Hematopoietic cell-based and non-hematopoietic cell-based strategies for immune tolerance induction in living-donor renal transplantation: A systematic review

Wolfe, 1999, Comparison of mortality in all patients on dialysis, patients on dialysis awaiting transplantation, and recipients of a first cadaveric transplant, N Engl J Med, 341, 1725, 10.1056/NEJM199912023412303 Hariharan, 2000, Improved graft survival after renal transplantation in the United States, 1988 to 1996, N Engl J Med, 342, 605, 10.1056/NEJM200003023420901 Lodhi, 2011, Solid organ allograft survival improvement in the United States: the long-term does not mirror the dramatic short-term success, Am J Transp, 11, 1226, 10.1111/j.1600-6143.2011.03539.x Karuthu, 2012, Common infections in kidney transplant recipients, Clin J Am Soc Nephrol, 7, 2058, 10.2215/CJN.04410512 Krynitz, 2013, Risk of skin cancer and other malignancies in kidney, liver, heart and lung transplant recipients 1970 to 2008--a Swedish population-based study, Int J Cancer, 132, 1429, 10.1002/ijc.27765 Chowdhury, 2019, Post-transplant diabetes mellitus, Clin Med (Lond), 19, 392, 10.7861/clinmed.2019-0195 Rao, 2018, Cardiovascular disease after kidney transplant, Semin Nephrol, 38, 291, 10.1016/j.semnephrol.2018.02.008 Madariaga, 2016, Effect of tolerance versus chronic immunosuppression protocols on the quality of life of kidney transplant recipients, JCI Insight, 1, 10.1172/jci.insight.87019 Sellarés, 2012, Understanding the causes of kidney transplant failure: the dominant role of antibody-mediated rejection and nonadherence, Am J Transplant, 12, 388, 10.1111/j.1600-6143.2011.03840.x Sayegh, 2007, Clinical update: immunosuppression minimisation, Lancet (London, England), 369, 1676, 10.1016/S0140-6736(07)60762-4 Orlando, 2010, Clinical operational tolerance after renal transplantation: current status and future challenges, Ann Surg, 252, 915, 10.1097/SLA.0b013e3181f3efb0 Schardt, 2007, Utilization of the PICO framework to improve searching PubMed for clinical questions, BMC Med Inform Decis Mak, 7, 16, 10.1186/1472-6947-7-16 Page, 2021, The PRISMA 2020 statement: an updated guideline for reporting systematic reviews, BMJ, 372 Li, 2022, Chapter 5: Collecting data Critical Appraisal Skills Programme, 2018 Jeremy Howick, 2011 Higgins, 2011, Chapter 4.6.1: Characteristics of included studies Mathew, 2000, Donor bone marrow-derived chimeric cells present in renal transplant recipients infused with donor marrow. I. Potent regulators of recipient antidonor immune responses, Transplantation, 70, 1675, 10.1097/00007890-200012270-00003 Lee, 2020, Inducing transient mixed chimerism for allograft survival without maintenance immunosuppression with combined kidney and bone marrow transplantation: protocol optimization, Transplantation, 104, 1472, 10.1097/TP.0000000000003006 Ciancio, 2002, Effect of living-related donor bone marrow infusion on chimerism and in vitro immunoregulatory activity in kidney transplant recipients, Transplantation, 74, 488, 10.1097/00007890-200208270-00010 Vondran, 2012, In vitro and in vivo proof of tolerance after two-step haploidentical bone marrow and kidney transplantation of the same donor, Transplantation, 93, e23, 10.1097/TP.0b013e3182492247 Kawai, 2014, Long-term results in recipients of combined HLA-mismatched kidney and bone marrow transplantation without maintenance immunosuppression, Am J Transplant, 14, 1599, 10.1111/ajt.12731 Trivedi, 2005, Allogeneic hematopoietic stem-cell transplantation, mixed chimerism, and