Does ex vivo CD34+ positive selection influence outcome after autologous hematopoietic stem cell transplantation in systemic sclerosis patients?

Transcription

1 Bone Marrow Transplantation (2016) 51, Macmillan Publishers Limited All rights reserved /16 SPECIAL REPORT Does ex vivo CD34+ positive selection influence outcome after autologous hematopoietic stem cell transplantation in systemic sclerosis patients? MC Oliveira 1, M Labopin 2, J Henes 3, J Moore 4, ND Papa 5, A Cras 6,7, I Sakellari 8, R Schroers 9, HU Scherer 10, A Cuneo 11, S Kyrcz-Krzemien 12, T Daikeler 13, T Alexander 14, J Finke 15, M Badoglio 16, B Simões 17, JA Snowden 18 and D Farge 19,20, for the EBMT Autoimmune Diseases Working Party This EBMT Autoimmune Disease Working Party study aimed to evaluate the influence of CD34+ positive graft selection (CD34+) on the outcome of systemic sclerosis (SSc) patients after autologous hematopoietic stem cell transplantation (AHSCT). Clinical and laboratory data from 138 SSc patients at diagnosis, before and after AHSCT were retrospectively analyzed. CD34+ selection was performed in 47.1% (n = 65) patients. By multivariate analysis adjusting for all factors differing between the two groups (without or with CD34+), there was no statistically significant difference in terms of overall survival (hazard ratio (HR): 0.98, 95% confidence interval (CI) , P = 0.96), PFS (HR: 1.55, 95% CI , P = 0.17) and incidence of relapse or progression (HR: 1.70, 95% CI , P = 0.13). We demonstrate that CD34+ does not add benefit to the outcome of SSc patient treated with AHSCT. These findings should be further confirmed by prospective randomized trials. Bone Marrow Transplantation (2016) 51, ; doi: /bmt ; published online 7 December 2015 INTRODUCTION Systemic sclerosis (SSc) is a chronic autoimmune disease (AD) that affects skin and internal organs. 1 Severe progressive cutaneous SSc with visceral involvement has a poor prognosis, with mortality rates that may reach 30% 5 years after diagnosis, despite standard therapies. 2,3 In the past 20 years, autologous hematopoietic stem cell transplantation (AHSCT) has been shown to be effective to treat severe or rapidly progressive SSc. Improved skin score and quality of life and at least stabilization of lung function were consistently reported in early phase II trials. 4 8 Recently, the phase II ASSIST 9 and the larger phase III ASTIS 10 prospective randomized trials showed better survival rates and improved skin, lung and functional status in patients treated with AHSCT as compared with monthly IV cyclophosphamide. Still, the transplant-related mortality reaching 10% and disease-progression rates of around 20 30% after AHSCT indicate that further improvements are still warranted Among current strategies to increase safety and efficacy of AHSCT, the benefit of ex vivo CD34+ positive selection of the graft remains debated. This study was therefore designed to evaluate the influence of ex vivo CD34+ selection on the outcome of SSc patients treated with AHSCT. PATIENTS AND METHODS This Autoimmune Disease Working Party (ADWP) multicenter retrospective study followed the European Society for Blood and Marrow Transplantation (EBMT) guidelines ( All EBMT-affiliated centers with eligible SSc patients were invited to participate. The study was approved in each participating center, according to local institutional review board rules, and full informed consent was obtained from all patients before AHSCT. Patients with diagnosis of SSc according to the American College of Rheumatology criteria and having received a first AHSCT between 2000 and 2012 were included, while those having been treated with irradiation as part of the transplant conditioning regimen or enrolled in the former EBMT ASTIS trial 10 were excluded. For centers that agreed to participate, primary data were collected, when available, using a standardized SSc minimal essential data B form. Data were collected by questionnaire or by the electronic EBMT data management system ProMISe. All EBMT participating centers were requested to report all consecutive transplants. Additional clinical and laboratory data at