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Post-Transplant Events

T-lymphocyte reconstitution following rigorously T-cell-depleted versus unmodified autologous stem cell transplants

Bone Marrow Transplantation volume 37, pages 763–772 (2006)Cite this article

Abstract

We compared the kinetics of T-cell recovery after extensive ex vivo and in vivo T-cell depleted autologous stem cell transplantation (SCT) for multiple sclerosis (MS; n=8) with unmodified SCT for hematological malignancies (HM; n=39). Both patient group showed a very protracted recovery of ‘naive’ CD4+, 45R0− (≈CD45RA+) T-cells. Within the ‘primed’ CD4+, 45R0+ T-cells, the ‘central memory’ cells expressing the CD62L and CD27 markers were the slowest to recover. The repopulating T-cells were highly activated, as shown by increased expression of HLA-DR and the apoptosis marker CD95. The capability of CD4+ and CD8+ T-cells to produce IFN-γ, IL-2 and TNF-α had reached normal ranges from 2 months post SCT onwards. Unexpectedly, the kinetics of T-cell recovery between 3 and 12 months post transplant was similar in T-depleted and unmodified SCT. Before SCT, the HM patients showed lymphopenia of all T-cell subsets, upregulated HLA-DR and CD95 expression and increased cytokine responses. We suggest that the similar kinetics of T-cell recovery in the two patient groups may be explained by the susceptibility to apoptosis of the activated CD4+ T-cells in the autografts of the HM patients. This susceptibility to apoptosis would interfere with a swift and sustained CD4+ T-cell regeneration post SCT.

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References

  1. Van Gelder M, Kinwel-Bohre EP, Van Bekkum DW . Treatment of experimental allergic encephalomyelitis in rats with total body irradiation and syngeneic BMT. Bone Marrow Transplant 1993; 11: 233–241.

    CAS  PubMed  Google Scholar 

  2. Karussis DM, Vourka-Karussis U, Mizrachi-Koll R, Abramsky O . Acute/relapsing experimental autoimmune encephalomyelitis: introduction of long lasting, antigen-specific tolerance by syngeneic bone marrow transplantation. Multiple Sclerosis 1999; 5: 17–21.

    Article  CAS  PubMed  Google Scholar 

  3. Traynor AE, Schroeder J, Rosa RM, Cheng D, Stefka J, Mujais S et al. Treatment of severe systemic lupus erythematosus with high-dose chemotherapy and haemopoietic stem-cell transplantation: a phase I study. Lancet 2000; 356: 701–707.

    Article  CAS  PubMed  Google Scholar 

  4. Openshaw H, Nash RA, McSweeney PA . High-dose immunosuppression and hemopoietic stem cell transplantation in autoimmune diseases: clinical review. Biol Blood Marrow Transplant 2002; 8: 223–248.

    Article  Google Scholar 

  5. Nash RA, Bowen JD, McSweeney PA, Pavletic SZ, Maravilla KR, Park MS et al. High-dose immunosuppressive therapy and autologous stem cell transplantation for severe multiple sclerosis. Blood 2003; 102: 2364–2372.

    Article  CAS  PubMed  Google Scholar 

  6. Samijn JPA, Te Boekhorst PAW, Mondria T, Van Doorn PA, Flach HZ, van der Meché FG et al. Intense T-cell depletion followed by autologous bone marrow transplantation for severe multiple sclerosis. J Neurol Neurosurg Psychiatry 2006; 77: 46–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. 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 

  8. Bomberger C, Sing-Jairam M, Rodey G, Guerriero A, Yeager AM, Flemming WH et al. Lymphoid reconstitution after autologous PBSC transplantation with FACS-sorted CD34+ hematopoietic progenitors. Blood 1998; 91: 2588–2600.

    CAS  PubMed  Google Scholar 

  9. Vescio R, Schiller G, Stewart AK, Ballester O, Noga S, Rugo H et al. Multicenter phase III trial to evaluate CD34+ selected versus unselected autologous peripheral blood progenitor cell transplantation in multiple myeloma. Blood 1999; 93: 1858–1868.

    CAS  PubMed  Google Scholar 

  10. Rutella S, Rumi C, Laurenti L, Pierelli L, Sora’ F, Sica S et al. Immune reconstitution after transplantation of autologous peripheral CD34+ cells: analysis of predictive factors and comparison with unselected progenitor transplants. Br J Haematol 2000; 108: 105–115.

    Article  CAS  PubMed  Google Scholar 

  11. Douek DC, Vescio RA, Betts MR, Brenchley JM, Hill BJ, Zhang L 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 

  12. Nachbaur D, Kropshofer G, Heitger A, Latzer K, Glassl H, Ludescher C et al. Phenotypic and functional lymphocyte recovery after CD34+-enriched versus non-T cell-depleted autologous peripheral blood stem cell transplantation. J Hematother Stem Cell Res 2000; 9: 727–736.