tolerance in living related donor renal allograft recipients, Transplant Proc, 37, 737, 10.1016/j.transproceed.2005.01.028 Fangmann, 2011, Kidney transplant from the same donor without maintenance immunosuppression after previous hematopoietic stem cell transplant, Am J Transplant, 11, 156, 10.1111/j.1600-6143.2010.03352.x Scandling, 2012, Tolerance and withdrawal of immunosuppressive drugs in patients given kidney and hematopoietic cell transplants, Am J Transp, 12, 1133, 10.1111/j.1600-6143.2012.03992.x Leventhal, 2013, Genomic biomarkers correlate with HLA-identical renal transplant tolerance, J Am Soc Nephrol, 24, 1376, 10.1681/ASN.2013010068 Leventhal, 2015, Immune reconstitution/immunocompetence in recipients of kidney plus hematopoietic stem/facilitating cell transplants, Transplantation, 99, 288, 10.1097/TP.0000000000000605 Vanikar, 2018, Six years' experience of tolerance induction in renal transplantation using stem cell therapy, Clin Immunol, 187, 10, 10.1016/j.clim.2017.07.024 Vanikar, 2011, Effect of co-transplantation of mesenchymal stem cells and hematopoietic stem cells as compared to hematopoietic stem cell transplantation alone in renal transplantation to achieve donor hypo-responsiveness, Int Urol Nephrol, 43, 225, 10.1007/s11255-009-9659-1 Vanikar, 2012, Stem cell transplantation in living donor renal transplantation for minimization of immunosuppression, Transplantation, 94, 845, 10.1097/TP.0b013e3182664000 Tan, 2012, Induction therapy with autologous mesenchymal stem cells in living-related kidney transplants: a randomized controlled trial, Jama, 307, 1169, 10.1001/jama.2012.316 Peng, 2013, Donor-derived mesenchymal stem cells combined with low-dose tacrolimus prevent acute rejection after renal transplantation: a clinical pilot study, Transplantation, 95, 161, 10.1097/TP.0b013e3182754c53 Mathew, 2018, A phase I clinical trial with ex vivo expanded recipient regulatory T cells in living donor kidney transplants, Sci Rep, 8, 7428, 10.1038/s41598-018-25574-7 Roemhild, 2020, Regulatory T cells for minimising immune suppression in kidney transplantation: phase I/IIa clinical trial, bmj, 371 Sawitzki, 2020, Regulatory cell therapy in kidney transplantation (The ONE Study): a harmonised design and analysis of seven non-randomised, single-arm, phase 1/2A trials, Lancet (London, England), 395, 1627, 10.1016/S0140-6736(20)30167-7 Harden, 2021, Feasibility, long-term safety, and immune monitoring of regulatory T cell therapy in living donor kidney transplant recipients, Am J Transplant, 21, 1603, 10.1111/ajt.16395 Owen, 1945, Immunogenetic consequences of vascular anastomoses between bovine twins, Science, 102, 400, 10.1126/science.102.2651.400 Billingham, 1953, Actively acquired tolerance'of foreign cells, Nature, 172, 603, 10.1038/172603a0 Billingham, 1952, Tolerance to homografts, twin diagnosis, and the freemartin condition in cattle, Heredity, 6, 201, 10.1038/hdy.1952.20 Slavin, 1977, Induction of specific tissue transplantation tolerance using fractionated total lymphoid irradiation in adult mice: long-term survival of allogeneic bone marrow and skin grafts, J Exp Med, 146, 34, 10.1084/jem.146.1.34 Bluestone, 2010, The Immune Tolerance Network at 10 years: tolerance research at the bedside, Nat Rev Immunol, 10, 797, 10.1038/nri2869 Massart, 2016, The DESCARTES-Nantes survey of kidney transplant recipients displaying clinical operational tolerance identifies 35 new tolerant patients and 34 almost tolerant patients, Nephrol Dial Transplant, 31, 1002, 