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Immune reconstitution following hematopoietic progenitor cell transplantation: challenges for the future

Bone Marrow Transplantation volume 35, pages S53–S57 (2005)Cite this article

Summary:

Successful hematopoietic progenitor cell transplantation requires rapid and complete transfer of the donor hematopoietic and immune systems to the host. Whereas the uncontrolled transfer of a nontolerant donor immune system results in GVHD in many cases, strategies which diminish GVHD also diminish immune reconstitution. Thus, the reliable, rapid and safe transfer of immunity from donor to host remains a major challenge for the field. Advances in the understanding of the biology of immune reconstitution have elucidated that thymic-dependent immune reconstitution can restore global immunity, but is especially vulnerable to toxicities associated with transplant. Alternatively, homeostatic peripheral expansion can be exploited for targeted immunity toward pathogens and tumors, but is difficult to manipulate without exacerbating GVHD risk. New translatable strategies are needed to safely augment one or both of these pathways in the setting of allogeneic hematopoietic progenitor cell transplantation.

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References

  1. Ochs L, Shu XO, Miller J et al. Late infections after allogeneic bone marrow transplantations: comparison of incidence in related and unrelated donor transplant recipients. Blood 1995; 86: 3979–3986.

    CAS  PubMed  Google Scholar 

  2. Roy V, Ochs L, Weisdorf D . Late infections following allogeneic bone marrow transplantation: suggested strategies for prophylaxis. Leuk Lymphoma 1997; 26: 1–15.

    Article  CAS  PubMed  Google Scholar 

  3. Storek J, Espino G, Dawson MA et al. Low B-cell and monocyte counts on day 80 are associated with high infection rates between days 100 and 365 after allogeneic marrow transplantation. Blood 2000; 96: 3290–3293.

    CAS  PubMed  Google Scholar 

  4. Chen CS, Boeckh M, Seidel K et al. Incidence, risk factors, and mortality from pneumonia developing late after hematopoietic stem cell transplantation. Bone Marrow Transplant 2003; 32: 515–522.

    Article  PubMed  Google Scholar 

  5. Storek J . B-cell immunity after allogeneic hematopoietic cell transplantation. Cytotherapy 2002; 4: 423–424.

    Article  CAS  PubMed  Google Scholar 

  6. Storek J, Viganego F, Dawson MA et al. Factors affecting antibody levels after allogeneic hematopoietic cell transplantation. Blood 2003; 101: 3319–3324.

    Article  CAS  PubMed  Google Scholar 

  7. Miller RA, Stutman O . T cell repopulation from functionally restricted splenic progenitors: 10 000-fold expansion documented by using limiting dilution analyses. J Immunol 1984; 133: 2925–2932.

    CAS  PubMed  Google Scholar 

  8. Stutman O . Postthymic T-cell development. Immunol Rev 1986; 91: 159–194.

    Article  CAS  PubMed  Google Scholar 

  9. 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 

  10. 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 

  11. Hakim FT, Cepeda R, Kaimei S et al. Constraints on CD4 recovery post chemotherapy in adults: thymic insufficiency and apoptotic decline of expanded peripheral CD4 cells. Blood 1997; 90: 3789–3798.

    CAS  PubMed  Google Scholar 

  12. Mackall CL, Bare CV, Titus JA 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 

  13. Goldrath AW, Bevan MJ . Low-affinity ligands for the TCR drive proliferation of mature CD8+ T cells in lymphopenic hosts. Immunity 1999; 11: 183–190.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Goldrath AW, Bevan MJ . Selecting and maintaining a diverse T-cell repertoire. Nature 1999; 402: 255–262.

    Article  CAS  PubMed  Google Scholar 

  15. 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 

  16. 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 

  17. Roux E, Helg C, Fumont-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 

  18. Zinkernagel RM, Althage A, Callahan G, Welsh RM . On the immunocompetence of H-2 incompatible irradiation bone marrow chimeras. J Immunol 1980; 124: 2356–2365.

