880
Views
28
CrossRef citations to date
0
Altmetric
Review

The role of regulatory T cells in graft-versus-host disease management

, &
Pages 141-154 | Received 06 Sep 2019, Accepted 23 Dec 2019, Published online: 11 Jan 2020

References

  • Zeiser R, Blazar BR. Acute graft-versus-host disease - biologic process, prevention, and therapy. N Engl J Med. 2017;377(22):2167–2179.
  • Antin JH, Ferrara JL. Cytokine dysregulation and acute graft-versus-host disease. Blood. 1992;80(12):2964–2968.
  • Ferrara JL, Levine JE, Reddy P, et al. Graft-versus-host disease. Lancet. 2009;373(9674):1550–1561.
  • Zeiser R, Blazar BR. Pathophysiology of chronic graft-versus-host disease and therapeutic targets. N Engl J Med. 2017;377(26):2565–2579.
  • Socie G, Ritz J. Current issues in chronic graft-versus-host disease. Blood. 2014;124(3):374–384.
  • Sakaguchi S, Yamaguchi T, Nomura T, et al. Regulatory T cells and immune tolerance. Cell. 2008;133(5):775–787.
  • Sakaguchi S, Sakaguchi N, Asano M, et al. 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):1151–1164.
  • Baecher-Allan C, Brown JA, Freeman GJ, et al. CD4+CD25high regulatory cells in human peripheral blood. J Immunol. 2001;167(3):1245–1253.
  • Stephens LA, Mottet C, Mason D, et al. Human CD4(+)CD25(+) thymocytes and peripheral T cells have immune suppressive activity in vitro. Eur J Immunol. 2001;31(4):1247–1254.
  • Jonuleit H, Schmitt E, Stassen M, et al. Identification and functional characterization of human CD4(+)CD25(+) T cells with regulatory properties isolated from peripheral blood. J Exp Med. 2001;193(11):1285–1294.
  • Dieckmann D, Plottner H, Berchtold S, et al. Ex vivo isolation and characterization of CD4(+)CD25(+) T cells with regulatory properties from human blood. J Exp Med. 2001;193(11):1303–1310.
  • Taams LS, Smith J, Rustin M, et al. Human anergic/suppressive CD4(+)CD25(+) T cells: a highly differentiated and apoptosis-prone population. Eur J Immunol. 2001;31(4):1122–1131.
  • Ng WF, Duggan PJ, Ponchel F, et al. Human CD4(+)CD25(+) cells: a naturally occurring population of regulatory T cells. Blood. 2001;98(9):2736–2744.
  • Levings MK, Sangregorio R, Roncarolo MG. Human cd25(+)cd4(+) t regulatory cells suppress naive and memory T cell proliferation and can be expanded in vitro without loss of function. J Exp Med. 2001;193(11):1295–1302.
  • Seddiki N, Santner-Nanan B, Martinson J, et al. Expression of interleukin (IL)-2 and IL-7 receptors discriminates between human regulatory and activated T cells. J Exp Med. 2006;203(7):1693–1700.
  • Liu W, Putnam AL, Xu-yu Z, et al. CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ T reg cells. J Exp Med. 2006;203(7):1701–1711.
  • Smith TR, Kumar V. Revival of CD8+ Treg-mediated suppression. Trends Immunol. 2008;29(7):337–342.
  • Robb RJ, Lineburg KE, Kuns RD, et al. Identification and expansion of highly suppressive CD8(+)FoxP3(+) regulatory T cells after experimental allogeneic bone marrow transplantation. Blood. 2012;119(24):5898–5908.
  • Beres AJ, Haribhai D, Chadwick AC, et al. CD8+ Foxp3+ regulatory T cells are induced during graft-versus-host disease and mitigate disease severity. J Immunol. 2012;189(1):464–474.
  • Churlaud G, Pitoiset F, Jebbawi F, et al. Human and mouse CD8(+)CD25(+)FOXP3(+) regulatory T cells at steady state and during interleukin-2 therapy. Front Immunol. 2015;6:171.
  • Rudensky AY. Regulatory T cells and Foxp3. Immunol Rev. 2011;241(1):260–268.
