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Review

Clinical Manufacturing of Regulatory T Cell Products For Adoptive Cell Therapy and Strategies to Improve Therapeutic Efficacy

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Article: 2164159 | Received 20 Oct 2022, Accepted 27 Dec 2022, Published online: 22 Jan 2023

References

  • Sakaguchi S, Yamaguchi T, Nomura T, Ono M. Regulatory T cells and immune tolerance. Cell. 2008;133(5):775–17. doi:10.1016/j.cell.2008.05.009.
  • Liu W, Putnam AL, Xu-Yu Z, Szot GL, Lee MR, Zhu S, Gottlieb PA, Kapranov P, Gingeras TR, de St. Groth BF, et al. CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ Treg cells. J Exp Med. 2006;203(7):1701–11. doi:10.1084/jem.20060772.
  • Barzaghi F, Amaya Hernandez LC, Neven B, Ricci S, Kucuk ZY, Bleesing JJ, Nademi Z, Slatter MA, Ulloa ER, Shcherbina A, et al. Long-term follow-up of IPEX syndrome patients after different therapeutic strategies: an international multicenter retrospective study. J Allergy Clin Immunol. 2018;141(3):1036–49 e5. doi:10.1016/j.jaci.2017.10.041.
  • Bennett CL, Christie J, Ramsdell F, Brunkow ME, Ferguson PJ, Whitesell L, Kelly TE, Saulsbury FT, Chance PF, Ochs HD, et al. The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat Genet. 2001;27(1):20–21. doi:10.1038/83713.
  • Raffin C, Vo LT, Bluestone JA. Treg cell-based therapies: challenges and perspectives. Nat Rev Immunol. 2020;20(3):158–72. doi:10.1038/s41577-019-0232-6.
  • Sakaguchi S, Mikami N, Wing JB, Tanaka A, Ichiyama K, Ohkura N. Regulatory T cells and human disease. Annu Rev Immunol. 2020;38(1):541–66. doi:10.1146/annurev-immunol-042718-041717.
  • Chinen T, Kannan AK, Levine AG, Fan X, Klein U, Zheng Y, Gasteiger G, Feng Y, Fontenot JD, Rudensky AY. An essential role for the IL-2 receptor in treg cell function. Nat Immunol. 2016;17(11):1322–33. doi:10.1038/ni.3540.
  • Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol. 1995;155(3):1151–64. doi:10.4049/jimmunol.155.3.1151.
  • Tang Q, Henriksen KJ, Bi M, Finger EB, Szot G, Ye J, Masteller EL, McDevitt H, Bonyhadi M, Bluestone JA. In vitro-expanded antigen-specific regulatory T cells suppress autoimmune diabetes. J Exp Med. 2004;199(11):1455–65. doi:10.1084/jem.20040139.
  • Hefazi M, Bolivar-Wagers S, Blazar BR, Romero MP. Regulatory T cell therapy of graft-versus-host disease: advances and challenges. Int J Mol Sci. 2021;23(1):22. doi:10.3390/ijms23010022.
  • Taylor PA, Lees CJ, Blazar BR. The infusion of ex vivo activated and expanded CD4(+)CD25(+) immune regulatory cells inhibits graft-versus-host disease lethality. Blood. 2002;99(10):3493–99. doi:10.1182/blood.V99.10.3493.
  • Cohen JL, Trenado A, Vasey D, Klatzmann D, Salomon BL. CD4(+)CD25(+) immunoregulatory T cells: new therapeutics for graft-versus-host disease. J Exp Med. 2002;196(3):401–06. doi:10.1084/jem.20020090.
  • Edinger M, Hoffmann P, Ermann J, Drago K, Fathman CG, Strober S, Negrin RS. CD4+CD25+ regulatory T cells preserve graft-versus-tumor activity while inhibiting graft-versus-host disease after bone marrow transplantation. Nat Med. 2003;9(9):1144–50. doi:10.1038/nm915.
  • Hoffmann P, Ermann J, Edinger M, Fathman CG, Strober S. Donor-type CD4(+)CD25(+) regulatory T cells suppress lethal acute graft-versus-host disease after allogeneic bone marrow transplantation. J Exp Med. 2002;196(3):389–99. doi:10.1084/jem.20020399.
  • Xia G, He J, Leventhal JR. Ex vivo-expanded natural CD4+CD25+ regulatory T cells synergize with host T-cell depletion to promote long-term survival of allografts. Am J Transplant. 2008;8(2):298–306. doi:10.1111/j.1600-6143.2007.02088.x.
  • Sagoo P, Ali N, Garg G, Nestle FO, Lechler RI, Lombardi G. Human regulatory T cells with alloantigen specificity are more potent inhibitors of alloimmune skin graft damage than polyclonal regulatory T cells. Sci Transl Med. 2011;3(83):83ra42. doi:10.1126/scitranslmed.3002076.
