24.1% (n = 14), p < 0.05). Similar numbers of patients in each group developed HLA-specific antibodies after a mean of 25 months (Figure 1), with no differences in the number of patients with donor-specific antibody (DSA) or nondonor-specific antibody (NDSA). The total lymphocyte count was assessed longitudinally following transplantation as shown in Figure 2. Lymphocyte depletion was profound in the alemtuzumab group and repopulation occurred gradually over the first year. By 9 months post-transplantation there was no longer any statistically significant difference between the lymphocyte counts in the two groups. Further analysis of the absolute numbers of lymphocyte subpopulations in the peripheral blood was carried out using trucount beads at a mean of 25 months post-transplantation. Figure 3 represents the proportion of total lymphocytes and the absolute numbers of lymphocytes in the two intervention groups and the two control groups. In comparison to the healthy controls, patients in both the alemtuzumab and basiliximab groups were lymphopenic at the time of sampling. The proportion and the absolute number of CD3+ T lymphocytes were less in the alemtuzumab group when compared to both the healthy volunteers and dialysis patients. In large part this was due to the significantly depleted CD4+ lymphocyte population in this group. There was also an increase in the proportion of both CD19+ B cells and NK cells in the alemtuzumab group when compared to both control groups. The absolute numbers were only increased in comparison to dialysis patients due to relative lymphopenia of this population compared to healthy controls. When the same set of controls were compared to the basiliximab group, no significant differences were demonstrated in the proportions of any of the lymphocyte subsets but the absolute number of CD3+ T cells, CD4+ T cells, CD19+ B cells and NK cells were significantly lower than in healthy controls. This is once again a reflection of the relative lymphopenia of these patients. Further analysis within the CD4+ T- and B-cell compartments is summarized in Figures 4 and 5. Within the CD4+ T-cell compartment of patients treated with alemtuzumab, the ratio of naïve (CD45RA+ CD45RO-) to memory cells (CD45RA− CD45RO+) was not significantly different to either healthy controls or dialysis patients even though a trend toward a higher ratio could be seen. In contrast the basiliximab group had a significantly higher ratio of naïve to memory CD4+ cells in comparison to both healthy controls and dialysis patients (Figure 5a)Figure 5:Comparison of CD4+ T- and B-cell subsets in the control groups and alemtuzumab/basiliximab groups. Patients in the basiliximab group have a significantly higher naïve to memory CD4+ T-cell ratio, while a similar trend was seen in the alemtuzumab group as well, the results were not statistically significant (5a). The alemtuzumab group had the highest naïve to memory B ratio when compared to both control groups and even the basiliximab group had a high naïve to memory B-cell ratio when compared to healthy controls but the results were not significantly different to those of the dialysis controls (5b). The proportion of transitional B cells were significantly higher in the alemtuzumab group when compared to both the controls groups but the absolute numbers were only high in comparison to the dialysis patients. In contrast, the absolute number of the transitional B cells were significantly lower in the basiliximab group when compared to healthy controls (5c). While the proportion and absolute numbers of the B regs were significantly lower in the basiliximab group when compared to healthy controls they were comparable in the alemtuzumab group (5d).View Large Image Figure ViewerDownload Hi-res image Download (PPT) Within the reconstituted B-cell compartment, the alemtuzumab group had a significantly higher number of CD19+CD27−IgD+ naive cells when compared to both healthy controls and dialysis patients. This group also had a lower number of memory B cells (both CD19+CD27+IgD+ nonclass switched and CD19+CD27+IgD− class switched) when compared to healthy controls but these numbers were similar to those seen in dialysis patients. This was reflected in a significantly higher naïve to memory B-cell ratio in the alemtuzumab group when compared to both control groups (Figure 5b). Furthermore the alemtuzumab group had a significantly higher proportion of transitional B cells when compared to both control groups with absolute numbers that were restored to levels found in healthy