  • Sakaguchi S, Miyara M, Costantino CM, et al. FOXP3+ regulatory T cells in the human immune system. Nat Rev Immunol. 2010;10(7):490–500.
  • Ziegler SF. FOXP3: of mice and men. Annu Rev Immunol. 2006;24:209–226.
  • Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol. 2003;4(4):330–336.
  • Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science. 2003;299(5609):1057–1061.
  • Khattri R, Cox T, Yasayko S-A, et al. An essential role for Scurfin in CD4+CD25+ T regulatory cells. Nat Immunol. 2003;4(4):337–342.
  • Brunkow ME, Jeffery EW, Hjerrild KA, et al. Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse. Nat Genet. 2001;27(1):68–73.
  • Bennett CL, Christie J, Ramsdell F, et al. The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat Genet. 2001;27(1):20–21.
  • Chatila TA, Blaeser F, Ho N, et al. JM2, encoding a fork head-related protein, is mutated in X-linked autoimmunity-allergic disregulation syndrome. J Clin Invest. 2000;106(12):R75–81.
  • Wildin RS, Ramsdell F, Peake J, et al. X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy. Nat Genet. 2001;27(1):18–20.
  • Wan YY, Flavell RA. Regulatory T-cell functions are subverted and converted owing to attenuated Foxp3 expression. Nature. 2007;445(7129):766–770.
  • Yagi H, Nomura T, Nakamura K, et al. Crucial role of FOXP3 in the development and function of human CD25+CD4+ regulatory T cells. Int Immunol. 2004;16(11):1643–1656.
  • Roncador G, Brown P, Maestre L, et al. Analysis of FOXP3 protein expression in human CD4+CD25+ regulatory T cells at the single-cell level. Eur J Immunol. 2005;35(6):1681–1691.
  • Zorn E, Kim HT, Lee SJ, et al. Reduced frequency of FOXP3+ CD4+CD25+ regulatory T cells in patients with chronic graft-versus-host disease. Blood. 2005;106(8):2903–2911.
  • Miyara M, Amoura Z, Parizot C, et al. The immune paradox of sarcoidosis and regulatory T cells. J Exp Med. 2006;203(2):359–370.
  • Shevach EM, Thornton AM. tTregs, pTregs, and iTregs: similarities and differences. Immunol Rev. 2014;259(1):88–102.
  • Togashi Y, Shitara K, Nishikawa H. Regulatory T cells in cancer immunosuppression - implications for anticancer therapy. Nat Rev Clin Oncol. 2019;16(6):356–371.
  • Miyara M, Yoshioka Y, Kitoh A, et al. Functional delineation and differentiation dynamics of human CD4+ T cells expressing the FoxP3 transcription factor. Immunity. 2009;30(6):899–911.
  • Shevach EM. Mechanisms of foxp3+ T regulatory cell-mediated suppression. Immunity. 2009;30(5):636–645.
  • Ramsdell F, Ziegler SF. FOXP3 and scurfy: how it all began. Nat Rev Immunol. 2014;14(5):343–349.
  • Lu L, Barbi J, Pan F. The regulation of immune tolerance by FOXP3. Nat Rev Immunol. 2017;17(11):703–717.
  • Josefowicz SZ, Lu LF, Rudensky AY. Regulatory T cells: mechanisms of differentiation and function. Annu Rev Immunol. 2012;30:531–564.
  • Allard B, Longhi MS, Robson SC, et al. The ectonucleotidases CD39 and CD73: novel checkpoint inhibitor targets. Immunol Rev. 2017;276(1):121–144.
  • Taylor PA, Noelle RJ, Blazar BR. CD4(+)CD25(+) immune regulatory cells are required for induction of tolerance to alloantigen via costimulatory blockade. J Exp Med. 2001;193(11):1311–1318.
  • 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):3493–3499.
  • Cohen JL, Trenado A, Vasey D, et al. CD4(+)CD25(+) immunoregulatory T Cells: new therapeutics for graft-versus-host disease. J Exp Med. 2002;196(3):401–406.
  • Hoffmann P, Ermann J, Edinger M, et al. 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):389–399.
  • Edinger M, Hoffmann P, Ermann J, et al. 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):1144–1150.
