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Immune Reconstitution

A prospective comparison of immune reconstitution in pediatric recipients of positively selected CD34+ peripheral blood stem cells from unrelated donors vs recipients of unmanipulated bone marrow from related donors

Summary:

Positively selected CD34+ hematopoietic stem cells from unrelated donors (UD-HSCT) have been successfully transplanted, but little is known about immune reconstitution in this setting. Here we report a prospective comparison of immune reconstitution in recipients of UD-HSCT and of unmanipulated bone marrow from matched sibling donors (MSD-BMT). T-cell reconstitution occurred more than 100 days later in the UD-HSCT than in the MSD-BMT group. The first T cells after UD-HSCT were almost exclusively CD45RO+ HLA-DR+, whereas early-emerging T cells after MSD-BMT more frequently expressed CD62L, CD28, and CD25. In both groups, numbers of CD45RA+ naive T cells increased after 180 days. After UD-HSCT, the T-cell-receptor (TCR)-repertoire was severely skewed and showed significantly reduced diversity during the first year, but only minor abnormalities were seen after MSD-BMT. TCR-diversity increased simultaneously with the number of naive T cells. In both groups, we observed transient expansions of γδ T cells. B cells were reconstituted more rapidly in UD-HSCT than in MSD-BMT recipients, whereas the rapidity of NK-cell reconstitution was similar in the two groups. In summary, T-cell reconstitution was slower after UD-HSCT than after MSD-BMT because of the delayed recovery of early memory-type T cells with reduced TCR-diversity, whereas naive T-, NK-, and B cells were reconstituted similarly in the two groups.

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References

  1. Ringden O, Remberger M, Runde V et al. Peripheral blood stem cell transplantation from unrelated donors: a comparison with marrow transplantation. Blood 1999; 94: 455–464.

    CAS  PubMed  Google Scholar 

  2. Cutler C, Antin JH . Peripheral blood stem cells for allogeneic transplantation: a review. Stem Cells 2001; 19: 108–117.

    Article  CAS  PubMed  Google Scholar 

  3. Ottinger HD, Beelen DW, Scheulen B et al. Improved immune reconstitution after allotransplantation of peripheral blood stem cells instead of bone marrow. Blood 1996; 88: 2775–2779.

    CAS  PubMed  Google Scholar 

  4. Storek J, Dawson MA, Storer B et al. Immune reconstitution after allogeneic marrow transplantation compared with blood stem cell transplantation. Blood 2001; 97: 3380–3389.

    Article  CAS  PubMed  Google Scholar 

  5. Cutler C, Giri S, Jeyapalan S et al. Acute and chronic graft-versus-host disease after allogeneic peripheral-blood stem-cell and bone marrow transplantation: a meta-analysis. J Clin Oncol 2001; 19: 3685–3691.

    Article  CAS  PubMed  Google Scholar 

  6. Socie G, Stone JV, Wingard JR et al. Long-term survival and late deaths after allogeneic bone marrow transplantation. Late Effects Working Committee of the International Bone Marrow Transplant Registry. N Engl J Med 1999; 341: 14–21.

    Article  CAS  PubMed  Google Scholar 

  7. Kondo M, Kojima S, Horibe K et al. Risk factors for chronic graft-versus-host disease after allogeneic stem cell transplantation in children. Bone Marrow Transplant 2001; 27: 727–730.

    Article  CAS  PubMed  Google Scholar 

  8. O'Donnell PV, Myers B, Edwards J et al. CD34 selection using three immunoselection devices: comparison of T-cell depleted allografts. Cytotherapy 2001; 3: 483–488.

    Article  CAS  PubMed  Google Scholar 

  9. Schumm M, Lang P, Taylor G et al. Isolation of highly purified autologous and allogeneic peripheral CD34+ cells using the CliniMACS device. J Hematother 1999; 8: 209–218.

    Article  CAS  PubMed  Google Scholar 

  10. Handgretinger R, Klingebiel T, Lang P et al. Megadose transplantation of purified peripheral blood CD34(+) progenitor cells from HLA-mismatched parental donors in children. Bone Marrow Transplant 2001; 27: 777–783.

    Article  CAS  PubMed  Google Scholar 

  11. Davison GM, Novitzky N, Kline A et al. Immune reconstitution after allogeneic bone marrow transplantation depleted of T cells. Transplantation 2000; 69: 1341–1347.

    Article  CAS  PubMed  Google Scholar 

  12. Small TN, Papadopoulos EB, Boulad F et al. Comparison of immune reconstitution after unrelated and related T-cell-depleted bone marrow transplantation: effect of patient age and donor leukocyte infusions. Blood 1999; 93: 467–480.

