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Immune regulation in hematopoietic cell transplantation

Bone Marrow Transplantation volume 54, pages 765–768 (2019)Cite this article

Abstract

Immune regulation is critically important in health and disease. These immune effects have direct relevance in the setting of allogeneic hematopoietic cell transplantation (HCT), principally for the control of aberrant immune reactions, such as graft-versus-host disease (GVHD). Murine models have been critically important to evaluate the potential of two of the most potent immune regulatory cells CD4+CD25+FoxP+ regulatory T cells (Treg) and invariant natural killer T cells (iNKT cells). These cells have been shown to be remarkably effective in murine models to control GVHD and allow for the maintenance of graft-versus-tumor (GVT) effects. Interestingly, there are critical interactions between these different cell populations. Future studies are aimed at exploring the biology of these important regulatory cells and to translate these concepts to the clinic that holds promise for controlling some of the major challenges of allogeneic HCT.

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References

  1. Beilhack A, Schulz S, Baker J, Beilhack GF, Wieland CB, Herman EI, et al. In vivo analyses of early events in acute graft-versus-host disease reveal sequential infiltration of T-cell subsets. Blood. 2005;106:1113–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. 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;99:3493–9.

    Article  CAS  PubMed  Google Scholar 

  3. Hoffmann P, Edinger M, Negrin RS, Fathman CG, Strober S, Ermann J. CD4+CD25+ regulatory T cells act in secondary lymphoid organs to protect from lethal acute GVHD. Blood. 2002;100:142a.

    Google Scholar 

  4. 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;196:401–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Edinger M, Hoffmann P, Ermann J, Drago K, Fathman CG, Strober S, 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;9:1144–50.

    Article  CAS  PubMed  Google Scholar 

  6. Trenado A, Charlotte F, Fisson S, Yagello M, Klatzmann D, Salomon BL, 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;112:1688–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Jones SC, Murphy GF, Korngold R. Post-hematopoietic cell transplantation control of graft-versus-host disease by donor CD425 T cells to allow an effective graft-versus-leukemia response. Biol Blood Marrow Transplant. 2003;9:243–56.

    Article  PubMed  Google Scholar 

  8. Nguyen VH, Zeiser R, Dasilva DL, Chang DS, Beilhack A, Contag CH, et al. In vivo dynamics of regulatory T-cell trafficking and survival predict effective strategies to control graft-versus-host disease following allogeneic transplantation. Blood. 2007;109:2649–56.

    Article  CAS  PubMed  Google Scholar 

  9. Nguyen VH, Shashidhar S, Chang DS, Ho L, Kambham N, Bachmann M, et al. The impact of regulatory T cells on T-cell immunity following hematopoietic cell transplantation. Blood. 2008;111:945–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Zeiser R, Nguyen VH, Beilhack A, Buess M, Schulz S, Baker J, et al. Inhibition of CD4+CD25+ regulatory T-cell function by calcineurin-dependent interleukin-2 production. Blood. 2006;108:390–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Negrin RS, Contag CH. In vivo imaging using bioluminescence: a tool for probing graft-versus-host disease. Nat Rev Immunol. 2006;6:484–90.

    Article  CAS  PubMed  Google Scholar 

  12. Brunstein CG, Miller JS, Cao Q, McKenna DH, Hippen KL, Curtsinger J, et al. Infusion of ex vivo expanded T regulatory cells in adults transplanted with umbilical cord blood: safety profile and detection kinetics. Blood. 2011;117:1061–70. https://doi.org/10.1182/blood-2010-07-293795.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Brunstein CG, Miller JS, McKenna DH, Hippen KL, DeFor TE, Sumstad D, et al. Umbilical cord blood-derived T regulatory cells to prevent GVHD: kinetics, toxicity profile, and clinical effect. Blood. 2016;127:1044–51. https://doi.org/10.1182/blood-2015-06-653667.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Di Ianni M, Falzetti F, Carotti A, Terenzi A, Castellino F, Bonifacio E, et al. Tregs prevent GVHD and promote immune reconstitution in HLA-haploidentical transplantation. Blood. 2011;117:3921–8. https://doi.org/10.1182/blood-2010-10-311894.

    Article  PubMed  Google Scholar 

  15. Martelli MF, Di Ianni M, Ruggeri L, Falzetti F, Carotti A, Terenzi A, et al. HLA-haploidentical transplantation with regulatory and conventional T-cell adoptive immunotherapy prevents acute leukemia relapse. Blood. 2014;124:638–44. https://doi.org/10.1182/blood-2014-03-564401.