  • Xiao F, Ma L, Zhao M, Huang G, Mirenda V, Dorling A, Lechler R, Lombardi G. Ex vivo expanded human regulatory T cells delay islet allograft rejection via inhibiting islet-derived monocyte chemoattractant protein-1 production in CD34+ stem cells-reconstituted NOD-scid IL2rgammanull mice. PLoS One. 2014;9(3):e90387. doi:10.1371/journal.pone.0090387.
  • Issa F, Hester J, Goto R, Nadig SN, Goodacre TE, Wood K. Ex vivo-expanded human regulatory T cells prevent the rejection of skin allografts in a humanized mouse model. Transplantation. 2010;90(12):1321–27. doi:10.1097/TP.0b013e3181ff8772.
  • Nadig SN, Wieckiewicz J, Wu DC, Warnecke G, Zhang W, Luo S, Schiopu A, Taggart DP, Wood KJ. In vivo prevention of transplant arteriosclerosis by ex vivo-expanded human regulatory T cells. Nat Med. 2010;16(7):809–13. doi:10.1038/nm.2154.
  • Bashuda H, Kimikawa M, Seino K, Kato Y, Ono F, Shimizu A, Yagita H, Teraoka S, Okumura K. Renal allograft rejection is prevented by adoptive transfer of anergic T cells in nonhuman primates. J Clin Invest. 2005;115(7):1896–902. doi:10.1172/JCI23743.
  • Ezzelarab MB, Thomson AW. Adoptive cell therapy with tregs to improve transplant outcomes: the promise and the stumbling blocks. Curr Transplant Rep. 2016;3(4):265–74. doi:10.1007/s40472-016-0114-9.
  • Ma A, Qi S, Song L, Hu Y, Dun H, Massicotte E, Dupuis M, Daloze P, Chen H. Adoptive transfer of CD4+CD25+ regulatory cells combined with low-dose sirolimus and anti-thymocyte globulin delays acute rejection of renal allografts in Cynomolgus monkeys. Int Immunopharmacol. 2011;11(5):618–29. doi:10.1016/j.intimp.2010.11.001.
  • Elias S, Rudensky AY. Therapeutic use of regulatory T cells for graft-versus-host disease. Br J Haematol. 2019;187(1):25–38. doi:10.1111/bjh.16157.
  • Romano M, Tung SL, Smyth LA, Lombardi G. Treg therapy in transplantation: a general overview. Transpl Int. 2017;30(8):745–53. doi:10.1111/tri.12909.
  • Terry LV, Oo YH. The next frontier of regulatory T Cells: promising immunotherapy for autoimmune diseases and organ transplantations. Front Immunol. 2020;11:565518. doi:10.3389/fimmu.2020.565518.
  • Brunstein CG, Miller JS, Cao Q, McKenna DH, Hippen KL, Curtsinger J, DeFor T, Levine BL, June CH, Rubinstein P, et al. Infusion of ex vivo expanded T regulatory cells in adults transplanted with umbilical cord blood: safety profile and detection kinetics. Blood. 2011;117(3):1061–70. doi:10.1182/blood-2010-07-293795.
  • Brunstein CG, Miller JS, McKenna DH, Hippen KL, DeFor TE, Sumstad D, Curtsinger J, Verneris MR, MacMillan ML, Levine BL, et al. Umbilical cord blood-derived T regulatory cells to prevent GVHD: kinetics, toxicity profile, and clinical effect. Blood. 2016;127(8):1044–51. doi:10.1182/blood-2015-06-653667.
  • Chandran S, Tang Q, Sarwal M, Laszik ZG, Putnam AL, Lee K, Leung J, Nguyen V, Sigdel T, Tavares EC, et al. Polyclonal regulatory T cell therapy for control of inflammation in kidney transplants. Am J Transplant. 2017;17(11):2945–54. doi:10.1111/ajt.14415.
  • Mathew JM, Hv J, LeFever A, Konieczna I, Stratton C, He J, Huang X, Gallon L, Skaro A, Ansari MJ, et al. A phase I clinical trial with ex vivo expanded recipient regulatory T cells in living donor kidney transplants. Sci Rep. 2018;8(1):7428. doi:10.1038/s41598-018-25574-7.
  • Theil A, Tuve S, Oelschlagel U, Maiwald A, Dohler D, Ossmann D, Zenkel A, Wilhelm C, Middeke JM, Shayegi N, et al. Adoptive transfer of allogeneic regulatory T cells into patients with chronic graft-versus-host disease. Cytotherapy. 2015;17(4):473–86. doi:10.1016/j.jcyt.2014.11.005.