10.1093/ndt/gfv437 Mastoridis, 2017, Immunotolerance in liver transplantation, 095 Feng, 2012, Complete immunosuppression withdrawal and subsequent allograft function among pediatric recipients of parental living donor liver transplants, Jama, 307, 283, 10.1001/jama.2011.2014 Levitsky, 2011, Operational tolerance: past lessons and future prospects, Liver Transpl, 17, 222, 10.1002/lt.22265 Morris, 2015, Tracking donor-reactive T cells: Evidence for clonal deletion in tolerant kidney transplant patients, Sci Transl Med, 7, 272ra210, 10.1126/scitranslmed.3010760 Wekerle, 1998, Extrathymic T cell deletion and allogeneic stem cell engraftment induced with costimulatory blockade is followed by central T cell tolerance, J Exp Med, 187, 2037, 10.1084/jem.187.12.2037 Schietinger, 2014, Tolerance and exhaustion: defining mechanisms of T cell dysfunction, Trends Immunol, 35, 51, 10.1016/j.it.2013.10.001 Pilat, 2010, Treg-therapy allows mixed chimerism and transplantation tolerance without cytoreductive conditioning, Am J Transp, 10, 751, 10.1111/j.1600-6143.2010.03018.x Savage, 2018, Early expansion of donor-specific Tregs in tolerant kidney transplant recipients, JCI Insight, 3, 10.1172/jci.insight.124086 Mahr, 2017, Transplantation tolerance through hematopoietic chimerism: progress and challenges for clinical translation, Front Immunol, 8, 1762, 10.3389/fimmu.2017.01762 Wherry, 2015, Molecular and cellular insights into T cell exhaustion, Nat Rev Immunol, 15, 486, 10.1038/nri3862 Penaloza-MacMaster, 2014, Interplay between regulatory T cells and PD-1 in modulating T cell exhaustion and viral control during chronic LCMV infection, J Exp Med, 211, 1905, 10.1084/jem.20132577 Perruche, 2008, CD3-specific antibody-induced immune tolerance involves transforming growth factor-beta from phagocytes digesting apoptotic T cells, Nat Med, 14, 528, 10.1038/nm1749 You, 2015, Differential sensitivity of regulatory and effector T cells to cell death: a prerequisite for transplant tolerance, Front Immunol, 6, 242, 10.3389/fimmu.2015.00242 Cechova, 2018, Chimerism as an important marker in post-transplant monitoring chimerism monitoring, Hla, 92, 60, 10.1111/tan.13407 Anderson, 1951, The use of skin grafting to distinguish between monozygotic and dizygotic twins in cattle, Heredity, 5, 379, 10.1038/hdy.1951.38 Mathew, 2003, Immune responses and their regulation by donor bone marrow cells in clinical organ transplantation, Transpl Immunol, 11, 307, 10.1016/S0966-3274(03)00056-X Starzl, 1992, Cell migration, chimerism, and graft acceptance, Lancet (London, England), 339, 1579, 10.1016/0140-6736(92)91840-5 Ciancio, 2004, Donor bone marrow infusion in deceased and living donor renal transplantation, Yonsei Med J, 45, 998, 10.3349/ymj.2004.45.6.998 Garcia-Morales, 1996, An assessment of the effects of cadaver donor bone marrow on kidney allograft recipient blood cell chimerism by a novel technique combining PCR and flow cytometry1, Transplantation, 62, 1149, 10.1097/00007890-199610270-00021 Ciancio, 2001, Six-year clinical effect of donor bone marrow infusions in renal transplant patients, Transplantation, 71, 827, 10.1097/00007890-200104150-00002 Casiraghi, 2020, Kidney transplant tolerance associated with remote autologous mesenchymal stromal cell administration, Stem Cells Transl Med, 9, 427, 10.1002/sctm.19-0185 Fehr, 2004, Tolerance induction in clinical transplantation, Transpl Immunol, 13, 117, 10.1016/j.trim.2004.05.009 Monaco, 1976, Possible active enhancement of a human cadaver renal allograft with