  • Trenado A, Charlotte F, Fisson S, et al. 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):1688–1696.
  • Wolf D, Barreras H, Bader CS, et al. Marked in vivo donor regulatory T cell expansion via interleukin-2 and TL1A-Ig stimulation ameliorates graft-versus-host disease but preserves graft-versus-leukemia in recipients after hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2017;23(5):757–766.
  • Miura Y, Thoburn CJ, Bright EC, et al. Association of Foxp3 regulatory gene expression with graft-versus-host disease. Blood. 2004;104(7):2187–2193.
  • Fuji S, Shindo T. Friend or foe? Mogamulizumab in allogeneic hematopoietic stem cell transplantation for adult T-cell leukemia/lymphoma. Stem Cell Investig. 2016;3:70.
  • Fuji S, Inoue Y, Utsunomiya A, et al. Pretransplantation Anti-CCR4 antibody mogamulizumab against adult T-cell leukemia/lymphoma is associated with significantly increased risks of severe and corticosteroid-refractory graft-versus-host disease, nonrelapse mortality, and overall mortality. J Clin Oncol. 2016;34(28):3426–3433.
  • Ito A, Ishida T, Yano H, et al. Defucosylated anti-CCR4 monoclonal antibody exercises potent ADCC-mediated antitumor effect in the novel tumor-bearing humanized NOD/Shi-scid, IL-2Rgamma(null) mouse model. Cancer Immunol Immunother. 2009;58(8):1195–1206.
  • Rezvani K, Mielke S, Ahmadzadeh M, et al. High donor FOXP3-positive regulatory T-cell (Treg) content is associated with a low risk of GVHD following HLA-matched allogeneic SCT. Blood. 2006;108(4):1291–1297.
  • Danby RD, Zhang W, Medd P, et al. High proportions of regulatory T cells in PBSC grafts predict improved survival after allogeneic haematopoietic SCT. Bone Marrow Transplant. 2016;51(1):110–118.
  • Magenau JM, Qin X, Tawara I, et al. Frequency of CD4(+)CD25(hi)FOXP3(+) regulatory T cells has diagnostic and prognostic value as a biomarker for acute graft-versus-host-disease. Biol Blood Marrow Transplant. 2010;16(7):907–914.
  • Xhaard A, Moins-Teisserenc H, Busson M, et al. Reconstitution of regulatory T-cell subsets after allogeneic hematopoietic SCT. Bone Marrow Transplant. 2014;49(8):1089–1092.
  • Arimoto K, Kadowaki N, Ishikawa T, et al. FOXP3 expression in peripheral blood rapidly recovers and lacks correlation with the occurrence of graft-versus-host disease after allogeneic stem cell transplantation. Int J Hematol. 2007;85(2):154–162.
  • Meignin V, Delatour R, Zuber J, et al. Numbers of Foxp3-expressing CD4+CD25high T cells do not correlate with the establishment of long-term tolerance after allogeneic stem cell transplantation. Exp Hematol. 2005;33(8):894–900.
  • Ukena SN, Grosse J, Mischak-Weissinger E, et al. Acute but not chronic graft-versus-host disease is associated with a reduction of circulating CD4(+)CD25 (high)CD127 (low/-) regulatory T cells. Ann Hematol. 2011;90(2):213–218.
  • Clark FJ, Gregg R, Piper K, et al. Chronic graft-versus-host disease is associated with increased numbers of peripheral blood CD4+CD25high regulatory T cells. Blood. 2004;103(6):2410–2416.
  • Trovillion EM, Gloude NJ, Anderson EJ, et al. Relationship of post-transplant thymopoiesis with CD4(+)FoxP3(+) regulatory T cell recovery associated with freedom from chronic graft versus host disease. Bone Marrow Transplant. 2019;54(6):917–920.
  • Rieger K, Loddenkemper C, Maul J, et al. Mucosal FOXP3+ regulatory T cells are numerically deficient in acute and chronic GvHD. Blood. 2006;107(4):1717–1723.
  • Alho AC, Kim HT, Chammas MJ, et al. Unbalanced recovery of regulatory and effector T cells after allogeneic stem cell transplantation contributes to chronic GVHD. Blood. 2016;127(5):646–657.