  • Trzonkowski P, Bieniaszewska M, Juscinska J, Dobyszuk A, Krzystyniak A, Marek N, Myśliwska J, Hellmann A. First-in-man clinical results of the treatment of patients with graft versus host disease with human ex vivo expanded CD4+CD25+CD127- T regulatory cells. Clin Immunol. 2009;133(1):22–26. doi:10.1016/j.clim.2009.06.001.
  • Koyama I, Bashuda H, Uchida K, Seino KI, Habu S, Nakajima I, Fuchinoue S, Okumura K, Teraoka S. A clinical trial with adoptive transfer of ex vivo-induced, donor-specific immune-regulatory cells in kidney transplantation – a second report. Transplantation. 2020;104(11):2415–23. doi:10.1097/TP.0000000000003149.
  • Sanchez-Fueyo A, Whitehouse G, Grageda N, Cramp ME, Lim TY, Romano M, Thirkell S, Lowe K, Fry L, Heward J, et al. Applicability, safety, and biological activity of regulatory T cell therapy in liver transplantation. Am J Transplant. 2020;20(4):1125–36. doi:10.1111/ajt.15700.
  • Tang Q, Vincenti F. Transplant trials with Tregs: perils and promises. J Clin Invest. 2017;127(7):2505–12. doi:10.1172/JCI90598.
  • Juneja T, Kazmi M, Mellace M, Saidi RF. Utilization of treg cells in solid organ transplantation. Front Immunol. 2022;13:746889. doi:10.3389/fimmu.2022.746889.
  • Safinia N, Grageda N, Scotta C, Thirkell S, Fry LJ, Vaikunthanathan T, Lechler RI, Lombardi G. Cell therapy in organ transplantation: our experience on the clinical translation of regulatory T cells. Front Immunol. 2018;9:354. doi:10.3389/fimmu.2018.00354.
  • Leventhal JR, Ildstad ST. Tolerance induction in HLA disparate living donor kidney transplantation by facilitating cell-enriched donor stem cell infusion: the importance of durable chimerism. Hum Immunol. 2018;79(5):272–76. doi:10.1016/j.humimm.2018.01.007.
  • Spitzer TR, Sykes M, Tolkoff-Rubin N, Kawai T, McAfee SL, Dey BR, Ballen K, Delmonico F, Saidman S, Sachs DH, et al. 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. 2011;91(6):672–76. doi:10.1097/TP.0b013e31820a3068.
  • Abbas AK, Benoist C, Bluestone JA, Campbell DJ, Ghosh S, Hori S, Jiang S, Kuchroo VK, Mathis D, Roncarolo MG, et al. Regulatory T cells: recommendations to simplify the nomenclature. Nat Immunol. 2013;14(4):307–08. doi:10.1038/ni.2554.
  • MacMillan ML, Hippen KL, McKenna DH, Kadidlo D, Sumstad D, DeFor TE, Brunstein CG, Holtan SG, Miller JS, Warlick ED, et al. First-in-human phase 1 trial of induced regulatory T cells for graft-versus-host disease prophylaxis in HLA-matched siblings. Blood Adv. 2021;5(5):1425–36. doi:10.1182/bloodadvances.2020003219.
  • Baecher-Allan C, Brown JA, Freeman GJ, Hafler DA. CD4+CD25high regulatory cells in human peripheral blood. J Immunol. 2001;167(3):1245–53. doi:10.4049/jimmunol.167.3.1245.
  • Dieckmann D, Plottner H, Berchtold S, Berger T, Schuler G. Ex vivo isolation and characterization of CD4(+)CD25(+) T cells with regulatory properties from human blood. J Exp Med. 2001;193(11):1303–10. doi:10.1084/jem.193.11.1303.
  • Abbas AK, Trotta E, Simeonov DR, Marson A, Bluestone JA. Revisiting IL-2: Biology and therapeutic prospects. Science Immunology. 2018;3(25). doi:10.1126/sciimmunol.aat1482.
  • MacDonald KN, Piret JM, Levings MK. Methods to manufacture regulatory T cells for cell therapy. Clin Exp Immunol. 2019;197(1):52–63. doi:10.1111/cei.13297.
  • Safinia N, Vaikunthanathan T, Fraser H, Thirkell S, Lowe K, Blackmore L, Whitehouse G, Martinez-Llordella M, Jassem W, Sanchez-Fueyo A, et al. Successful expansion of functional and stable regulatory T cells for immunotherapy in liver transplantation. Oncotarget. 2016;7(7):7563–77. doi:10.18632/oncotarget.6927.
  • Bernaldo-de-Quiros E, Cozar B, Lopez-Esteban R, Clemente M, Gil-Jaurena JM, Pardo C, Pita A, Pérez-Caballero R, Camino M, Gil N, et al. A novel GMP protocol to produce high-quality treg cells from the pediatric thymic tissue to be employed as cellular therapy. Front Immunol. 2022;13:893576. doi:10.3389/fimmu.2022.893576.