    CAS  PubMed  Google Scholar 

  13. Handgretinger R, Schumm M, Lang P et al. Transplantation of megadoses of purified haploidentical stem cells. Ann NY Acad Sci 1999; 872: 351–361.

    Article  CAS  PubMed  Google Scholar 

  14. Schlegel PG, Aharoni R, Chen Y et al. A synthetic random basic copolymer with promiscuous binding to class II major histocompatibility complex molecules inhibits T-cell proliferative responses to major and minor histocompatibility antigens in vitro and confers the capacity to prevent murine graft-versus-host disease in vivo. Proc Natl Acad Sci USA 1996; 93: 5061–5066.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Gorski J, Yassai M, Zhu X et al. Circulating T cell repertoire complexity in normal individuals and bone marrow recipients analyzed by CDR3 size spectratyping. Correlation with immune status. J Immunol 1994; 152: 5109–5119.

    CAS  PubMed  Google Scholar 

  16. Gorski J, Piatek T, Yassai M et al. Improvements in repertoire analysis by CDR3 size spectratyping. Bifamily PCR. Ann NY Acad Sci 1995; 756: 99–102.

    Article  CAS  PubMed  Google Scholar 

  17. Wu C, Chillemi A, Alyea E et al. Reconstitution of T-cell receptor repertoire diversity following T-cell depleted allogeneic bone marrow transplantation is related to hematopoietic chimerism. Blood 2000; 95: 352–359.

    CAS  PubMed  Google Scholar 

  18. Mackall CL, Bare CV, Granger LA et al. Thymic-independent T cell regeneration occurs via antigen-driven expansion of peripheral T cells resulting in a repertoire that is limited in diversity and prone to skewing. J Immunol 1996; 156: 4609–4616.

    CAS  PubMed  Google Scholar 

  19. Gorla R, Airo P, Ferremi-Leali P et al. Predominance of ‘memory’ phenotype within CD4+ and CD8+ lymphocyte subsets after allogeneic BMT. Bone Marrow Transplant 1993; 11: 346–347.

    CAS  PubMed  Google Scholar 

  20. Hamann D, Baars PA, Rep MH et al. Phenotypic and functional separation of memory and effector human CD8+ T cells. J Exp Med 1997; 186: 1407–1418.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Lum LG . The kinetics of immune reconstitution after human marrow transplantation. Blood 1987; 69: 369–3680.

    CAS  PubMed  Google Scholar 

  22. Foot AB, Potter MN, Donaldson C et al. Immune reconstitution after BMT in children. Bone Marrow Transplant 1993; 11: 7–13.

    CAS  PubMed  Google Scholar 

  23. Godthelp BC, van Tol MJ, Vossen JM et al. T-Cell immune reconstitution in pediatric leukemia patients after allogeneic bone marrow transplantation with T-cell-depleted or unmanipulated grafts: evaluation of overall and antigen-specific T-cell repertoires. Blood 1999; 94: 4358–4369.

    CAS  PubMed  Google Scholar 

  24. Guillaume T, Rubinstein DB, Symann M . Immune reconstitution and immunotherapy after autologous hematopoietic stem cell transplantation. Blood 1998; 92: 1471–1490.

    CAS  PubMed  Google Scholar 

  25. Mackall CL, Fleisher TA, Brown MR et al. Age, thymopoiesis, and CD4+ T-lymphocyte regeneration after intensive chemotherapy. N Engl J Med 1995; 332: 143–149.

    Article  CAS  PubMed  Google Scholar 

  26. Heitger A, Neu N, Kern H et al. Essential role of the thymus to reconstitute naive (CD45RA+) T-helper cells after human allogeneic bone marrow transplantation. Blood 1997; 90: 850–857.

    CAS  PubMed  Google Scholar 

  27. Roux E, Dumont-Girard F, Starobinski M et al. Recovery of immune reactivity after T-cell-depleted bone marrow transplantation depends on thymic activity. Blood 2000; 96: 2299–2303.

    CAS  PubMed  Google Scholar 

  28. Mackall CL, Gress RE . Pathways of T-cell regeneration in mice and humans: implications for bone marrow transplantation and immunotherapy. Immunol Rev 1997; 157: 61–72.

    Article  CAS  PubMed  Google Scholar 

  29. Roux E, Helg C, Dumont-Girard F et al. Analysis of T-cell repopulation after allogeneic bone marrow transplantation: significant differences between recipients of T-cell depleted and unmanipulated grafts. Blood 1996; 87: 3984–3992.