  • Brunstein CG, Miller JS, Cao Q, 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):1061–1070.
  • Brunstein CG, Miller JS, McKenna DH, et al. Umbilical cord blood-derived T regulatory cells to prevent GVHD: kinetics, toxicity profile, and clinical effect. Blood. 2016;127(8):1044–1051.
  • Parmar S, Liu X, Tung SS, et al. Third-party umbilical cord blood-derived regulatory T cells prevent xenogenic graft-versus-host disease. Cytotherapy. 2014;16(1):90–100.
  • Parmar S, Liu X, Najjar A, 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):1502–1506.
  • Siegmund K, Feuerer M, Siewert C, et al. Migration matters: regulatory T-cell compartmentalization determines suppressive activity in vivo. Blood. 2005;106(9):3097–3104.
  • Ohmori K, Fukui F, Kiso M, et al. Identification of cutaneous lymphocyte-associated antigen as sialyl 6-sulfo Lewis X, a selectin ligand expressed on a subset of skin-homing helper memory T cells. Blood. 2006;107(8):3197–3204.
  • Kellner JN, Delemarre EM, Yvon E, et al. Third party, umbilical cord blood derived regulatory T-cells for prevention of graft versus host disease in allogeneic hematopoietic stem cell transplantation: feasibility, safety and immune reconstitution. Oncotarget. 2018;9(86):35611–35622.
  • Bertaina A, Roncarolo MG. Graft engineering and adoptive immunotherapy: new approaches to promote immune tolerance after hematopoietic stem cell transplantation. Front Immunol. 2019;10:1342.
  • Di Ianni M, Falzetti F, Carotti A, et al. Tregs prevent GVHD and promote immune reconstitution in HLA-haploidentical transplantation. Blood. 2011;117(14):3921–3928.
  • Martelli MF, Di Ianni M, Ruggeri L, et al. HLA-haploidentical transplantation with regulatory and conventional T-cell adoptive immunotherapy prevents acute leukemia relapse. Blood. 2014;124(4):638–644.
  • Luznik L, Bolaños-Meade J, Zahurak M, et al. High-dose cyclophosphamide as single-agent, short-course prophylaxis of graft-versus-host disease. Blood. 2010;115(16):3224–3230.
  • Luznik L, Jones RJ, Fuchs EJ. High-dose cyclophosphamide for graft-versus-host disease prevention. Curr Opin Hematol. 2010;17(6):493–499.
  • Kanakry CG, Ganguly S, Zahurak M, et al. Aldehyde dehydrogenase expression drives human regulatory T cell resistance to posttransplantation cyclophosphamide. Sci Transl Med. 2013;5(211):211ra157.
  • Ganguly S, Ross DB, Panoskaltsis-Mortari A, et al. Donor CD4+ Foxp3+ regulatory T cells are necessary for posttransplantation cyclophosphamide-mediated protection against GVHD in mice. Blood. 2014;124(13):2131–2141.
  • Wachsmuth LP, Patterson MT, Eckhaus MA, et al. Post-transplantation cyclophosphamide prevents graft-versus-host disease by inducing alloreactive T cell dysfunction and suppression. J Clin Invest. 2019;129(6):2357–2373.
  • Meyer EH, Laport G, Xie BJ, et al. Transplantation of donor grafts with defined ratio of conventional and regulatory T cells in HLA-matched recipients. JCI Insight. 2019;4(10):e127244.
  • McDonald-Hyman C, Flynn R, Panoskaltsis-Mortari A, et al. Therapeutic regulatory T-cell adoptive transfer ameliorates established murine chronic GVHD in a CXCR5-dependent manner. Blood. 2016;128(7):1013–1017.
  • Trzonkowski P, Bieniaszewska M, Juscinska J, et al. 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.
  • Theil A, Tuve S, Oelschlägel U, et al. Adoptive transfer of allogeneic regulatory T cells into patients with chronic graft-versus-host disease. Cytotherapy. 2015;17(4):473–486.
  • Rosenberg SA, Yang JC, Topalian SL, et al. Treatment of 283 consecutive patients with metastatic melanoma or renal cell cancer using high-dose bolus interleukin 2. JAMA. 1994;271(12):907–913.