antilymphocyte serum (ALS) and donor bone marrow: case report of an initial attempt, Surgery, 79, 384 Monaco, 1966, Studies on heterologous anti-lymphocyte serum in mice. III. Immunologic tolerance and chimerism produced across the H-2 locus with adult thymectomy and anti-lymphocyte serum, Ann N Y Acad Sci, 129, 190, 10.1111/j.1749-6632.1966.tb12851.x Barber, 1991, Long-term results of a controlled prospective study with transfusion of donor-specific bone marrow in 57 cadaveric renal allograft recipients, Transplantation, 51, 70, 10.1097/00007890-199101000-00011 Kawai, 2008, HLA-mismatched renal transplantation without maintenance immunosuppression, N Engl J Med, 358, 353, 10.1056/NEJMoa071074 Scandling, 2008, Tolerance and chimerism after renal and hematopoietic-cell transplantation, N Engl J Med, 358, 362, 10.1056/NEJMoa074191 Leventhal, 2012, Ildstad, Chimerism and tolerance without GVHD or engraftment syndrome in HLA-mismatched combined kidney and hematopoietic stem cell transplantation, Sci Transl Med, 4, 124ra128, 10.1126/scitranslmed.3003509 Busque, 2020, 12 Leventhal, 2013, Tolerance induction in HLA disparate living donor kidney transplantation by donor stem cell infusion: durable chimerism predicts outcome, Transplantation, 95, 169, 10.1097/TP.0b013e3182782fc1 Scandling, 2015, Chimerism, graft survival, and withdrawal of immunosuppressive drugs in HLA matched and mismatched patients after living donor kidney and hematopoietic cell transplantation, Am J Transp, 15, 695, 10.1111/ajt.13091 Mathew, 2000, Donor bone marrow-derived chimeric cells present in renal transplant recipients infused with donor marrow. I. Potent regulators of recipient antidonor immune Responses1, Transplantation, vol. 70, 1675, 10.1097/00007890-200012270-00003 Chatenoud, 1997, CD3 antibody-induced dominant self tolerance in overtly diabetic NOD mice, J Immunol, 158, 2947, 10.4049/jimmunol.158.6.2947 You, 2012, Induction of allograft tolerance by monoclonal CD3 antibodies: a matter of timing, Am J Transp, 12, 2909, 10.1111/j.1600-6143.2012.04213.x Long, 2016, Partial exhaustion of CD8 T cells and clinical response to teplizumab in new-onset type 1 diabetes, Sci Immunol, 1, 10.1126/sciimmunol.aai7793 Spitzer, 2011, Long-term follow-up of recipients of combined human leukocyte antigen-matched bone marrow and kidney transplantation for multiple myeloma with end-stage renal disease, Transplantation, 91, 672, 10.1097/TP.0b013e31820a3068 Chhabra, 2017, HSCT-based approaches for tolerance induction in renal transplant, Transplantation, 101, 2682, 10.1097/TP.0000000000001837 Farris, 2011, Acute renal endothelial injury during marrow recovery in a cohort of combined kidney and bone marrow allografts, Am J Transplant, 11, 1464, 10.1111/j.1600-6143.2011.03572.x Yilmaz, 2015, A successful renal transplantation case after stem cell transplantation, Transplant Proc, 47, 2233, 10.1016/j.transproceed.2015.05.012 Kaufman, 1994, Phenotypic characterization of a novel bone marrow-derived cell that facilitates engraftment of allogeneic bone marrow stem cells, Blood, 84, 2436, 10.1182/blood.V84.8.2436.2436 Zuber, 2017, Transplant tolerance through mixed chimerism, Nephrol Therap, 13, S127, 10.1016/j.nephro.2017.01.017 Sobrino, 2023, Human kidney-derived hematopoietic stem cells can support long-term multilineage hematopoiesis, Kidney Int, 103, 70, 10.1016/j.kint.2022.08.024 Gondos, 2013, Kidney graft survival in Europe and the United States: strikingly different long-term outcomes, Transplantation, 95, 267, 