Advertisement

T Regulatory Cells in Donor Grafts May Predict the Severity of Acute Graft Versus Host Disease After Matched Sibling Donor Allogenic Peripheral Blood Stem Cell Transplantation

  • Dinesh Chandra
  • Jasdeep Singh
  • Roopam Deka
  • Ankur Ahuja
  • Rahul Sharma
  • Pravas Mishra
  • Tulika Seth
  • Manoranjan Mahapatra
  • Lalit Kumar
  • Seema Tyagi
  • Renu Saxena
  • Hara Prasad Pati
Original Article
  • 2 Downloads

Abstract

Acute graft-versus-host disease (aGVHD) and relapse are major issues for patients undergoing allogenic hematopoietic stem cell transplant (allo-HSCT). T-regulatory (Treg) cells in the donor graft are negatively correlated with the incidence of aGVHD without any impact on relapse. In this study to determine the association of Treg cells with aGVHD in allo-HSCT patients. Thirty-two patients with hematological disorders, who underwent allo-HSCT. Twenty-nine patients who achieved engraftment were enrolled in the study. Treg cells were quantified in donor graft by flowcytometry and were assessed for their association with aGVHD and other clinical outcomes. Fifteen of 29 patients developed aGVHD. According to the occurrence and severity of aGVHD, patients were divided into two groups: 20 (68.9%) patients with grade 0–I aGVHD and 9 (31.1%) patients with grade II–IV aGVHD. Treg cells/CD4 ratio was significantly higher in the grade 0–I aGVHD group than in grade II–IV aGVHD group, (p = 0.0002). We could not find the association of CD34 dose (p = 0.55) or CD3 dose (p = 0.57) with the severity of aGVHD. Higher Treg cells/CD4 ratio in donor graft was associated with less severe aGVHD. Though more studies are needed, Treg cells/CD4 ratio may be used as a predictive marker for severity of aGVHD in post allo-HSCT.

Keywords

T-regulatory cells Acute GVHD Allo-HSCT 

Notes

Acknowledgements

The authors would like to thank, Mrs Veena Pandey, MA, Statistician, and Mr Rajesh, Technical staff, Flowcytometry Lab, AIIMS, New Delhi.

Compliance with Ethical Standards

Conflict of interest

Authors have no conflict of interest to declare.

Ethical Approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This article does not contain any studies with animals performed by any of the authors.

Informed Consent

Informed consent was obtained from all individual participants included in the study.