  • Yu AL, Gilman AL, Ozkaynak MF, et al. Anti-GD2 antibody with GM-CSF, interleukin-2, and isotretinoin for neuroblastoma. N Engl J Med. 2010;363(14):1324–1334.
  • Soiffer RJ, Murray C, Gonin R, et al. Effect of low-dose interleukin-2 on disease relapse after T-cell-depleted allogeneic bone marrow transplantation. Blood. 1994;84(3):964–971.
  • Zorn E, Mohseni M, Kim H, et al. Combined CD4+ donor lymphocyte infusion and low-dose recombinant IL-2 expand FOXP3+ regulatory T cells following allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2009;15(3):382–388.
  • Koreth J, Matsuoka K-I, Kim HT, et al. Interleukin-2 and regulatory T cells in graft-versus-host disease. N Engl J Med. 2011;365(22):2055–2066.
  • Koreth J, Kim HT, Jones KT, et al. Efficacy, durability, and response predictors of low-dose interleukin-2 therapy for chronic graft-versus-host disease. Blood. 2016;128(1):130–137.
  • Whangbo JS, Kim HT, Nikiforow S, et al. Functional analysis of clinical response to low-dose IL-2 in patients with refractory chronic graft-versus-host disease. Blood Adv. 2019;3(7):984–994.
  • Belizaire R, Kim HT, Poryanda SJ, et al. Efficacy and immunologic effects of extracorporeal photopheresis plus interleukin-2 in chronic graft-versus-host disease. Blood Adv. 2019;3(7):969–979.
  • Whangbo JS, Kim HT, Mirkovic N, et al. Dose-escalated interleukin-2 therapy for refractory chronic graft-versus-host disease in adults and children. Blood Adv. 2019;3(17):2550–2561.
  • Betts BC, Pidala J, Kim J, et al. IL-2 promotes early Treg reconstitution after allogeneic hematopoietic cell transplantation. Haematologica. 2017;102(5):948–957.
  • Kennedy-Nasser AA, Ku S, Castillo-Caro P, et al. 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):2215–2225.
  • Matsuoka K, Koreth J, Kim HT, et al. Low-dose interleukin-2 therapy restores regulatory T cell homeostasis in patients with chronic graft-versus-host disease. Sci Transl Med. 2013;5(179):179ra43.
  • Zeiser R, Negrin RS. Interleukin-2 receptor downstream events in regulatory T cells: implications for the choice of immunosuppressive drug therapy. Cell Cycle. 2008;7(4):458–462.
  • Bensinger SJ, Walsh PT, Zhang J, et al. Distinct IL-2 receptor signaling pattern in CD4+CD25+ regulatory T cells. J Immunol. 2004;172(9):5287–5296.
  • Battaglia M, Stabilini A, Migliavacca B, et al. 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):8338–8347.
  • Battaglia M, Stabilini A, Roncarolo MG. Rapamycin selectively expands CD4+CD25+FoxP3+ regulatory T cells. Blood. 2005;105(12):4743–4748.
  • Zeiser R, Leveson-Gower DB, Zambricki EA, et al. Differential impact of mammalian target of rapamycin inhibition on CD4+CD25+Foxp3+ regulatory T cells compared with conventional CD4+ T cells. Blood. 2008;111(1):453–462.
  • Abraham RT, Wiederrecht GJ. Immunopharmacology of rapamycin. Annu Rev Immunol. 1996;14:483–510.
  • Zeiser R, Nguyen VH, Beilhack A, et al. Inhibition of CD4+CD25+ regulatory T-cell function by calcineurin-dependent interleukin-2 production. Blood. 2006;108(1):390–399.
  • Sugiyama H, Maeda Y, Nishimori H, et al. Mammalian target of rapamycin inhibitors permit regulatory T cell reconstitution and inhibit experimental chronic graft-versus-host disease. Biol Blood Marrow Transplant. 2014;20(2):183–191.
  • Singh K, Stempora L, Harvey RD, et al. Superiority of rapamycin over tacrolimus in preserving nonhuman primate Treg half-life and phenotype after adoptive transfer. Am J Transplant. 2014;14(12):2691–2703.