10.1097/TP.0b013e3182708ea8 Elwood, 1997, Microchimerism and rejection in clinical transplantation, Lancet, 349, 1358, 10.1016/S0140-6736(96)09105-2 Kishikawa, 2014, Early microchimerism in peripheral blood following kidney transplantation, 388 Wood, 1996, Chimerism and transplantation tolerance: cause and effect, Immunol Today, 17, 584, 10.1016/S0167-5699(96)10069-4 Auchincloss, 2001, In search of the elusive Holy Grail: the mechanisms and prospects for achieving clinical transplantation tolerance, Am J Transplant, 1, 6, 10.1034/j.1600-6143.2001.010103.x Fehr, 2008, Clinical experience with mixed chimerism to induce transplantation tolerance, Transpl Int, 21, 1118, 10.1111/j.1432-2277.2008.00783.x Ruiz, 2013, Transplant tolerance: new insights and strategies for long-term allograft acceptance, Clin Dev Immunol, 2013, 10.1155/2013/210506 O'Neill, 1996, PCR amplification of short tandem repeat sequences allows serial studies of chimaerism/engraftment following BMT in rodents, Bone Marrow Transplant, 17, 265 Van Tol, 1998, Simultaneous detection of X and Y chromosomes by two-colour fluorescence in situ hybridization in combination with immunophenotyping of single cells to document chimaerism after sex-mismatched bone marrow transplantation, Bone Marrow Transplant, 21, 497, 10.1038/sj.bmt.1701122 Bader, 1998, Serial and quantitative analysis of mixed hematopoietic chimerism by PCR in patients with acute leukemias allows the prediction of relapse after allogeneic BMT, Bone Marrow Transplant, 21, 487, 10.1038/sj.bmt.1701119 Molloy, 1996 Fourtounas, 2008, Microchimerism in peripheral blood and urine in renal transplant recipients: preliminary results, 3434 Ciancio, 2001, Six-year clinical effect of donor bone marrow infusions in renal transplant Patients1, Transplantation, 71, 827, 10.1097/00007890-200104150-00002 Yamada, 2014, Use of CTLA4Ig for induction of mixed chimerism and renal allograft tolerance in nonhuman primates, Am J Transplant, 14, 2704, 10.1111/ajt.12936 Casiraghi, 2018, Mesenchymal stromal cells for tolerance induction in organ transplantation, Hum Immunol, 79, 304, 10.1016/j.humimm.2017.12.008 Putnam, 2013, Clinical grade manufacturing of human alloantigen-reactive regulatory T cells for use in transplantation, Am J Transp, 13, 3010, 10.1111/ajt.12433 Mathew, 2018, Generation and characterization of alloantigen-specific regulatory T cells For clinical transplant tolerance, Sci Rep, 8, 1136, 10.1038/s41598-018-19621-6 Kawai, 2018, Regulatory T cells for tolerance, Hum Immunol, 79, 294, 10.1016/j.humimm.2017.12.013 Marín, 2018, Tolerogenic dendritic cells in solid organ transplantation: where do we stand?, Front Immunol, 9, 274, 10.3389/fimmu.2018.00274 Podestà, 2019, Mesenchymal stromal cells for transplant tolerance, Front Immunol, 10, 10.3389/fimmu.2019.01287 Caplan, 2011, The MSC: an injury drugstore, Cell Stem Cell, 9, 11, 10.1016/j.stem.2011.06.008 Dominici, 2006, Minimal criteria for defining multipotent mesenchymal stromal cells. The international society for cellular therapy position statement, Cytotherapy, 8, 315, 10.1080/14653240600855905 Ricordi, 2013, Back to the future: mesenchimal stem cells, CellR4, 152 Crisan, 2008, A perivascular origin for mesenchymal stem cells in multiple human organs, Cell Stem Cell, 3, 301, 10.1016/j.stem.2008.07.003 Corselli, 2013, Identification of perivascular mesenchymal stromal/stem cells by flow cytometry, Cytometry A, 83, 714, 10.1002/cyto.a.22313 Hoogduijn, 2007, Human heart, spleen, and perirenal fat-derived mesenchymal