controls (Figure 5c). The proportion and absolute number of CD5+CD1dhi B cells in this group were comparable to healthy controls but higher than dialysis patients (Figure 5d). There was a relative increase in the numbers of naïve B cells in the basiliximab group when compared to both the controls although this difference was not as marked as that in the alemtuzumab group (Figure 5b). However, in contrast to the alemtuzumab group, the basiliximab group had significantly lower absolute numbers of both transitional B cells (Figure 5c) and CD5+CD1dhi regulatory B cells (Figure 5d). We sought to correlate the lymphocyte phenotype with graft function assessed by eGFR at the time of the analysis and by ΔeGFR, an indicator of the stability of graft function between 6 and 25 months after transplantation. Table 2 summarizes the correlation of absolute numbers of lymphocyte subsets with both eGFR and ΔeGFR. There was a significant correlation between graft function and the absolute numbers of B cells, naïve B cells, transitional B cells and regulatory B-cell cells in the alemtuzumab group. A similar correlation was demonstrated between these subsets and stability of graft function. These correlations remained statistically significant in a multivariate analysis after adjusting for significant confounding clinical variables including recipient age, donor age and donor recover creatinine (Supporting Table 1).Table 2:Correlation of lymphocyte phenotype to graft functionSpearman RSpearman RSpearmanSpearman RLymphocyte phenotype(eGFR)p-Value(Δ eGFR)(eGFR)(Δ eGFR)p-ValueCD4+ T ells1.50.3−0.140.30.40.0070.20.2CD8+ T cells0.10.5−0.20.30.20.20.10.3CD4−CD8− T cells0.20.20.140.30.060.7−0.020.9Naïve CD4+ T cells0.20.10.030.90.6<0.0010.30.1Memory CD4+ T cells0.020.9−0.10.50.10.4−0.020.9NK cells0.10.40.10.30.170.2−0.060.7B cells0.30.030.30.040.360.020.160.3Naïve B cells0.30.030.40.0030.40.010.250.1Class unswitched memory B cells0.350.010.150.30.30.040.070.7Class switched memory B cells−0.120.4−0.20.20.10.4−0.10.3Transitional B cells0.30.020.50.0010.30.030.10.3Regulatory B cells0.340.010.40.0030.40.0080.30.03eGFR was calculated at the time of sampling (a mean of 25 months after transplantation).Δ eGFR was the difference between the eGFR at 6 months and at the time of sampling. Open table in a new tab eGFR was calculated at the time of sampling (a mean of 25 months after transplantation). Δ eGFR was the difference between the eGFR at 6 months and at the time of sampling. In the basiliximab group there were significant correlations between absolute numbers of CD4+ T cells, and in particular CD4+ CD45RA+ cells, and eGFR but not ΔeGFR. Naïve and transitional B cells also correlated with eGFR but not ΔeGFR. Regulatory B cells correlated with both eGFR and ΔeGFR. Both the alemtuzumab and basiliximab groups were divided into tertiles (stratified by absolute numbers of transitional B cells, regulatory B cells and naïve B cells) for further functional analysis. Figure 6 demonstrates that the patients with the highest numbers of these B-cell subsets were almost entirely restricted to the alemtuzumab group, although there was some overlap with the basiliximab group in lower tertiles. There was a stepwise increase in the eGFR and ΔeGFR across the three tertiles of all three B-cell subsets within the alemtuzumab group. Patients in the lowest tertile of all three B subsets had the worst eGFR and the greatest deterioration in eGFR while the converse was true of patients in the highest tertile. Patients with the highest tertiles of transitional and regulatory B cells had no DSA, and only one patient in the highest tertile for naive B cells had a DSA (Figure 7). Such a significant relationship could not be demonstrated across the tertiles of the basiliximab group although there was a significant trend toward better eGFR in the tertiles with higher number of B-cell subsets (Figure S1).Figure 7:Comparison of eGFR, ΔeGFR and HLA-specific antibodies across the three tertiles based on the absolute numbers of the naive B cells, transitional B cells and regulatory B cells. For all three B-cell subtypes, the lowest tertile had the lowest eGFR" @default.
• W1603235615 created "2016-06-24" @default.
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• W1603235615 date "2012-04-01" @default.
• W1603235615 modified "2023-10-15" @default.
• W1603235615 title "An Analysis of Lymphocyte Phenotype After Steroid Avoidance With Either Alemtuzumab or Basiliximab Induction in Renal Transplantation" @default.
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