    Article  CAS  PubMed  Google Scholar 

  13. Damiani D, Stocchi R, Masolini P, Michelutti A, Geromin A, Sperotto A et al. CD34+-selected versus unmanipulated autologous stem cell transplantation in multiple myeloma: impact on dendritic and immune recovery and on complications due to infections. Ann Oncol 2003; 14: 475–480.

    Article  CAS  PubMed  Google Scholar 

  14. Malphettes M, Carcelain G, Saint-Mezard P, Leblond V, Altes HK, Marolleau JP et al. Evidence for naive T-cell repopulation despite thymus irradiation after autologous transplantation in adults with multiple myeloma: role of ex vivo CD34+ selection and age. Blood 2003; 101: 1891–1897.

    Article  CAS  PubMed  Google Scholar 

  15. Storek J, Zhao Z, Lin E, Berger T, McSweeney PA, Nash RA et al. Recovery from and consequences of severe iatrogenic lymphopenia (induced to treat autoimmune diseases). Clin Immunol 2004; 113: 285–298.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Muraro PA, Douek DC, Packer A, Chung K, Guenaga FJ, Cassiani-Ingoni R et al. Thymic output generates a new and diverse TCR repertoire after autologous stem cell transplantation in multiple sclerosis patients. J Exp Med 2005; 201: 805–816.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Sutherland DR, Keeney M, Gratama JW . Enumeration of CD34+ hematopoietic stem and progenitor cells. Curr Prot Cytometry 2003, 6.4.1–6.4.25.

  18. Schnizlein-Bick CT, Spritzler J, Wilkening CL, Nicholson JK, O'Gorman MR . Evaluation of TruCount absolute-count tubes for determining CD4 and CD8 cell numbers in human immunodeficiency virus-positive adults. Site Investigators and The NIAID DAIDS New Technologies Evaluation Group. Clin Diag Lab Immunol 2000; 7: 336–343.

    CAS  Google Scholar 

  19. Glencross D, Scott LE, Jani IV, Barnett D, Janossy G . CD45-assisted PanLeucogating for accurate, cost-effective dual-platform CD4+ T-cell enumeration. Cytometry 2002; 15: 69–77.

    Article  Google Scholar 

  20. Sallusto F, Lenig D, Förster R, Lipp M, Lanzavecchia A . Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature 1999; 401: 708–712.

    Article  CAS  PubMed  Google Scholar 

  21. Baars PA, Maurice MM, Rep M, Hooibrink B, Van Lier RAW . Heterogeneity of the circulating human CD4+ T cell population. J Immunol 1995; 154: 17–25.

    CAS  PubMed  Google Scholar 

  22. Gratama JW, Van Esser JWJ, Lamers CHJ, Tournay C, Löweberg B, Bolhuis RL et al. Tetramer-based quantification of cytomegalovirus (CMV)-specific CD8+ T lymphocytes in T-cell-depleted stem cell grafts and after transplantation may identify patients at risk for progressive CMV infection. Blood 2001; 98: 1358–1364.

    Article  CAS  PubMed  Google Scholar 

  23. Bigby M, Wang P, Fierro JF, Sy MS . Phorbol myristate acetate-induced down-modulation of CD4 is dependent on calmodulin and intracellular calcium. J Immunol 1990; 144: 3111–3116.

    CAS  PubMed  Google Scholar 

  24. Luo T, Downing JR, Garcia JV . Induction of phosphorylation of human immunodeficiency virus type 1 Nef and enhancement of CD4 downregulation by phorbol myristate acetate. J Virol 1997; 71: 2535–2539.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Rothman KJ . Modern epidemiology. Little, Brown and Company: Boston, 1986.

    Google Scholar 

  26. Crippa F, Holmberg L, Carter RA, Hooper H, Marr KA, Bensinger W et al. Infectious complications after autologous CD34-selected peripheral blood stem cell transplantation. Biol Blood Marrow Transplant 2002; 8: 281–289.

    Article  PubMed  Google Scholar 

  27. Talmadge JE, Reed E, Ino K, Kessinger A, Kuszynski C, Heimann D et al. Rapid immunologic reconstitution following transplantation with mobilized peripheral blood stem cells as compared to bone marrow. Bone Marrow Transplant 1997; 19: 161–172.

    Article  CAS  PubMed  Google Scholar 

  28. Kalwak K, Gorczynska E, Toporski J, Turkiewicz D, Slociak M, Ussowicz M et al. Immune reconstitution after haematopoietic cell transplantation in children: immunophenotype analysis with regard to factors affecting the speed of recovery. Br J Haematol 2002; 118: 74–89.

    Article  CAS  PubMed  Google Scholar 

  29. Hoepfner S, Haut PR, O’Gorman M, Kletzel M . Rapid immune reconstitution following autologous hematopoietic stem cell transplantation in children: a single institution experience. Bone Marrow Transplant 2003; 31: 285–290.