  • Dijke IE, Hoeppli RE, Ellis T, Pearcey J, Huang Q, McMurchy AN, Boer K, Peeters AMA, Aubert G, Larsen I, et al. Discarded human thymus is a novel source of stable and long-lived therapeutic regulatory T cells. Am J Transplant. 2016;16(1):58–71. doi:10.1111/ajt.13456.
  • Golab K, Grose R, Trzonkowski P, Wickrema A, Tibudan M, Marek-Trzonkowska N, Matosz S, Solomina J, Ostrega D, Millis JM, et al. Utilization of leukapheresis and CD4 positive selection in Treg isolation and the ex-vivo expansion for a clinical application in transplantation and autoimmune disorders. Oncotarget. 2016;7(48):79474–84. doi:10.18632/oncotarget.13101.
  • Patel P, Mahmud D, Park Y, Yoshinaga K, Mahmud N, Rondelli D. Clinical grade isolation of regulatory T cells from G-CSF mobilized peripheral blood improves with initial depletion of monocytes. Am J Blood Res. 2015;5:79–85.
  • Ukena SN, Velaga S, Goudeva L, Ivanyi P, Olek S, Falk CS, Ganser A, Franzke A. Human regulatory T cells of G-CSF mobilized allogeneic stem cell donors qualify for clinical application. PLoS One. 2012;7(12):e51644. doi:10.1371/journal.pone.0051644.
  • Safinia N, Scotta C, Vaikunthanathan T, Lechler RI, Lombardi G. Regulatory T cells: serious contenders in the promise for immunological tolerance in transplantation. Front Immunol. 2015;6:438. doi:10.3389/fimmu.2015.00438.
  • Mamo T, Hippen KL, MacMillan ML, Brunstein CG, Miller JS, Wagner JE, Blazar BR, McKenna DH. Regulatory T cells: a review of manufacturing and clinical utility. Transfusion. 2022;62(4):904–15. doi:10.1111/trf.16797.
  • Eggenhuizen PJ, Ng BH, Ooi JD. Treg enhancing therapies to treat autoimmune diseases. Int J Mol Sci. 2020;22(1):21. doi:10.3390/ijms22010021.
  • Bluestone JA, Buckner JH, Fitch M, Gitelman SE, Gupta S, Hellerstein MK, Herold KC, Lares A, Lee MR, Li K, et al. Type 1 diabetes immunotherapy using polyclonal regulatory T cells. Sci Transl Med. 2015;7(315):315ra189. doi:10.1126/scitranslmed.aad4134.
  • Canavan JB, Scotta C, Vossenkamper A, Goldberg R, Elder MJ, Shoval I, Marks E, Stolarczyk E, Lo JW, Powell N, et al. Developing in vitro expanded CD45RA + regulatory T cells as an adoptive cell therapy for Crohn’s disease. Gut. 2016;65(4):584–94. doi:10.1136/gutjnl-2014-306919.
  • Marek-Trzonkowska N, Mysliwiec M, Dobyszuk A, Grabowska M, Techmanska I, Juscinska J, Wujtewicz MA, Witkowski P, Młynarski W, Balcerska A, et al. Administration of CD4+CD25highCD127− regulatory T cells preserves β-Cell function in type 1 diabetes in children. Diabetes Care. 2012;35(9):1817–20. doi:10.2337/dc12-0038.
  • Marin Morales JM, Munch N, Peter K, Freund D, Oelschlagel U, Holig K, Böhm T, Flach A-C, Keßler J, Bonifacio E, et al. Automated clinical grade expansion of regulatory T cells in a fully closed system. Front Immunol. 2019;10:38. doi:10.3389/fimmu.2019.00038.
  • Alsuliman A, Appel SH, Beers DR, Basar R, Shaim H, Kaur I, Zulovich J, Yvon E, Muftuoglu M, Imahashi N, et al. A robust, good manufacturing practice-compliant, clinical-scale procedure to generate regulatory T cells from patients with amyotrophic lateral sclerosis for adoptive cell therapy. Cytotherapy. 2016;18(10):1312–24. doi:10.1016/j.jcyt.2016.06.012.
  • Fraser H, Safinia N, Grageda N, Thirkell S, Lowe K, Fry LJ, Scottá C, Hope A, Fisher C, Hilton R, et al. A rapamycin-based GMP-compatible process for the isolation and expansion of regulatory T cells for clinical trials. Mol Ther Methods Clin Dev. 2018;8:198–209. doi:10.1016/j.omtm.2018.01.006.