stem cells have immunomodulatory capacities, Stem Cells Dev, 16, 597, 10.1089/scd.2006.0110 Strioga, 2012, Same or not the same? Comparison of adipose tissue-derived versus bone marrow-derived mesenchymal stem and stromal cells, Stem Cells Dev, 21, 2724, 10.1089/scd.2011.0722 Menard, 2013, Clinical-grade mesenchymal stromal cells produced under various good manufacturing practice processes differ in their immunomodulatory properties: standardization of immune quality controls, Stem Cells Dev, 22, 1789, 10.1089/scd.2012.0594 Garakani, 2017, Recent progress in cell therapy in solid organ transplantation, Int J Organ Transp Med, 8, 125 Beyth, 2005, Human mesenchymal stem cells alter antigen-presenting cell maturation and induce T-cell unresponsiveness, Blood, 105, 2214, 10.1182/blood-2004-07-2921 Meisel, 2004, Human bone marrow stromal cells inhibit allogeneic T-cell responses by indoleamine 2, 3-dioxygenase–mediated tryptophan degradation, Blood, 103, 4619, 10.1182/blood-2003-11-3909 Ren, 2008, Mesenchymal stem cell-mediated immunosuppression occurs via concerted action of chemokines and nitric oxide, Cell Stem Cell, 2, 141, 10.1016/j.stem.2007.11.014 English, 2009, Cell contact, prostaglandin E2 and transforming growth factor beta 1 play non-redundant roles in human mesenchymal stem cell induction of CD4+ CD25Highforkhead box P3+ regulatory T cells, Clin Exp Immunol, 156, 149, 10.1111/j.1365-2249.2009.03874.x Duffy, 2011, Mesenchymal stem cell inhibition of T-helper 17 cell-differentiation is triggered by cell–cell contact and mediated by prostaglandin E2 via the EP4 receptor, Eur J Immunol, 41, 2840, 10.1002/eji.201141499 Obermajer, 2014, Conversion of Th17 into IL-17Aneg regulatory T cells: a novel mechanism in prolonged allograft survival promoted by mesenchymal stem cell–supported minimized immunosuppressive therapy, J Immunol, 193, 4988, 10.4049/jimmunol.1401776 Luz-Crawford, 2013, Mesenchymal stem cells generate a CD4+ CD25+ Foxp3+ regulatory T cell population during the differentiation process of Th1 and Th17 cells, Stem Cell Res Therapy, 4, 1, 10.1186/scrt216 Hsu, 2013, Prostaglandin E2 potentiates mesenchymal stem cell–induced IL-10+ IFN-γ+ CD4+ regulatory T cells to control transplant arteriosclerosis, J Immunol, 190, 2372, 10.4049/jimmunol.1202996 Tabera, 2008, The effect of mesenchymal stem cells on the viability, proliferation and differentiation of B-lymphocytes, Haematologica, 93, 1301, 10.3324/haematol.12857 Newell, 2010, Identification of a B cell signature associated with renal transplant tolerance in humans, J Clin Invest, 120, 1836, 10.1172/JCI39933 Djouad, 2007, Mesenchymal stem cells inhibit the differentiation of dendritic cells through an interleukin-6-dependent mechanism, Stem Cells, 25, 2025, 10.1634/stemcells.2006-0548 Melief, 2013, Multipotent stromal cells induce human regulatory T cells through a novel pathway involving skewing of monocytes toward anti-inflammatory macrophages, Stem Cells, 31, 1980, 10.1002/stem.1432 Perico, 2011, Autologous mesenchymal stromal cells and kidney transplantation: a pilot study of safety and clinical feasibility, Clin J Am Soc Nephrol, 6, 412, 10.2215/CJN.04950610 Thomson, 2019, Regulatory dendritic cells for human organ transplantation, Transplant Rev, 33, 130, 10.1016/j.trre.2019.05.001 Ochando, 2017, Nanoparticle-based modulation and monitoring of antigen-presenting cells in organ transplantation, Front Immunol, 8, 1888, 10.3389/fimmu.2017.01888 Ohnmacht, 2009, Constitutive ablation of dendritic cells breaks