    Article  CAS  PubMed  Google Scholar 

  30. Schlenke P, Sheikhzadeh S, Weber K, Wagner T, Kirchner H . Immune reconstitution and production of intracellular cytokines in T lymphocyte populations following autologous peripheral blood stem cell transplantation. Bone Marrow Transplant 2001; 28: 251–257.

    Article  CAS  PubMed  Google Scholar 

  31. Koehne G, Zeller W, Stockschlaeder M, Zander AR . Phenotype of lymphocyte subsets after autologous peripheral blood stem cell transplantation. Bone Marrow Transplant 1997; 19: 149–156.

    Article  CAS  PubMed  Google Scholar 

  32. Diviné M, Boutolleau D, Delfau-Larue MH, Beaujeau F, Jovault H, Reyes F et al. Poor lymphocyte recovery following CD34-selected autologous peripheral blood stem cell transplantation for non-Hodgkin's lymphoma. Br J Haematol 1999; 105: 349–360.

    Article  PubMed  Google Scholar 

  33. Galy A, Rudraraju S, Baynes R, Klein J . Recovery of lymphocytic and dendritic cell subsets after autologous CD34+ cell transplantation. Bone Marrow Transplant 2000; 25: 1249–1255.

    Article  CAS  PubMed  Google Scholar 

  34. Singh RK, Varney ML, Buyukberber S, Ino K, Ageitos AG, Reed E et al. Fas-FasL-mediated CD4+ T-cell apoptosis following stem cell transplantation. Cancer Res 1999; 59: 3107–3111.

    CAS  PubMed  Google Scholar 

  35. Hakim FT, Cepeda R, Kaimei S, Mackall CL, McAtee N, Zujewski J et al. Constraints on CD4 recovery postchemotherapy in adults: thymic insufficiency and apoptotic decline of expanded peripheral CD4 cells. Blood 1997; 90: 3789–3798.

    CAS  PubMed  Google Scholar 

  36. Mackall CL, Fleisher TA, Brown MR, Andrich MP, Chen CC, Feuerstein IM et al. Distinctions between CD8+ and CD4+ T-cell regenerative pathways result in prolonged T-cell subset imbalance after intensive chemotherapy. Blood 1997; 89: 3700–3707.

    CAS  PubMed  Google Scholar 

  37. Singh RK, Varney ML, Ino K, Vose JM, Bierman PJ, Talmadge JE . Immune dysfunction despite high levels of immunoregulatory cytokine gene expression in autologous peripheral blood stem cell transplanted non-Hodgkin's lymphoma patients. Exp Hematol 2000; 28: 499–507.

    Article  CAS  PubMed  Google Scholar 

  38. Fagnoni FF, Lozza L, Zibera C, Zambelli A, Ponchio L, Jibelli N et al. Cytotoxic chemotherapy preceding apheresis of peripheral blood progenitor cells can affect the early reconstitution phase of naïve T cells after autologous transplantation. Bone Marrow Transplant 2003; 31: 31–38.

    Article  CAS  PubMed  Google Scholar 

  39. Arens R, Baars PA, Jak M, Tesselaar K, Van Der Valk M, Van Oers MH et al. Cutting edge: CD95 maintains effector T cell homeostasis in chronic immune activation. J Immunol 2005; 174: 5915–5920.

    Article  CAS  PubMed  Google Scholar 

  40. Porrata LF, Markovic SN . Timely reconstitution of immune competence affects clinical outcome following autologous stem cell transplantation. Clin Exp Med 2004; 4: 78–85.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We are grateful to J Kraan, R van der Linden, N de Leeuw, K van Rooyen and J Doekaharan–van der Sluis for their technical assistance.

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Authors and Affiliations

  1. Department of Hematology, Erasmus Medical Center, Rotterdam, The Netherlands

    P A W te Boekhorst, J J Cornelissen & B Löwenberg

  2. Department of Medical Oncology, Erasmus Medical Center, Rotterdam, The Netherlands

    C H J Lamers & J W Gratama

  3. Department of Hematology, HAGA Hospitals, The Hague, The Netherlands

    M R Schipperus

  4. Department of Neurology, Erasmus Medical Center, Rotterdam, The Netherlands

    R Q Hintzen

  5. Department of Trials & Statistics, Erasmus Medical Center, Rotterdam, The Netherlands

    B van der Holt

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  1. P A W te Boekhorst
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Correspondence to P A W te Boekhorst.

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te Boekhorst, P., Lamers, C., Schipperus, M. et al. T-lymphocyte reconstitution following rigorously T-cell-depleted versus unmodified autologous stem cell transplants. Bone Marrow Transplant 37, 763–772 (2006). https://doi.org/10.1038/sj.bmt.1705333

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