diagnosis, before and after AHSCT were 1 Division of Clinical Immunology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil; 2 EBMT, Hôpital Saint Antoine, Paris, France; 3 Medizinische Universitätsklinik Abt. II, Tübingen, Germany; 4 Department of Haematology, St Vincent s Hospital, Sydney, New South Wales, Australia; 5 Scleroderma Clinic, U.O.C. Day Hospital Rheumatology, Osp. G. Pini, Milan, Italy; 6 Assistance Publique-Hôpitaux de Paris, Saint-Louis Hospital, Cell Therapy Unit, Cord Blood Bank and CIC-BT501, Paris, France; 7 INSERM UMRS 1140, Paris Descartes, Faculté de Pharmacie, Paris, France; 8 Bone Marrow Transplantation Unit, George Papanicolaou General Hospital, Thessaloniki, Greece; 9 Ruhr-Universität Bochum, Medizinische Klinik Knappschaftskrankenhaus, Bochum, Germany; 10 Department of Rheumatology, Leiden University Medical Centre, Leiden, The Netherlands; 11 University of Ferrara St Anna Hospital, Ferrara, Italy; 12 Department of Hematology and Bone Marrow Transplantation, Medical University of Silesia, Katowice, Poland; 13 Department of Rheumatology, University Hospital Basel, Basel, Switzerland; 14 Department of Rheumatology and Clinical Immunology, Charité University Medicine Berlin, Berlin, Germany; 15 Department of Medicine Hematology and Oncology, University of Freiburg, Freiburg, Germany; 16 EBMT Paris Office, Hôpital Saint Antoine, Paris, France; 17 Division of Hematology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil; 18 Department of Hematology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK; 19 Paris 7 University, INSERM U1160, Paris, France and 20 Unité de Médecine Interne et Pathologie Vasculaire, Saint Louis Hospital, Assistance Publique des Hôpitaux de Paris, Paris 7 Denis Diderot University, Paris, France. Correspondence: Dr MC Oliveira, Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto, Avenida dos Bandeirantes 3900, Ribeirão Preto, Sao Paulo , Brazil. mcarolor@usp.br or Professor D Farge, EBMT Autoimmune Diseases Working Party Chair, Unité Clinique de Médecine Interne UF 04: Maladies Auto-immunes et Pathologie Vasculaire, Hôpital Saint-Louis, AP-HP Assistance Publique des Hôpitaux de Paris, INSERM UMRS 1160, Paris 7 Denis Diderot Université, Paris, France. dominique.farge-bancel@sls.aphp.fr Received 23 July 2015; revised 22 October 2015; accepted 23 October 2015; published online 7 December 2015

2 502 collected. Completed questionnaires were sent by local investigators to the ADWP EBMT data manager and evaluated for completion and consistency. Statistics Study end points were PFS, overall survival (OS), 100-day non-relapse mortality (NRM) and incidence of relapse or progression (RI). Patient-, disease- and transplant-related variables of the CD34+ selected and nonselected groups were compared, using Chi-square or Fisher exact test for categorical variables and Mann Whitney test for continuous variables. Probabilities of PFS and OS were calculated using the Kaplan Meier estimate. Cumulative incidence functions were used to estimate relapse and NRM in a competing risk setting. Univariate analyses used log-rank test for OS and PFS; Gray s test for cumulative incidence. Multivariate analyses were performed using Cox proportional-hazard model. All factors differing between two groups in terms of distribution associated with a non-restrictive P-value o0.15 were included in the model. All tests were two-sided with type I error rate fixed at 5. Statistical analyses were performed with the IBM-SPSS-Statistics, version 22 (IBM, Armonk, NY, USA) and R3.1.2 (R Development Core Team, Vienna, Austria) software packages. RESULTS AND DISCUSSION The study enrolled 138 SSc patients from 14 different transplant centers who fulfilled the inclusion criteria. All, but one patient who died shortly after cell infusion, engrafted with median time to absolute neutrophil counts /L of 11 days (range: 7 46). The 100-day NRM was 3.6%. The 3-year PFS and OS were respectively 6% (95% confidence interval (CI) ) and 82.7% ( ). The 5-year PFS and OS were 6% ( ) and 81.3% ( ) for the whole study group. Ex vivo positive CD34+ selection of the graft (CD34+) had been performed in 47.1% (n = 