    CAS  PubMed  Google Scholar 

  30. Eyrich M, Croner T, Leiler C et al. Distinct contributions of CD4+ and CD8+ naive and memory T-cell subsets to overall TCR-repertoire complexity following transplantation of T-cell depleted CD34 selected hematopoietic progenitor cells from unrelated donors. Blood 2002; 100: 1915–1918.

    Article  CAS  PubMed  Google Scholar 

  31. Cavazzana-Calvo M, Bensoussan D, Jabado N et al. Prevention of EBV-induced B-lymphoproliferative disorder by ex vivo marrow B-cell depletion in HLA-phenoidentical or non-identical T-depleted bone marrow transplantation. Br J Haematol 1998; 103: 543–551.

    Article  CAS  PubMed  Google Scholar 

  32. Finke J, Bertz H, Schmoor C et al. Allogeneic bone marrow transplantation from unrelated donors using in vivo anti-T-cell globulin. Br J Haematol 2000; 111: 303–313.

    Article  CAS  PubMed  Google Scholar 

  33. Kojima S, Inaba J, Yoshimi A et al. Unrelated donor marrow transplantation in children with severe aplastic anaemia using cyclophosphamide, anti-thymocyte globulin and total body irradiation. Br J Haematol 2001; 114: 706–711.

    Article  CAS  PubMed  Google Scholar 

  34. Kroger N, Zabelina T, Kruger W et al. Anti-thymocyte-globulin as part of the preparative regimen prevents graft failure and severe graft versus host disease (GvHD) in allogeneic stem cell transplantation from unrelated donors. Ann Hematol 2001; 80: 209–215.

    Article  CAS  PubMed  Google Scholar 

  35. Remberger M, Mattsson J, Ringden O . Polyclonal anti-T-cell globulin as part of the preparative regimen for pediatric allogeneic stem-cell transplantation. Pediatr Transplant 2001; 5: 285–292.

    Article  CAS  PubMed  Google Scholar 

  36. Eyrich M, Lang P, Lal S et al. A prospective analysis of the pattern of immune reconstitution following transplantation of HLA-disparate hematopoietic stem cells from parental donors. Br J Haematol 2001; 114: 422–432.

    Article  CAS  PubMed  Google Scholar 

  37. Akatsuka Y, Cerveny C, Hansen JA . T cell receptor clonal diversity following allogeneic marrow grafting. Hum Immunol 1996; 48: 125–134.

    Article  CAS  PubMed  Google Scholar 

  38. Nordoy T, Kolstad A, Endresen P et al. Persistent changes in the immune system 4–10 years after ABMT. Bone Marrow Transplant 1999; 24: 873–878.

    Article  CAS  PubMed  Google Scholar 

  39. Lang P, Handgretinger R, Niethammer D et al. Transplantation of highly purified CD34+ progenitor cells from unrelated donors in pediatric leukemia. Blood 2003; 101: 1630–1636.

    Article  CAS  PubMed  Google Scholar 

  40. Weinberg K, Blazar BR, Wagner JE et al. Factors affecting thymic function after allogeneic hematopoietic stem cell transplantation. Blood 2001; 97: 1458–1466.

    Article  CAS  PubMed  Google Scholar 

  41. Okumura M, Fujii Y, Inada K et al. Both CD45RA+ and CD45RA- subpopulations of CD8+ T cells contain cells with high levels of lymphocyte function-associated antigen-1 expression, a phenotype of primed T cells. J Immunol 1993; 150: 429–437.

    CAS  PubMed  Google Scholar 

  42. Fehse B, Frerk O, Goldmann M et al. Efficient depletion of alloreactive donor T lymphocytes based on expression of two activation-induced antigens (CD25 and CD69). Br J Haematol 2000; 109: 644–651.

    Article  CAS  PubMed  Google Scholar 

  43. Montagna D, Yvon E, Calcaterra V et al. Depletion of alloreactive T cells by a specific anti-interleukin-2 receptor p55 chain immunotoxin does not impair in vitro antileukemia and antiviral activity. Blood 1999; 93: 3550–3557.

    CAS  PubMed  Google Scholar 

  44. Gudmundsdottir H, Turka LA . A closer look at homeostatic proliferation of CD4+ T cells: costimulatory requirements and role in memory formation. J Immunol 2001; 167: 3699–3707.

    Article  CAS  PubMed  Google Scholar 

  45. Murali Krishna K, Ahmed R . Cutting edge: naive T cells masquerading as memory cells. J Immunol 2000; 165: 1733–1737.

    Article  CAS  PubMed  Google Scholar 

  46. Douek DC, Vescio RA, Betts MR et al. Assessment of thymic output in adults after haematopoietic stem-cell transplantation and prediction of T-cell reconstitution. Lancet 2000; 355: 1875–1881.