  • Scotta C, Fanelli G, Hoong SJ, et al. Impact of immunosuppressive drugs on the therapeutic efficacy of ex vivo expanded human regulatory T cells. Haematologica. 2016;101(1):91–100.
  • Wu Y, Borde M, Heissmeyer V, et al. FOXP3 controls regulatory T cell function through cooperation with NFAT. Cell. 2006;126(2):375–387.
  • Cutler C, Logan B, Nakamura R, et al. Tacrolimus/sirolimus vs tacrolimus/methotrexate as GVHD prophylaxis after matched, related donor allogeneic HCT. Blood. 2014;124(8):1372–1377.
  • Gooptu M, Kim HT, Howard A, et al. Effect of sirolimus on immune reconstitution following myeloablative allogeneic stem cell transplantation: an ancillary analysis of a randomized controlled trial comparing tacrolimus/sirolimus and tacrolimus/methotrexate (Blood and Marrow Transplant Clinical Trials Network/BMT CTN 0402). Biol Blood Marrow Transplant. 2019;25(11):2143–2151.
  • Peccatori J, Forcina A, Clerici D, et al. Sirolimus-based graft-versus-host disease prophylaxis promotes the in vivo expansion of regulatory T cells and permits peripheral blood stem cell transplantation from haploidentical donors. Leukemia. 2015;29(2):396–405.
  • Cutler CS, Koreth J, Ritz J. Mechanistic approaches for the prevention and treatment of chronic GVHD. Blood. 2017;129(1):22–29.
  • Sarantopoulos S, Cardones AR, Sullivan KM. How we treat refractory chronic graft-versus-host disease. Blood. 2019;133:1191–1200.
  • Przepiorka D, Kernan NA, Ippoliti C, et al. Daclizumab, a humanized anti-interleukin-2 receptor alpha chain antibody, for treatment of acute graft-versus-host disease. Blood. 2000;95(1):83–89.
  • Massenkeil G, Rackwitz S, Genvresse I, et al. Basiliximab is well tolerated and effective in the treatment of steroid-refractory acute graft-versus-host disease after allogeneic stem cell transplantation. Bone Marrow Transplant. 2002;30(12):899–903.
  • Chakupurakal G, García-Márquez MA, Shimabukuro-Vornhagen A, et al. Immunological effects in patients with steroid-refractory graft-versus-host disease following treatment with basiliximab, a CD25 monoclonal antibody. Eur J Haematol. 2016;97(2):121–127.
  • Locke FL, Pidala J, Storer B, et al. CD25 blockade delays regulatory T cell reconstitution and does not prevent graft-versus-host disease after allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2017;23(3):405–411.
  • Tchao N, Gorski KS, Yuraszeck T, et al. Amg 592 Is an investigational IL-2 mutein that induces highly selective expansion of regulatory T cells. Blood. 2017;130(Suppl 1):696.
  • Peterson LB, Bell CJM, Howlett SK, et al. A long-lived IL-2 mutein that selectively activates and expands regulatory T cells as a therapy for autoimmune disease. J Autoimmun. 2018;95:1–14.
  • Ward NC, Yu A, Moro A, et al. IL-2/CD25: a long-acting fusion protein that promotes immune tolerance by selectively targeting the IL-2 receptor on regulatory T cells. J Immunol. 2018;201(9):2579–2592.
  • Copsel S, Wolf D, Komanduri KV, et al. The promise of CD4(+)FoxP3(+) regulatory T-cell manipulation in vivo: applications for allogeneic hematopoietic stem cell transplantation. Haematologica. 2019;104(7):1309–1321.
  • Zhang Q, Lu W, Liang C-L, et al. Chimeric Antigen Receptor (CAR) Treg: a promising approach to inducing immunological tolerance. Front Immunol. 2018;9:2359.
  • Bluestone JA, Tang Q. Treg cells-the next frontier of cell therapy. Science. 2018;362(6411):154–155.
  • MacDonald KG, Hoeppli RE, Huang Q, et al. Alloantigen-specific regulatory T cells generated with a chimeric antigen receptor. J Clin Invest. 2016;126(4):1413–1424.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.