References

  1. 1.
    Shlomchik WD (2007) Graft-versus-host disease. Nat Rev Immunol 7(5):340–352CrossRefGoogle Scholar
  2. 2.
    Loiseau P, Busson M, Balere ML, Dormoy A, Bignon JD, Gagne K et al (2007) HLA Association with hematopoietic stem cell transplantation outcome: the number of mismatches at HLA-A, -B, -C, -DRB1, or -DQB1 is strongly associated with overall survival. Biol Blood Marrow Transplant 13(8):965–974CrossRefGoogle Scholar
  3. 3.
    Gershon RK, Kondo K (1971) Infectious immunological tolerance. Immunology 21(06):903–914Google Scholar
  4. 4.
    Edinger M, Hoffmann P, Ermann J, Drago K, Fathman CG, Strober S et al (2003) CD4+ CD25+ regulatory T cells preserve graft-versus-tumor activity while inhibiting graft-versus-host disease after bone marrow transplantation. Nat Med 9(9):1144–1150CrossRefGoogle Scholar
  5. 5.
    Lim HW, Broxmeyer HE, Kim CH (2006) Regulation of trafficking receptor expression in human forkhead box P3+ regulatory T cells. J Immunol 177(2):840–851CrossRefGoogle Scholar
  6. 6.
    Liu W, Putnam AL, Xu-Yu Z, Szot GL, Lee MR, Zhu S et al (2006) CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ T reg cells. J Exp Med 203(7):1701–1711CrossRefGoogle Scholar
  7. 7.
    Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M (1995) 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 155(3):1151–1164Google Scholar
  8. 8.
    Taylor PA, Lees CJ, Blazar BR (2002) The infusion of ex vivo activated and expanded CD4CD25 immune regulatory cells inhibits graft-versus-host disease lethality. Blood 99(10):3493–3499CrossRefGoogle Scholar
  9. 9.
    Rezvani K, Mielke S, Ahmadzadeh M, Kilical Y, Savani BN, Zeilah J et al (2006) High donor FOXP3-positive regulatory T-cell (Treg) content is associated with a low risk of GVHD following HLA-matched allogeneic SCT. Blood 108(10):1291–1297CrossRefGoogle Scholar
  10. 10.
    Wolf D, Wolf AM, Fong D, Rumpold H, Strasak A, Clausen J et al (2007) Regulatory T-cells in the graft and the risk of acute graft-versus-host disease after allogeneic stem cell transplantation. Transplantation 83(8):1107–1113CrossRefGoogle Scholar
  11. 11.
    Fang Z, Hua Z, Changying L, Jianmin W, Chengjuan L, Kangli X, Jing C (2013) High level of CD4+ CD25+ CD127-treg cells in donor graft is associated with a low risk of aGVHD after allo-HSCT for children with hematologic malignancies. J Cell Sci Ther 4:148.  https://doi.org/10.4172/2157-7013.1000148 Google Scholar
  12. 12.
    Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J et al (1995) Consensus conference on acute GVHD grading. Bone Marrow Transplant 15(6):825–828Google Scholar
  13. 13.
    Jagasia M, Arora M, Flowers ME, Chao NJ, McCarthy PL, Cutler CS et al (2012) Risk factors for acute GVHD and survival after hematopoietic cell transplantation. Blood 119(1):296–307CrossRefGoogle Scholar
  14. 14.
    Asano M, Toda M, Sakaguchi N, Sakaguchi S (1996) Autoimmune disease as a consequence of developmental abnormality of a T cell subpopulation. J Exp Med 184(2):387–396CrossRefGoogle Scholar
  15. 15.
    Itoh M, Takahashi T, Sakaguchi N, Kuniyasu Y, Shimizu J, Otsuka F et al (1999) Thymus and autoimmunity: production of CD25CD4 naturally anergic and suppressive T cells as a key function of the thymus in maintaining immunologic self-tolerance. J Immunol 162(9):5317–5326Google Scholar
  16. 16.
    Johnson BD, Konkol MC, Truitt RL (2002) CD25 immuno-regulatory T-cells of donor origin suppress alloreactivity after BMT. Biol Blood Marrow Transplant 8(10):525–535CrossRefGoogle Scholar
  17. 17.
    Danby RD, Zhang W, Medd P, Littlewood TJ, Peniket A, Rocha V et al (2016) High proportion of regulatory T cells in PBSC graft predicts improved survival after allogenic hematopoietic SCT. Bone Marrow Transplant 51(1):110–118CrossRefGoogle Scholar
  18. 18.
    Pabst C, Schirutschke H, Ehninger G, Bornhauser M, Platzbecker U (2007) The graft content of donor T-cells expressing gamma-delta TCR+ and CD4+ Foxp3+ predicts the risk of acute graft versus host disease after transplantation of allogeneic peripheral blood stem cells from unrelated donors. Clin Cancer Res 13(10):2916–2922CrossRefGoogle Scholar
  19. 19.
    Stanzani M, Martins SL, Saliba RM, St John LS, Bryan S, Couriel D et al (2004) CD25 expression on donor CD4+ or CD8+ T cells is associated with an increased risk for graft-versus host disease after HLA-identical stem cell transplantation in humans. Blood 103(3):1140–1146CrossRefGoogle Scholar
  20. 20.
    Zaucha JM, Gooley T, Bensinger WI, Heimfeld S, Chauncey TR, Zaucha R et al (2001) CD34 cell dose in granulocyte colony-stimulating factor mobilized peripheral blood mononuclear cell grafts affects engraftment kinetics and development of extensive chronic graft-versus-host disease after human leukocyte antigen-identical sibling transplantation. Blood 98(12):3221–3227CrossRefGoogle Scholar
  21. 21.
    Przepiorka D, Smith TL, Folloder J, Khouri I, Ueno NT, Mehra R et al (1999) Risk factors for acute graft-versus-host disese after allogeneic blood stem cell transplantation. Blood 94(4):1465–1470Google Scholar
  22. 22.
    Czerw T, Labopin M, Schmid C, Cornelissen J, Chevallier P, Blaise D (2016) High CD3+ and CD34+ peripheral blood stem cell grafts content is associated with increased risk of graft-versus-host disease without beneficial effect on disease control after reduced intensity conditioning allogeneic transplantation from matched unrelated donors for acute myeloid leukemia—an analysis from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation. Oncotarget 7(19):27255–27266CrossRefGoogle Scholar
  23. 23.
    Gaziev J, Isgrò A, Marziali M, Daniele N, Gallucci C, Sodani P et al (2012) Higher CD3(+) and CD34(+) cell doses in the graft increase the incidence of acute GVHD in children receiving BMT for thalassemia. Bone Marrow Transplant 47(1):107–114CrossRefGoogle Scholar
  24. 24.
    Urbano-Ispizua A, Rozman C, Pimentel P, Solano C, de la Rubia J, Brunet S et al (2002) Risk factors for acute graft-versus-host disease in patients undergoing transplantation with CD 34+ selected blood cells from HLA-identical siblings. Blood 100(2):724–727CrossRefGoogle Scholar
  25. 25.
    Champlin RE, Schmitz N, Horowitz MM, Chapuis B, Chopra R, Cornelissen JJ et al (2000) Blood stem cells compared with bone marrow as a source of hematopoietic cells for allogeneic transplantation. Blood 95(12):3702–3709Google Scholar

Copyright information

© Indian Society of Hematology and Blood Transfusion 2019

Authors and Affiliations

  • Dinesh Chandra
    • 1
  • Jasdeep Singh
    • 2
  • Roopam Deka
    • 2
  • Ankur Ahuja
    • 2
  • Rahul Sharma
    • 2
  • Pravas Mishra
    • 2
  • Tulika Seth
    • 2
  • Manoranjan Mahapatra
    • 2
  • Lalit Kumar
    • 3
  • Seema Tyagi
    • 2
  • Renu Saxena
    • 2
  • Hara Prasad Pati
    • 2
  1. 1.Department of HematologySanjay Gandhi Post Graduate Institute of Medical SciencesLucknowIndia
  2. 2.Department of HematologyAll India Institute of Medical Sciences (AIIMS)New DelhiIndia
  3. 3.Medical Oncology, IRCHAll India Institute of Medical Sciences (AIIMS)New DelhiIndia

Personalised recommendations