self-tolerance of CD4 T cells and results in spontaneous fatal autoimmunity, J Exp Med, 206, 549, 10.1084/jem.20082394 Bériou, 2005, Donor-specific allograft tolerance by administration of recipient-derived immature dendritic cells and suboptimal immunosuppression, Transplantation, 79, 969, 10.1097/01.TP.0000158277.50073.35 Pêche, 2005, Prolongation of heart allograft survival by immature dendritic cells generated from recipient type bone marrow progenitors, Am J Transplant, 5, 255, 10.1111/j.1600-6143.2004.00683.x Segovia, 2014, Autologous dendritic cells prolong allograft survival through Tmem176b-dependent antigen cross-presentation, Am J Transplant, 14, 1021, 10.1111/ajt.12708 H. Nantes University, 2018 A. National Institute of, D. Infectious, P, 2023 R. University of, 2018 Mohr, 2019, The role of FOXP3+ regulatory T cells in human autoimmune and inflammatory diseases, Clin Exp Immunol, 197, 24, 10.1111/cei.13288 Miyara, 2009, Functional delineation and differentiation dynamics of human CD4+ T cells expressing the FoxP3 transcription factor, Immunity, 30, 899, 10.1016/j.immuni.2009.03.019 Wing, 2019, Human FOXP3+ regulatory T cell heterogeneity and function in autoimmunity and cancer, Immunity, 50, 302, 10.1016/j.immuni.2019.01.020 Dudreuilh, 2020, Potential application of T-follicular regulatory cell therapy in transplantation, Front Immunol, 11 Gagliani, 2010, Antigen-specific dependence of Tr1-cell therapy in preclinical models of islet transplant, Diabetes, 59, 433, 10.2337/db09-1168 Abbas, 2013, Regulatory T cells: recommendations to simplify the nomenclature, Nat Immunol, 14, 307, 10.1038/ni.2554 Grazia Roncarolo, 2006, Interleukin-10-secreting type 1 regulatory T cells in rodents and humans, Immunol Rev, 212, 28, 10.1111/j.0105-2896.2006.00420.x Sakaguchi, 2005, Naturally arising Foxp3-expressing CD25+ CD4+ regulatory T cells in immunological tolerance to self and non-self, Nat Immunol, 6, 345, 10.1038/ni1178 Franzese, 2013, Regulatory T cells in the immunodiagnosis and outcome of kidney allograft rejection, Clin Dev Immunol, 2013, 10.1155/2013/852395 Felix, 2007, Specificity of T-cell alloreactivity, Nat Rev Immunol, 7, 942, 10.1038/nri2200 Chandran, 2017, Polyclonal regulatory T cell therapy for control of inflammation in kidney transplants, Am J Transplant, 17, 2945, 10.1111/ajt.14415 Francis, 2011, Induction of transplantation tolerance converts potential effector T cells into graft-protective regulatory T cells, Eur J Immunol, 41, 726, 10.1002/eji.201040509 Leichner, 2016, TCR signaling by conventional CD4(+) T cells is required for optimal maintenance of peripheral regulatory T cell numbers, Immun Inflam Dis, 4, 148, 10.1002/iid3.100 Issa, 2010, Ex vivo-expanded human regulatory T cells prevent the rejection of skin allografts in a humanised mouse model, Transplantation, 90, 1321, 10.1097/TP.0b013e3181ff8772 Nadig, 2010, In vivo prevention of transplant arteriosclerosis by ex vivo–expanded human regulatory T cells, Nat Med, 16, 809, 10.1038/nm.2154 Fraser, 2018, A rapamycin-based GMP-compatible process for the isolation and expansion of regulatory T cells for clinical trials, Mol Therapy-Methods Clin Develop, 8, 198, 10.1016/j.omtm.2018.01.006 Braza, 2015, Central role of CD45RA- Foxp3hi memory regulatory T cells in clinical kidney transplantation tolerance, J Am Soc Nephrol, 26, 1795, 10.1681/ASN.2014050480 Sprangers, 2017, Origin of enriched regulatory T cells in patients receiving combined kidney-bone marrow transplantation to induce transplantation