65) of patients before AHSCT. Baseline characteristics were similar in the CD34+ and non-selected patients, except for the presence of Raynaud s phenomenon before SSc diagnosis and of heart involvement before mobilization, which were more frequent in CD34+ patients (Table 1). The CD34+ and non-selected patients were not significantly different for mobilization and conditioning regimens or for interval from mobilization to AHSCT, minimizing although not ruling out any bias imposed by the immunosuppressive regimen. The non-selected patients had all (100%) received serotherapy (antithymocyte globulins (ATG) or alemtuzumab) added to the conditioning regimen as compared with 83% of the CD34+ patients who received serotherapy (ATG) (P = 002). Among all patients treated with ATG (n = 121), 78 (64%) had received the rabbit and 43 (35%) the horse ATG formulation. When the 11 patients not receiving any serotherapy were removed from the analysis, there was no difference in outcomes between the CD34+ selected and non-selected groups. Of note, when the 127 patients receiving serotherapy were stratified based on the presence of heart involvement before mobilization, outcomes (PFS, OS, NRM and RI) were similar for both the CD34+ selected and non-selected groups (Table 2). The number of infused CD34+ cells/kg was similar between CD34+ and non-selected patients, indicating that ex vivo selection did not significantly impair cell recovery. By univariate analysis, patient age at diagnosis or at AHSCT, interval from diagnosis or from mobilization to AHSCT, the number of infused CD34+ cells/kg, modified Rodnan s skin score and the presence of Raynaud s phenomenon or lung involvement at diagnosis were not different in terms of OS, PFS, NRM and RI in the CD34+ and non-selected groups. There was also no difference between groups in terms of 100-day NRM (3.1% vs 4.1%; P = 0.75), 3-year OS (80% vs 85%; P = 1), PFS (51.2% vs 68.1%, P =6)andNRM(6%vs7%;P =0.98). The 3-year RI was higher in the CD34+ group (42.6% vs 24.8%; P = 4; Figure 1). These results were not confirmed when adjusting for other factors by multivariate analysis. By multivariate analysis, there was no statistically significant difference between the CD34+ and non-selected groups in terms of OS (hazard ratio (HR): 0.98; 95% CI ; P = 0.96), PFS (HR: 1.55, 95% CI : P = 0.17) and RI (HR: 1.70; 95% CI ; P = 0.13). For other factors, OS was lower in the presence of heart involvement at SSc diagnosis (HR: 6.69; 95% CI ; P = 002) and of modified Rodnan s skin score 424 at mobilization (HR: 2.62; 95% CI ; P = 4). The RI was higher in the presence of gastrointestinal involvement at SSc diagnosis (HR: 2.31; 95% CI ; P = 2). These results are supported by previous studies where we 13,14 and others 15 had shown that heart involvement in SSc negatively affects patient outcome. The main purpose of this study was to determine whether positive CD34+ selection influenced clinical outcomes of AHSCT in SSc patients. Graft selection may affect lymphocyte ontogeny and delay immune reconstitution after transplant, as shown in previous studies. 16,17 Indeed, in allogeneic transplants, CD34+ selection delayed the CD4 T-lymphocyte reconstitution process, but the difference disappeared 8 months after transplantation, when compared with non-selected patients under similar conditions. 16 In addition, when comparing haploidentical hematopoietic stem cell transplant outcomes after ex vivo CD34+ selection or in vivo purging (alemtuzumab), the incidence of infections was similar, 17 indicating that both depletion methods are equally immunosuppressive. Viral infections have been reported in AD patients after T-celldepleted AHSCT. 18,19 However, although only one study 20 specifically addressed the issue, there is a general lack of evidence for CD34+ selection in AD. 11,12,21,22 The exception is a lupus study 19 which provides weak support, suggesting that effects may be disease specific. In our study, graft selection had no impact on the clinical results, especially on the neutrophil engraftment and infections were reported in 30% (19/63) of the CD34+ selected vs 34% (19/56 ) of the non-selected group (P = 6). The potential risk of re-injecting pathological T-cells with nonselected grafts may be outweighed by high cost, reduced numbers of transplanted cells and increased immunosuppression in patients receiving CD34+ grafts. 