  • McKenna DH Jr., Sumstad D, Kadidlo DM, Batdorf B, Lord CJ, Merkel SC, Koellner CM, Curtsinger JM, June CH, Riley JL, et al. Optimization of cGMP purification and expansion of umbilical cord blood-derived T-regulatory cells in support of first-in-human clinical trials. Cytotherapy. 2017;19(2):250–62. doi:10.1016/j.jcyt.2016.10.011.
  • Parmar S, Liu X, Najjar A, Shah N, Yang H, Yvon E, Rezvani K, McNiece I, Zweidler-McKay P, Miller L, et al. Ex vivo fucosylation of third-party human regulatory T cells enhances anti-graft-versus-host disease potency in vivo. Blood. 2015;125(9):1502–06. doi:10.1182/blood-2014-10-603449.
  • Peters JH, Preijers FW, Woestenenk R, Hilbrands LB, Koenen HJ, Joosten I. Clinical grade treg: GMP isolation, improvement of purity by CD127 depletion, treg expansion, and treg cryopreservation. PLoS One. 2008;3(9):e3161. doi:10.1371/journal.pone.0003161.
  • Voskens CJ, Fischer A, Roessner S, Lorenz C, Hirschmann S, Atreya R, Neufert C, Atreya I, Neurath MF, Schuler G, et al. Characterization and expansion of autologous GMP-ready regulatory T cells for TREG-based cell therapy in patients with ulcerative colitis. Inflamm Bowel Dis. 2017;23(8):1348–59. doi:10.1097/MIB.0000000000001192.
  • Hoffmann P, Boeld TJ, Eder R, Albrecht J, Doser K, Piseshka B, Dada A, Niemand C, Assenmacher M, Orsó E, et al. Isolation of CD4+CD25+ regulatory T cells for clinical trials. Biol Blood Marrow Transplant. 2006;12(3):267–74. doi:10.1016/j.bbmt.2006.01.005.
  • Wichlan DG, Roddam PL, Eldridge P, Handgretinger R, Riberdy JM. Efficient and reproducible large-scale isolation of human CD4+ CD25+ regulatory T cells with potent suppressor activity. J Immunol Methods. 2006;315(1–2):27–36. doi:10.1016/j.jim.2006.06.014.
  • Wiesinger M, Stoica D, Roessner S, Lorenz C, Fischer A, Atreya R, Neufert CF, Atreya I, Scheffold A, Schuler-Thurner B. Good manufacturing practice-compliant production and lot-release of ex vivo expanded regulatory T cells as basis for treatment of patients with autoimmune and inflammatory disorders. Front Immunol. 2017;8:1371. doi:10.3389/fimmu.2017.01371.
  • Battaglia M, Stabilini A, Migliavacca B, Horejs-Hoeck J, Kaupper T, Roncarolo MG. Rapamycin promotes expansion of functional CD4+CD25+FOXP3+ regulatory T cells of both healthy subjects and type 1 diabetic patients. J Immunol. 2006;177(12):8338–47. doi:10.4049/jimmunol.177.12.8338.
  • Lu L, Qian XF, Rao JH, Wang XH, Zheng SG, Zhang F. Rapamycin promotes the expansion of CD4(+) Foxp3(+) regulatory T cells after liver transplantation. Transplant Proc. 2010;42(5):1755–57. doi:10.1016/j.transproceed.2009.10.008.
  • Ogino H, Nakamura K, Iwasa T, Ihara E, Akiho H, Motomura Y, Akahoshi K, Igarashi H, Kato M, Kotoh K, et al. Regulatory T cells expanded by rapamycin in vitro suppress colitis in an experimental mouse model. J Gastroenterol. 2012;47(4):366–76. doi:10.1007/s00535-011-0502-y.
  • Battaglia M, Stabilini A, Roncarolo MG. Rapamycin selectively expands CD4+CD25+FoxP3+ regulatory T cells. Blood. 2005;105(12):4743–48. doi:10.1182/blood-2004-10-3932.
  • Raimondi G, Sumpter TL, Matta BM, Pillai M, Corbitt N, Vodovotz Y, Wang Z, Thomson AW. Mammalian target of rapamycin inhibition and alloantigen-specific regulatory T cells synergize to promote long-term graft survival in immunocompetent recipients. J Immunol. 2010;184(2):624–36. doi:10.4049/jimmunol.0900936.
  • Fontenot JD, Rasmussen JP, Williams LM, Dooley JL, Farr AG, Rudensky AY. Regulatory T cell lineage specification by the forkhead transcription factor foxp3. Immunity. 2005;22(3):329–41. doi:10.1016/j.immuni.2005.01.016.
  • Gavin MA, Rasmussen JP, Fontenot JD, Vasta V, Manganiello VC, Beavo JA, Rudensky AY. Foxp3-dependent programme of regulatory T-cell differentiation. Nature. 2007;445(7129):771–75. doi:10.1038/nature05543.