    CAS  PubMed  Google Scholar 

  19. Ghayur T, Seemayer TA, Xenocostas A, Lapp WS . Complete sequential regeneration of graft-vs-host induced severely dysplastic thymuses. Implications for the pathogenesis of chronic graft-vs-host disease. Am J Pathol 1988; 133: 39–46.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Fukushi N, Arase H, Wang B et al. Thymus: a direct target tissue in graft-versus-host reaction after allogeneic bone marrow transplantation that results in abrogation of induction of self-tolerance. PNAS 1990; 87: 6301–6305.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Brochu S, Rioux-Masse B, Roy J et al. Massive activation-induced cell death of alloreactive T cells with apoptosis of bystander postthymic T cells prevents immune reconstitution in mice with graft-versus-host disease. Blood 1999; 94: 390–400.

    CAS  PubMed  Google Scholar 

  22. Porter DL, Collins RH, Hardy C et al. Treatment of relapsed leukemia after unrelated donor marrow transplantation with unrelated donor leukocyte infusions. Blood 2000; 95: 1214–1221.

    CAS  PubMed  Google Scholar 

  23. Dazzi F, Szydlo RM, Goldman JM . Donor lymphocyte infusions for relapse of chronic myeloid leukemia after allogeneic stem cell transplant: where we now stand. Exp Hematol 1999; 27: 1477–1486.

    Article  CAS  PubMed  Google Scholar 

  24. Helg C, Starobinski M, Jeannet M, Chapuis B . Donor lymphocyte infusion for the treatment of relapse after allogeneic hematopoietic stem cell transplantation. Leuk Lymphoma 1998; 29: 301–313.

    Article  CAS  PubMed  Google Scholar 

  25. Dudley ME, Wunderlich JR, Robbins PF et al. Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science 2002; 298: 850–854.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Molldrem JJ, Lee PP, Wang C et al. Evidence that specific T lymphocytes may participate in the elimination of chronic myelogenous leukemia. Nat Med 2000; 6: 1018–1023.

    Article  CAS  PubMed  Google Scholar 

  27. 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 

  28. Puel A, Ziegler SF, Buckley RH, Leonard WJ . Defective IL7R expression in T(−)B(+)NK(+) severe combined immunodeficiency. Nat Genet 1998; 20: 394–397.

    Article  CAS  PubMed  Google Scholar 

  29. Fry TJ, Moniuszko M, Creekmore S et al. IL-7 therapy dramatically alters peripheral T-cell homeostasis in normal and SIV-infected nonhuman primates. Blood 2003; 101: 2294–2299.

    Article  CAS  PubMed  Google Scholar 

  30. Sinha ML, Fry TJ, Fowler DH et al. Interleukin 7 worsens graft-versus-host disease. Blood 2002; 100: 2642–2649.

    Article  CAS  PubMed  Google Scholar 

  31. Fry TJ, Sinha M, Milliron M et al. Flt 3 ligand enhances thymic-dependent and thymic-independent immune reconstitution. Blood 2004; 104: 2794–2800.

    Article  CAS  PubMed  Google Scholar 

  32. 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 

  33. Napolitano LA, Lo JC, Gotway MB et al. Increased thymic mass and circulating naive CD4T cells in HIV-1-infected adults treated with growth hormone. AIDS 2002; 16: 1103–1111.

    Article  CAS  PubMed  Google Scholar 

  34. Olsen NJ, Kovacs WJ . Effects of androgens on T and B lymphocyte development. Immunol Res 2001; 23: 281–288.

    Article  CAS  PubMed  Google Scholar 

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  1. Pediatric Oncology Branch, National Cancer Institute, Bethesda, MD, USA

    T J Fry & C L Mackall

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  2. C L Mackall
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Correspondence to C L Mackall.

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Fry, T., Mackall, C. Immune reconstitution following hematopoietic progenitor cell transplantation: challenges for the future. Bone Marrow Transplant 35 (Suppl 1), S53–S57 (2005). https://doi.org/10.1038/sj.bmt.1704848

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