tolerance, Am J Transp, 17, 2020, 10.1111/ajt.14251 Hotta, 2016, Induced regulatory T cells in allograft tolerance via transient mixed chimerism, JCI Insight, 1, 10.1172/jci.insight.86419 Hu, 2013, Infiltrating Foxp3(+) regulatory T cells from spontaneously tolerant kidney allografts demonstrate donor-specific tolerance, Am J Transp, 13, 2819, 10.1111/ajt.12445 Kendal, 2011, Sustained suppression by Foxp3+ regulatory T cells is vital for infectious transplantation tolerance, J Exp Med, 208, 2043, 10.1084/jem.20110767 Brook, 2022, Transplantation Without Overimmunosuppression (TWO) study protocol: a phase 2b randomised controlled single-centre trial of regulatory T cell therapy to facilitate immunosuppression reduction in living donor kidney transplant recipients, BMJ Open, 12, 10.1136/bmjopen-2022-061864 Bacchetta, 2014, Immunological outcome in haploidentical-HSC transplanted patients treated with IL-10-anergized donor T cells, Front Immunol, 5, 16, 10.3389/fimmu.2014.00016 Oberbauer, 2020, A prospective controlled trial to evaluate safety and efficacy of in vitro expanded recipient regulatory T cell therapy and tocilizumab together with donor bone marrow infusion in HLA-mismatched living donor kidney transplant recipients (Trex001), Front Med, 7 Duran-Struuck, 2017, Effect of ex vivo-expanded recipient regulatory T cells on hematopoietic chimerism and kidney allograft tolerance across MHC barriers in cynomolgus macaques, Transplantation, 101, 274, 10.1097/TP.0000000000001559 Dawson, 2019, Systematic testing and specificity mapping of alloantigen-specific chimeric antigen receptors in regulatory T cells, JCI Insight, 4 Lamarche, 2022, Chimeric antigen receptor regulatory T cell in transplantation: The future of cell therapy?, Kidney Int Rep, 7, 1149, 10.1016/j.ekir.2022.04.003 Schreeb, 2022, Study design: human leukocyte antigen class I molecule A(∗)02-chimeric antigen receptor regulatory T cells in renal transplantation, Kidney Int Rep, 7, 1258, 10.1016/j.ekir.2022.03.030 Domenig, 2005, Roles of deletion and regulation in creating mixed chimerism and allograft tolerance using a nonlymphoablative irradiation-free protocol, J Immunol, 175, 51, 10.4049/jimmunol.175.1.51 Kurtz, 2004, Tolerance in mixed chimerism - a role for regulatory cells?, Trends Immunol, 25, 518, 10.1016/j.it.2004.08.007 Richard, 2009 Grégoire, 1995, Selecting the language of the publications included in a meta-analysis: is there a Tower of Babel bias?, J Clin Epidemiol, 48, 159, 10.1016/0895-4356(94)00098-B Scherer, 2018, Full publication of results initially presented in abstracts, Cochrane Database Syst Rev, 10.1002/14651858.MR000005.pub4 Waffenschmidt, 2019, Single screening versus conventional double screening for study selection in systematic reviews: a methodological systematic review, BMC Med Res Methodol, 19, 132, 10.1186/s12874-019-0782-0 Stumph, 2008, Comparison of peripheral blood and bone marrow samples for detection of post transplant mixed chimerism, Bone Marrow Transplant, 41, 589, 10.1038/sj.bmt.1705938 Johnstone, 2021, A large-scale bank of organ donor bone marrow and matched mesenchymal stem cells for promoting immunomodulation and transplant tolerance, Front Immunol, 12, 495, 10.3389/fimmu.2021.622604 Andrassy, 2019, Clinical tolerance trials in renal transplantation–Where do we stand?, OBM Transp, 3, 1, 10.21926/obm.transplant.1902070 Casiraghi, 2013, Mesenchymal stromal cells to promote solid organ transplantation tolerance, Curr Opin Organ Transplant, 18, 51, 10.1097/MOT.0b013e32835c5016