  • Kim JK, Klinger M, Benjamin J, Xiao Y, Erle DJ, Littman DR, Killeen N. Impact of the TCR signal on regulatory T cell homeostasis, function, and trafficking. PLoS One. 2009;4(8):e6580. doi:10.1371/journal.pone.0006580.
  • Vahl JC, Drees C, Heger K, Heink S, Fischer JC, Nedjic J, Ohkura N, Morikawa H, Poeck H, Schallenberg S, et al. Continuous T cell receptor signals maintain a functional regulatory T cell pool. Immunity. 2014;41(5):722–36. doi:10.1016/j.immuni.2014.10.012.
  • Schmidt AM, Lu W, Sindhava VJ, Huang Y, Burkhardt JK, Yang E, Riese MJ, Maltzman JS, Jordan MS, Kambayashi T. Regulatory T cells require TCR signaling for their suppressive function. J Immunol. 2015;194(9):4362–70. doi:10.4049/jimmunol.1402384.
  • Levine AG, Arvey A, Jin W, Rudensky AY. Continuous requirement for the TCR in regulatory T cell function. Nat Immunol. 2014;15(11):1070–78. doi:10.1038/ni.3004.
  • Salomon B, Lenschow DJ, Rhee L, Ashourian N, Singh B, Sharpe A, Bluestone JA. B7/CD28 costimulation is essential for the homeostasis of the CD4+CD25+ immunoregulatory T cells that control autoimmune diabetes. Immunity. 2000;12(4):431–40. doi:10.1016/S1074-7613(00)80195-8.
  • Tai X, Cowan M, Feigenbaum L, Singer A. CD28 costimulation of developing thymocytes induces Foxp3 expression and regulatory T cell differentiation independently of interleukin 2. Nat Immunol. 2005;6(2):152–62. doi:10.1038/ni1160.
  • Golovina TN, Mikheeva T, Suhoski MM, Aqui NA, Tai VC, Shan X, Lui R, Balcarcel RR, Fisher N, Levine BL. CD28 costimulation is essential for human T regulatory expansion and function. J Immunol. 2008;181(4):2855–68. doi:10.4049/jimmunol.181.4.2855.
  • He X, Smeets RL, van Rijssen E, Boots AM, Joosten I, Koenen HJ. Single CD28 stimulation induces stable and polyclonal expansion of human regulatory T cells. Sci Rep. 2017;7(1):43003. doi:10.1038/srep43003.
  • Hombach AA, Kofler D, Hombach A, Rappl G, Abken H. Effective proliferation of human regulatory T cells requires a strong costimulatory CD28 signal that cannot be substituted by IL-2. J Immunol. 2007;179(11):7924–31. doi:10.4049/jimmunol.179.11.7924.
  • Lin CH, Hunig T. Efficient expansion of regulatory T cells in vitro and in vivo with a CD28 superagonist. Eur J Immunol. 2003;33(3):626–38. doi:10.1002/eji.200323570.
  • Kellner JN, Yvon E, Parmar S. Ex vivo generation of umbilical cord blood T regulatory cells expressing the homing markers CD62L and cutaneous lymphocyte antigen. Oncotarget. 2018;9(72):33694–701. doi:10.18632/oncotarget.26097.
  • Todo S, Yamashita K, Goto R, Zaitsu M, Nagatsu A, Oura T, Watanabe M, Aoyagi T, Suzuki T, Shimamura T, et al. A pilot study of operational tolerance with a regulatory T-cell-based cell therapy in living donor liver transplantation. Hepatology. 2016;64(2):632–43. doi:10.1002/hep.28459.
  • Suhoski MM, Golovina TN, Aqui NA, Tai VC, Varela-Rohena A, Milone MC, Carroll RG, Riley JL, June CH. Engineering artificial antigen-presenting cells to express a diverse array of co-stimulatory molecules. Mol Ther. 2007;15(5):981–88. doi:10.1038/mt.sj.6300134.
  • Hippen KL, Merkel SC, Schirm DK, Sieben CM, Sumstad D, Kadidlo DM, McKenna DH, Bromberg JS, Levine BL, Riley JL. Massive ex Vivo expansion of human natural regulatory T Cells (T regs) with minimal loss of in Vivo functional activity. Sci Transl Med. 2011;3(83):83ra41. doi:10.1126/scitranslmed.3001809.
  • Sanchez-Fueyo A, Sandner S, Habicht A, Mariat C, Kenny J, Degauque N, Zheng XX, Strom TB, Turka LA, Sayegh MH, et al. Specificity of CD4+CD25+ regulatory T cell function in alloimmunity. J Immunol. 2006;176(1):329–34. doi:10.4049/jimmunol.176.1.329.