18,20,23,24 In the present study, CD34+ selection did not improve disease control after AHSCT. Unexpectedly, we detected a trend toward better outcomes in non-selected patients, with lower relapse rates and higher PFS. Although these findings may appear counter intuitive, it is possible that, besides removing autoreactive T-cells, the selection process may also eliminate regulatory T-cells and other protective cellular effectors. 25 Recent publications on post-transplantation immune monitoring in AD have shown that it is more important to promote a balance between tolerance and autoreactivity than to completely ablate the original immune system. 12,26,27 This is achieved via an increase in the number and function of regulatory cells, with thymic reactivation, emergence of a polyclonal TCR repertoire and normalization of epigenetic abnormalities among other immunological effects. 27,28 Therefore, the potential reinfusion of autoreactive T-cells within the non-selected graft may not be clinically relevant in SSc, as other mechanisms may be operating for reset of the immunological balance and disease control after AHSCT in AD. Further studies to explore details of CD34+ selection, such as the degree of T-cell depletion and post-transplant lymphocyte reconstitution, are still required. Finally, we cannot ignore that the retrospective nature of the study may have affected the results and limited its conclusions. Nevertheless, we believe that our findings do contribute to reduce costs, decrease the operational complexity and may increase safety of AHSCT for SSc. CONCLUSIONS This ADWP EBMT retrospective study demonstrates that ex vivo CD34+ selection of the graft does not add benefit to the OS, PFS and NRM in SSc patients after AHSCT. It also shows that SSc heart Bone Marrow Transplantation (2016) Macmillan Publishers Limited

3 Table 1. Patient and treatment characteristics Ex vivo manipulation Total (N = 138) P-value 503 No (n = 73) Yes (n = 65) Median follow-up, months 41 (1 145) 41 (1 161) 41 (1 161) Median age at diagnosis, years 34.6 (15 67) 39 (12 62) 37.8 ( ) 5 Median age at AHSCT, years 37.1 (17 68) 42.7 (17 62) 41 ( ) 9 Year of AHSCT 2009 ( ) 2008 ( ) 2009 ( ) 5 Year of AHSCT o (56.2%) 38 (58.5%) 79 (57.2%) (43.8%) 27 (41.5%) 59 (42.8%) Interval diagnosis to AHSCT, months 20.1 (2 146) 29.1 (3 256) 21.7 (2 256) 0.16 Interval mobilization to AHSCT, days 53 (22 337) 52 (8 204) 52.5 (8 337) 0.74 Number CD34+ cells infused 4.1 ( ) IQR: ( ) IQR: ( ) 0.50 mrss at mobilization 26 (2 49) IQR: (4 49) IQR: (2 49) 8 Patient gender Male 16 (22%) 23 (35%) 39 (28%) 8 Female 57 (78%) 42 (65%) 99 (72%) SSc type Limited 5 (7%) 7 (11%) 12 (9%) 1 Diffuse 68 (93%) 58 (89%) 126 (91%) Gastrointestinal involvement at diagnosis No 29 (40%) 35 (54%) 64 (46%) 0.10 Yes 44 (60%) 30 (46%) 74 (54%) Heart involvement at diagnosis No 64 (88%) 46 (71%) 110 (80%) 14 Yes 9 (12%) 19 (29%) 28 (20%) Lung involvement at diagnosis No 12 (17%) 16 (25%) 28 (20%) 5 Yes 60 (83%) 49 (75%) 109 (80%) Raynaud prior to diagnosis No 19 (26%) 5 (8%) 24 (18%) 05 Yes 54 (74%) 59 (92%) 113 (82%) Mobilization regimen Cyclo 2 g/m 2 60 (91.9%) 58 (98%) 118 (94%) 0.12 Cyclo 4 g/m 2 6 (9.1%) 1 (2%) 7 (6%) Conditioning regimen Cyclo only 0 11 (17%) 11 (8%) Cyclo+Alemtuzumab 6 (8%) 0 6 (4%) Cyclo+ATG 66 (90%) 52 (80%) 118 (86%) Other+ATG 1 (1%) 2 (3%) 3 (2%) Abbreviations: AHSCT = autologous hematopoietic stem cell transplantation; ATG = antithymocyte globulin; Cyclo = cyclophosphamide; IQR = interquartile range; mrss = modified Rodnan skin score; SSc = systemic sclerosis. P-values in bold correspond to significant results (Po5). a P-value is not relevant due to the low numbers in some groups. a Table 2. Clinical outcomes in CD34+ and non-selected transplants a in the presence or absence of heart involvement PFS OS NRM RI No heart involvement No selection (n = 64) 69.8 ( ) 87.5 ( ) 6.6 ( ) 23.6 ( ) CD34+ selection (n = 35) 56.6 ( ) 9 ( ) 4.4 ( ) 39 ( ) P Heart involvement No selection (n = 9) 55.6 ( ) 66.7 ( ) 11.1 (0.5 4) 33.3 ( ) CD34+ selection (n = 19) 35.5 ( ) 62.5 ( ) 10.5 ( 39.8) 54.0 (2 78.7) P Abbreviations: NRM = non-relapse mortality; OS = overall survival; RI = relapse incidence. a Transplants not including ATG in the conditioning regimen were excluded from the analysis (n = 11) Macmillan Publishers Limited Bone Marrow Transplantation (2016)