    Article  CAS  PubMed  Google Scholar 

  47. Cela ME, Holladay MS, Rooney CM et al. Gamma delta T lymphocyte regeneration after T lymphocyte-depleted bone marrow transplantation from mismatched family members or matched unrelated donors. Bone Marrow Transplant 1996; 17: 243–247.

    CAS  PubMed  Google Scholar 

  48. Hirokawa M, Horiuchi T, Kawabata Y et al. Reconstitution of gammadelta T cell repertoire diversity after human allogeneic hematopoietic cell transplantation and the role of peripheral expansion of mature T cell population in the graft. Bone Marrow Transplant 2000; 26: 177–185.

    Article  CAS  PubMed  Google Scholar 

  49. Lefrancois L, Olson S . Reconstitution of the extrathymic intestinal T cell compartment in the absence of irradiation. J Immunol 1997; 159: 538–541.

    CAS  Google Scholar 

  50. Laky K, Lefrancois L, von Freeden-Jeffry U et al. The role of IL-7 in thymic and extrathymic development of TCR gamma delta cells. J Immunol 1998; 161: 707–713.

    CAS  PubMed  Google Scholar 

  51. Ruggeri L, Capanni M, Casucci M et al. Role of natural killer cell alloreactivity in HLA-mismatched hematopoietic stem cell transplantation. Blood 1999; 94: 333–339.

    CAS  PubMed  Google Scholar 

  52. Ruggeri L, Capanni M, Urbani E et al. Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Science 2002; 295: 2097–2100.

    Article  CAS  PubMed  Google Scholar 

  53. Moretta L, Bottino C, Pende D et al. Human natural killer cells: their origin, receptors and function. Eur J Immunol 2002; 32: 1205–1211.

    Article  CAS  PubMed  Google Scholar 

  54. Reisner Y, Martelli MF . Transplantation tolerance induced by ‘mega dose’ CD34+ cell transplants. Exp Hematol 2000; 28: 119–127.

    Article  CAS  PubMed  Google Scholar 

  55. Handgretinger R, Lang P, Schumm M et al. Immunological aspects of haploidentical stem cell transplantation in children. Ann NY Acad Sci 2001; 938: 340–357.

    Article  CAS  PubMed  Google Scholar 

  56. Fry TJ, Christensen BL, Komschlies KL et al. Interleukin-7 restores immunity in athymic T-cell-depleted hosts. Blood 2001; 97: 1525–1533.

    Article  CAS  PubMed  Google Scholar 

  57. Bolotin E, Smogorzewska M, Smith S et al. Enhancement of thymopoiesis after bone marrow transplant by in vivo interleukin-7. Blood 1996; 88: 1887–1894.

    CAS  PubMed  Google Scholar 

  58. Min D, Taylor PA, Panoskaltsis-Mortari A et al. Protection from thymic epithelial cell injury by keratinocyte growth factor: a new approach to improve thymic and peripheral T-cell reconstitution after bone marrow transplantation. Blood 2002; 99: 4592–4600.

    Article  CAS  PubMed  Google Scholar 

  59. Schlegel P, Eyrich M, Bader P et al. OKT-3 based reconditioning regimen for early graft failure in HLA-non-identical stem cell transplants. Br J Haematol 2000; 111: 668–673.

    Article  CAS  PubMed  Google Scholar 

  60. Hannet I, Erkeller-Yuksel F, Lydyard P et al. Developmental and maturational changes in human blood lymphocyte subpopulations. Immunol Today 1992; 13: 215, 218.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank the staff of the BMT unit and outpatient department, as well as the technical staff of the stem cell processing unit, at the University Children's Hospital, Tübingen for their excellent and dedicated patient care. We also thank Sharon Naron for editorial assistance with the manuscript.

ME is the recipient of a postdoctoral fellowship awarded by the Else Übelmesser Foundation for Cancer Research (1.3-0415.221.18-03/97). This work was supported by a grant from the fortüne-Program of the University of Tübingen (#587/1999) and by Interdisciplinary Research Centre (IZKF) Program Project Grant IIA3 (1999–2002 to P.G.S.) of the University of Tübingen.

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Eyrich, M., Leiler, C., Lang, P. et al. A prospective comparison of immune reconstitution in pediatric recipients of positively selected CD34+ peripheral blood stem cells from unrelated donors vs recipients of unmanipulated bone marrow from related donors. Bone Marrow Transplant 32, 379–390 (2003). https://doi.org/10.1038/sj.bmt.1704158

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