  • Putnam AL, Safinia N, Medvec A, Laszkowska M, Wray M, Mintz MA, Trotta E, Szot GL, Liu W, Lares A, et al. Clinical grade manufacturing of human alloantigen-reactive regulatory T cells for use in transplantation. Am J Transplant. 2013;13(11):3010–20. doi:10.1111/ajt.12433.
  • Lee LM, Zhang H, Lee K, Liang H, Merleev A, Vincenti F, Maverakis E, Thomson AW, Tang Q. A comparison of ex vivo expanded human regulatory T cells using allogeneic stimulated B cells or monocyte-derived dendritic cells. Front Immunol. 2021;12:679675. doi:10.3389/fimmu.2021.679675.
  • Golshayan D, Jiang S, Tsang J, Garin MI, Mottet C, Lechler RI. In vitro-expanded donor alloantigen-specific CD4+CD25+ regulatory T cells promote experimental transplantation tolerance. Blood. 2007;109(2):827–35. doi:10.1182/blood-2006-05-025460.
  • Noyan F, Lee YS, Hardtke-Wolenski M, Knoefel AK, Taubert R, Baron U, Manns MP, Jaeckel E. Donor-specific regulatory T cells generated on donor B cells are superior to CD4+CD25high cells in controlling alloimmune responses in humanized mice. Transplant Proc. 2013;45(5):1832–37. doi:10.1016/j.transproceed.2013.01.073.
  • Trenado A, Fisson S, Braunberger E, Klatzmann D, Salomon BL, Cohen JL. Ex vivo selection of recipient-type alloantigen-specific CD4(+)CD25(+) immunoregulatory T cells for the control of graft-versus-host disease after allogeneic hematopoietic stem-cell transplantation. Transplantation. 2004;77:S32–4. doi:10.1097/01.TP.0000106470.07410.CA.
  • Tang Q, Leung J, Peng Y, Sanchez-Fueyo A, Lozano JJ, Lam A, Lee K, Greenland JR, Hellerstein M, Fitch M, et al. Selective decrease of donor-reactive T regs after liver transplantation limits T reg therapy for promoting allograft tolerance in humans. Sci Transl Med. 2022;14(669):eabo2628. doi:10.1126/scitranslmed.abo2628.
  • Tsang JY, Tanriver Y, Jiang S, Xue SA, Ratnasothy K, Chen D, Stauss HJ, Bucy RP, Lombardi G, Lechler R, et al. Conferring indirect allospecificity on CD4+CD25+ Tregs by TCR gene transfer favors transplantation tolerance in mice. J Clin Invest. 2008;118(11):3619–28. doi:10.1172/JCI33185.
  • Mathew JM, Voss JH, McEwen ST, Konieczna I, Chakraborty A, Huang X, He J, Gallon L, Kornbluth RS, Leventhal JR. Generation and characterization of alloantigen-specific regulatory T cells for clinical transplant tolerance. Sci Rep. 2018;8(1):1136. doi:10.1038/s41598-018-19621-6.
  • Trenado A, Charlotte F, Fisson S, Yagello M, Klatzmann D, Salomon BL, Cohen JL. Recipient-type specific CD4+CD25+ regulatory T cells favor immune reconstitution and control graft-versus-host disease while maintaining graft-versus-leukemia. J Clin Invest. 2003;112(11):1688–96. doi:10.1172/JCI17702.
  • Sawitzki B, Harden PN, Reinke P, Moreau A, Hutchinson JA, Game DS, Tang Q, Guinan EC, Battaglia M, Burlingham WJ, et al. 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. 2020;395(10237):1627–39. doi:10.1016/S0140-6736(20)30167-7.
  • Dong S, Hiam-Galvez KJ, Mowery CT, Herold KC, Gitelman SE, Esensten JH, Liu W, Lares AP, Leinbach AS, Lee M. The effect of low-dose IL-2 and treg adoptive cell therapy in patients with type 1 diabetes. JCI Insight. 2021;6(18):e147474. doi:10.1172/jci.insight.147474.
  • Koreth J, Matsuoka K, Kim HT, McDonough SM, Bindra B, Alyea EP, Armand P, Cutler C, Ho VT, Treister NS, et al. Interleukin-2 and regulatory T cells in graft-versus-host disease. N Engl J Med. 2011;365(22):2055–66. 3rd. doi:10.1056/NEJMoa1108188.
  • Kennedy-Nasser AA, Ku S, Castillo-Caro P, Hazrat Y, Wu MF, Liu H, Melenhorst J, Barrett AJ, Ito S, Foster A. Ultra low-dose IL-2 for GVHD prophylaxis after allogeneic hematopoietic stem cell transplantation mediates expansion of regulatory T cells without diminishing antiviral and antileukemic activity. Clin Cancer Res. 2014;20(8):2215–25. doi:10.1158/1078-0432.CCR-13-3205.