4 504 a b Overall survival Progression-free survival c Cumulative incidence of relapse No CD34+selection (n=73) CD34+selection (n=65) Figure 1. Kaplan Meier survival curves after AHSCT. (a) Overall survival curves from the CD34+ and non-selected patients are similar (P = 1); (b) PFS curves from the CD34+ and non-selected patients are at the limit of being considered different (P = 5); (c) RI is significantly higher in the CD34+ group of SSc patients (P = 4). involvement at baseline decreases OS and that gastrointestinal involvement contributes to disease progression after AHSCT. Further prospective randomized trials, under controlled and more homogeneous conditions, are warranted to confirm these findings. CONFLICT OF INTEREST The authors declare no conflict of interest. AUTHOR CONTRIBUTIONS DF, JS, MCO and ML conceived the study. DF, MCO, JH, JM, NDP, RS, IS, RS, HUS, SKK, TD, TA, JF, BS and JS planned the study and provided data; MB collected and managed the data; ML analyzed the data; MCO, DF and ML wrote the manuscript; DF and JS critically revised the manuscript. REFERENCES 1 Gabrielli A, Avvedimento EV, Krieg T. Scleroderma. N Engl J Med 2009; 360: Domsic RT, Medsger TA Jr. Connective tissue diseases: predicting death in SSc: planning and cooperation are needed. Nat Rev Rheumatol 2011; 7: Fransen J, Popa-Diaconu D, Hesselstrand R, Carreira P, Valentini G, Beretta L et al. Clinical prediction of 5-year survival in systemic sclerosis: validation of a simple prognostic model in EUSTAR centres. Ann Rheum Dis 2011; 70: Binks M, Passweg JR, Furst D, McSweeney P, Sullivan K, Besenthal C et al. Phase I/II trial of autologous stem cell transplantation in systemic sclerosis: procedure related mortality and impact on skin disease. Ann Rheum Dis 2001; 60: Farge D, Marolleau JP, Zohar S, Marjanovic Z, Cabane J, Mounier N et al. Autologous bone marrow transplantation in the treatment of refractory systemic sclerosis: early results from a French multicentre phase I-II study. Br J Haematol 2002; 119: Nash RA, McSweeney PA, Crofford LJ, Abidi M, Chen CS, Godwin JD et al. High-dose immunosuppressive therapy and autologous hematopoietic cell transplantation for severe systemic sclerosis: long-term follow-up of the US multicenter pilot study. Blood 2007; 110: Oyama Y, Barr WG, Statkute L, Corbridge T, Gonda EA, Jovanovic B et al. Autologous non-myeloablative hematopoietic stem cell transplantation in patients with systemic sclerosis. Bone Marrow Transplant 2007; 40: Farge D, Passweg J, van Laar JM, Marjanovic Z, Besenthal C, Finke J et al. Autologous stem cell transplantation in the treatment of systemic sclerosis: report from the EBMT/EULAR Registry. Ann Rheum Dis 2004; 63: Burt RK, Shah SJ, Dill K, Grant T, Gheorghiade M, Schroeder J et al. Autologous non-myeloablative haemopoietic stem-cell transplantation compared with pulse cyclophosphamide once per month for systemic sclerosis (ASSIST): an open-label, randomised phase 2 trial. Lancet 2011; 378: Van Laar JM, Farge D, Sont JK, Naraghi K, Marjanovic Z, Larghero J et al. Autologous hematopoietic stem cell transplantation vs intravenous pulse cyclophosphamide in diffuse cutaneous systemic sclerosis: a randomized clinical trial. JAMA 2014; 311: Farge D, Labopin M, Tyndall A, Fassas A, Mancardi GL, Van Laar J et al. Autologous hematopoietic stem cell transplantation for autoimmune diseases: an observational study on 12 years' experience from the European Group for Blood and Marrow Transplantation Working Party on Autoimmune diseases. Haematologica 2010; 95: Snowden JA, Saccardi R, Allez M, Ardizzone S, Arnold R, Cervera R et al. Haematopoietic SCT in severe autoimmune diseases: updated guidelines of the Bone Marrow Transplantation (2016) Macmillan Publishers Limited