    Article  CAS  PubMed  Google Scholar 

  16. Pierini A, Strober W, Moffett C, Baker J, Nishikii H, Alvarez M, et al. TNF-alpha priming enhances CD4+FoxP3+ regulatory T-cell suppressive function in murine GVHD prevention and treatment. Blood. 2016;128:866–71. https://doi.org/10.1182/blood-2016-04-711275.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Kim BS, Nishikii H, Baker J, Pierini A, Schneidawind D, Pan Y, et al. Treatment with agonistic DR3 antibody results in expansion of donor Tregs and reduced graft-versus-host disease. Blood. 2015;126:546–57. https://doi.org/10.1182/blood-2015-04-637587

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Nishikii H, Kim BS, Yokoyama Y, Chen Y, Baker J, Pierini A, et al. DR3 signaling modulates the function of Foxp3+ regulatory T cells and the severity of acute graft-versus-host disease. Blood. 2016;128:2846–58. https://doi.org/10.1182/blood-2016-06-723783.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Chen YB, Efebera YA, Johnston L, Ball ED, Avigan D, Lekakis LJ et al. Increased Foxp3+Helios+ Regulatory T Cells and Decreased Acute Graft-versus-Host Disease after Allogeneic Bone Marrow Transplantation in Patients Receiving Sirolimus and RGI-2001, an Activator of Invariant Natural Killer T Cells. Biol Blood Marrow Transplant 2017. https://doi.org/10.1016/j.bbmt.2017.01.069.

  20. Rubio MT, Bouillie M, Bouazza N, Coman T, Trebeden-Negre H, Gomez A et al. Pre-transplant donor CD4- invariant NKT cell expansion capacity predicts the occurrence of acute graft-versus-host disease. Leukemia 2016. https://doi.org/10.1038/leu.2016.281.

  21. Chaidos A, Patterson S, Szydlo R, Chaudhry MS, Dazzi F, Kanfer E, et al. Graft invariant natural killer T-cell dose predicts risk of acute graft-versus-host disease in allogeneic hematopoietic stem cell transplantation. Blood. 2012;119:5030–6. https://doi.org/10.1182/blood-2011-11-389304.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Malard F, Labopin M, Chevallier P, Guillaume T, Duquesne A, Rialland F, et al. Larger number of invariant natural killer T cells in PBSC allografts correlates with improved GVHD-free and progression-free survival. Blood. 2016;127:1828–35. https://doi.org/10.1182/blood-2015-12-688739.

    Article  CAS  PubMed  Google Scholar 

  23. Rubio MT, Bouillie M, Bouazza N, Coman T, Trebeden-Negre H, Gomez A, et al. Pre-transplant donor CD4(-) invariant NKT cell expansion capacity predicts the occurrence of acute graft-versus-host disease. Leukemia. 2017;31:903–12. https://doi.org/10.1038/leu.2016.281.

    Article  CAS  PubMed  Google Scholar 

  24. Schneidawind D, Pierini A, Alvarez M, Pan Y, Baker J, Buechele C et al. CD4+ invariant natural killer T cells protect from murine GVHD lethality through expansion of donor CD4+CD25+FoxP3+ regulatory T cells. Blood 2014. https://doi.org/10.1182/blood-2014-05-576017.

  25. Schneidawind D, Baker J, Pierini A, Buechele C, Luong RH, Meyer EH, et al. Third-party CD4+ invariant natural killer T cells protect from murine GVHD lethality. Blood. 2015;125:3491–3500. https://doi.org/10.1182/blood-2014-11-612762.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Du J, Paz K, Thangavelu G, Schneidawind D, Baker J, Flynn R, et al. Invariant natural killer T cells ameliorate murine chronic GVHD by expanding donor regulatory T cells. Blood. 2017;129:3121–5. https://doi.org/10.1182/blood-2016-11-752444.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Ronald JA, Kim BS, Gowrishankar G, Namavari M, Alam IS, D'Souza A, et al. A PET Imaging Strategy to Visualize Activated T Cells in Acute Graft-versus-Host Disease Elicited by Allogenic Hematopoietic Cell Transplant. Cancer Res. 2017;77:2893–902. https://doi.org/10.1158/0008-5472.CAN-16-2953.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Funding

Publication of this supplement was sponsored by Gilead Sciences Europe Ltd, Cell Source, Inc., The Chorafas Institute for Scientific Exchange of the Weizmann Institute of Science, Kiadis Pharma, Miltenyi Biotec, Celgene, Centro Servizi Congressuali, Almog Diagnostic.

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  1. Division of Blood and Marrow Transplantation, Department of Medicine, Stanford University, 269 W. Campus Drive, Room 2205, Stanford, CA, USA

    Robert S. Negrin

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  1. Robert S. Negrin
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Correspondence to Robert S. Negrin.

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The author received consulting fees from Amgen and Jazz Pharmaceuticals, owns equity in Magenta and BioEclipse, performs occasional medical legal work, and serves as Editor in Chief of Blood Advances.

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Negrin, R.S. Immune regulation in hematopoietic cell transplantation. Bone Marrow Transplant 54 (Suppl 2), 765–768 (2019). https://doi.org/10.1038/s41409-019-0600-7

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