  • Hartemann A, Bensimon G, Payan CA, Jacqueminet S, Bourron O, Nicolas N, Fonfrede M, Rosenzwajg M, Bernard C, Klatzmann D. Low-dose interleukin 2 in patients with type 1 diabetes: a phase 1/2 randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol. 2013;1(4):295–305. doi:10.1016/S2213-8587(13)70113-X.
  • Whangbo J, Nikiforow S, Kim HT, Wahl J, Reynolds CG, Chamling Rai S, Kim S, Burden A, Alho AC, Lacerda JF, et al. A phase 1 study of donor regulatory T-cell infusion plus low-dose interleukin-2 for steroid-refractory chronic graft-vs-host disease. Blood Adv. 2022;6(21):5786–96. doi:10.1182/bloodadvances.2021006625.
  • Whangbo JS, Kim HT, Nikiforow S, Koreth J, Alho AC, Falahee B, Kim S, Dusenbury K, Fields MJ, Reynolds CG. Functional analysis of clinical response to low-dose IL-2 in patients with refractory chronic graft-versus-host disease. Blood Adv. 2019;3(7):984–94 doi:10.1182/bloodadvances.2018027474.
  • Lim TY, Perpinan E, Londono MC, Miquel R, Ruiz P, Kurt AS, Codela E, Cross A, Berlin C, Hester J, et al. Low dose interleukin-2 selectively expands circulating regulatory T cells but fails to promote liver allograft tolerance in humans. J Hepatol. 2022;77:S809. doi:10.1016/S0168-8278(22)01920-1.
  • Sockolosky JT, Trotta E, Parisi G, Picton L, Su LL, Le AC, Chhabra A, Silveria SL, George BM, King IC, et al. Selective targeting of engineered T cells using orthogonal IL-2 cytokine-receptor complexes. Science. 2018;359(6379):1037–42. doi:10.1126/science.aar3246.
  • Jhunjhunwala S, Raimondi G, Glowacki AJ, Hall SJ, Maskarinec D, Thorne SH, Thomson AW, Little SR. Bioinspired controlled release of CCL22 recruits regulatory T cells in vivo. Adv Mater. 2012;24(35):4735–38. doi:10.1002/adma.201202513.
  • Fisher JD, Zhang W, Balmert SC, Aral AM, Acharya AP, Kulahci Y, Li J, Turnquist HR, Thomson AW, Solari MG, et al. In situ recruitment of regulatory T cells promotes donor-specific tolerance in vascularized composite allotransplantation. Sci Adv. 2020;6(11):eaax8429. doi:10.1126/sciadv.aax8429.
  • Li MO, Sanjabi S, Flavell RA. Transforming growth factor-beta controls development, homeostasis, and tolerance of T cells by regulatory T cell-dependent and -independent mechanisms. Immunity. 2006;25(3):455–71. doi:10.1016/j.immuni.2006.07.011.
  • Jhunjhunwala S, Balmert SC, Raimondi G, Dons E, Nichols EE, Thomson AW, Little SR. Controlled release formulations of IL-2, TGF-beta1 and rapamycin for the induction of regulatory T cells. J Control Release. 2012;159:78–84.
  • Hirai T, Simonetta F, Su LL, Picton L, Baker J, Seo K, Lohmeyer JK, Mavers M, Blazar BR, Garcia C, et al. Engineered IL-2 cytokine-cytokine receptor complex enables selective expansion of regulatory T cells and facilitates establishment of organ transplantation tolerance. Biol. Blood Marrow Transplant. 2020;26(3):S59–S60. doi:10.1016/j.bbmt.2019.12.226.
  • Hirai T, Ramos TL, Lin PY, Simonetta F, Su LL, Picton LK, Baker J, Lin J, Li P, Seo K. Selective expansion of regulatory T cells using an orthogonal IL-2/IL-2 receptor system facilitates transplantation tolerance. J Clin Invest. 2021;131(8): e139991. doi:10.1172/JCI139991.
  • Fuchs A, Gliwinski M, Grageda N, Spiering R, Abbas AK, Appel S, Bacchetta R, Battaglia M, Berglund D, Blazar B, et al. Minimum information about T regulatory cells: a step toward reproducibility and standardization. Front Immunol. 2017;8:1844. doi:10.3389/fimmu.2017.01844.
  • Atif M, Conti F, Gorochov G, Oo YH, Miyara M. Regulatory T cells in solid organ transplantation. Clin Transl Immunol. 2020;9(2):e01099. doi:10.1002/cti2.1099.
  • Gedaly R, De Stefano F, Turcios L, Hill M, Hidalgo G, Mitov MI, Alstott MC, Butterfield DA, Mitchell HC, Hart J, et al. mTOR inhibitor everolimus in regulatory T cell expansion for clinical application in transplantation. Transplantation. 2019;103(4):705–15. doi:10.1097/TP.0000000000002495.