5 European Group for Blood and Marrow Transplantation. Bone Marrow Transplant 2012; 47: Burt RK, Oliveira MC, Shah SJ, Moraes DA, Simoes B, Gheorghiade M et al. Cardiac involvement and treatment-related mortality after non-myeloablative haemopoietic stem-cell transplantation with unselected autologous peripheral blood for patients with systemic sclerosis: a retrospective analysis. Lancet 2013; 381: Saccardi R, Tyndall A, Coghlan G, Denton C, Edan G, Emdin M et al. Consensus statement concerning cardiotoxicity occurring during haematopoietic stem cell transplantation in the treatment of autoimmune diseases, with special reference tosystemic sclerosis and multiplesclerosis. Bone Marrow Transplant 2004; 34: Burt RK, Shah SJ, Gheorghiade M, Ruderman E, Schroeder J. Hematopoietic stem cell transplantation for systemic sclerosis: if you are confused, remember: it is a matter of the heart. J Rheumatol 2012; 39: Martínez C, Urbano-Ispizua A, Rozman C, Marín P, Rovira M, Sierra J et al. Immune reconstitution following allogeneic peripheral blood progenitor cell transplantation: comparison of recipients of positive CD34+ selected grafts with recipients of unmanipulated grafts. Exp Hematol 1999; 27: Marek A, Stern M, Chalandon Y, Ansari M, Ozsahin H, Güngör T et al. The impact of T-cell depletion techniques on the outcome after haploidentical hematopoietic SCT. Bone Marrow Transplant 2014; 49: Kohno K, Nagafuji K, Tsukamoto H, Horiuchi T, Takase K, Aoki K et al. Infectious complications in patients receiving autologous CD34-selected hematopoietic stem cell transplantation for severe autoimmune diseases. Transpl Infect Dis 2009; 11: Alchi B, Jayne D, Labopin M, Demin A, Sergeevicheva V, Alexander T et al. Autologous haematopoietic stem cell transplantation for systemic lupus erythematosus: data from the European Group for Blood and Marrow Transplantation registry. Lupus 2013; 22: Moore J, Brooks P, Milliken S, Biggs J, Ma D, Handel M et al. A pilot randomized trial comparing CD34-selected versus unmanipulated hemopoietic stem cell transplantation for severe, refractory rheumatoid arthritis. Arthritis Rheum 2002; 46: Saccardi R, Kozak T, Bocelli-Tyndall C, Fassas A, Kazis A, Havrdova E et al. Autologous stem cell transplantation for progressive multiple sclerosis: update of the European Group for Blood and Marrow Transplantation autoimmune diseases working party database. Mult Scler 2006; 12: Fassas A, Anagnostopoulos A, Kazis A, Kapinas K, Sakellari I, Kimiskidis V et al. Autologous stem cell transplantation in progressive multiple sclerosis an interim analysis of efficacy. J Clin Immunol 2000; 20: Carreras E, Saiz A, Marín P, Martínez C, Rovira M, Villamor N et al. CD34+ selected autologous peripheral blood stem cell transplantation for multiple sclerosis: report of toxicity and treatment results at one year of follow-up in 15 patients. Haematologica 2003; 88: Nash RA, Dansey R, Storek J, Georges GE, Bowen JD, Holmberg LA et al. Epstein-Barr virus-associated posttransplantation lymphoproliferative disorder after high-dose immunosuppressive therapy and autologous CD34-selected hematopoietic stem cell transplantation for severe autoimmune diseases. Biol Blood Marrow Transplant 2003; 9: Zhang L, Bertucci AM, Ramsey-Goldman R, Burt RK, Datta SK. Regulatory T cell (Treg) subsets return in patients with refractory lupus following stem cell transplantation and TGF-beta-producing CD8. Treg cells are associated with immunological remission of lupus. J Immunol 2009; 183: Marmont du Haut Champ AM. Hematopoietic stem cell transplantation for systemic lupus erythematosus. Clin Dev Immunol 2012; 2012: Alexander T, Bondanza A, Muraro PA, Greco R, Saccardi R, Daikeler T et al. SCT for severe autoimmune diseases: consensus guidelines of the European Society for Blood and Marrow Transplantation for immune monitoring and biobanking. Bone Marrow Transplant 2015; 50: Muraro PA, Robins H, Malhotra S, Howell M, Phippard D, Desmarais C et al. T cell repertoire following autologous stem cell transplantation for multiple sclerosis. J Clin Invest 2014; 124: Macmillan Publishers Limited Bone Marrow Transplantation (2016)