Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Graft-Versus-Host Disease

Plasma levels of IL-7 and IL-15 after reduced intensity conditioned allo-SCT and relationship to acute GVHD

Abstract

To assess the impact of homeostatic expansion on the occurrence of acute GVHD after reduced intensity conditioning (RIC) transplantation, systemic levels of IL-7 and IL-15 and expression of their specific receptor chains were prospectively investigated in 45 fully HLA-matched allograft recipients. IL-7 and IL-15 levels peaked at four- to fivefold over pre-conditioning values. IL-7 levels were inversely correlated to absolute T-cell counts. Peak IL-15 levels positively correlated to concurrent CRP levels, but normalized earlier than IL-7. These results indicate that the kinetic course of IL-7 depends mainly on initiation of T-cell recovery, while IL-15 depends more on peri-transplant inflammation after RIC. Longer duration of the rise in IL-7 levels was associated with preservation of a normal CD4/CD8 ratio. In all, 16 (35%) patients developed grade 2–4 acute GVHD at a median of 42 days post graft, preceded by higher IL-7 levels and more downregulation of IL-7 receptor α chain on CD4+ T cells than in patients without acute GVHD, suggesting enhanced homeostatic expansion. In multivariate analysis, IL-7 level measured on day +30 was the foremost predictive factor for grade 2–4 acute GVHD (P=0.002). Measurement of IL-7 level after RIC transplantation might help predict risk of subsequent acute GvHD.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3

Similar content being viewed by others

References

  1. Mielcarek M, Storb R . Graft-vs-host disease after non-myeloablative hematopoietic cell transplantation. Leuk Lymphoma 2005; 46: 1251–1260.

    Article  CAS  PubMed  Google Scholar 

  2. Johnston L . Acute graft-versus-host disease: differing risk with differing graft sources and conditioning intensity. Best Pract Res Clin Haematol 2008; 21: 177–192.

    Article  CAS  PubMed  Google Scholar 

  3. Michallet M, Le QH, Mohty M, Prébet T, Nicolini F, Boiron JM et al. Predictive factors for outcomes after reduced intensity conditioning hematopoietic stem cell transplantation for hematological malignancies: a 10-year retrospective analysis from the Société Française de Greffe de Moelle et de Thérapie Cellulaire. Exp Hematol 2008; 36: 535–544.

    Article  PubMed  Google Scholar 

  4. Storek J, Geddes M, Khan F, Huard B, Helg C, Chalandon Y et al. Reconstitution of the immune system after hematopoietic stem cell transplantation in humans. Semin Immunopathol 2008; 30: 425–437.

    Article  PubMed  Google Scholar 

  5. Seggewiss R, Einsele H . Immune reconstitution after allogeneic transplantation and expanding options for immunomodulation: an update. Blood 2010; 115: 3861–3868.

    Article  CAS  PubMed  Google Scholar 

  6. Landfried K, Wolff D, Holler E . Pathophysiology and management of graft-versus-host disease in the era of reduced-intensity conditioning. Curr Opin Oncol 2009; 21 (Suppl 1): S39–S41.

    Article  PubMed  Google Scholar 

  7. Ma A, Koka R, Burkett P . Diverse functions of IL-2, IL-15, and IL-7 in lymphoid homeostasis. Annu Rev Immunol 2006; 24: 657–679.

    Article  CAS  PubMed  Google Scholar 

  8. Mazzucchelli R, Durum S . Interleukin-7 receptor expression: intelligent design. Nat Rev Immunol 2007; 7: 144–154.

    Article  CAS  PubMed  Google Scholar 

  9. Fry T, Mackall C . The many faces of IL-7: from lymphopoiesis to peripheral T cell maintenance. J Immunol 2005; 174: 6571–6576.

    Article  CAS  PubMed  Google Scholar 

  10. Alpdogan O, Eng J, Muriglan S, Willis L, Hubbard V, Tjoe K et al. Interleukin-15 enhances immune reconstitution after allogeneic bone marrow transplantation. Blood 2005; 105: 865–873.

    Article  CAS  PubMed  Google Scholar 

  11. Sandau MM, Winstead CJ, Jameson SC . IL-15 is required for sustained lymphopenia-driven proliferation and accumulation of CD8T cells. J Immunol 2007; 179: 120–125.

    Article  CAS  PubMed  Google Scholar 

  12. Boyiadzis M, Memon S, Carson J, Allen K, Szczepanski MJ, Vance BA et al. Up-regulation of NK cell activating receptors following allogeneic hematopoietic stem cell transplantation under a lymphodepleting reduced intensity regimen is associated with elevated IL-15 levels. Biol Blood Marrow Transplant 2008; 14: 290–300.

    Article  CAS  PubMed  Google Scholar 

  13. Thiant S, Yakoub-Agha I, Magro L, Trauet J, Coiteux V, Jouet JP et al. Plasma levels of IL-7 and IL-15 in the first month after myeloablative BMT are predictive biomarkers of both acute GVHD and relapse. Bone Marrow Transplant 2010; 45: 1546–1552.

    Article  CAS  PubMed  Google Scholar 

  14. Kumaki S, Minegishi M, Fujie H, Sasahara Y, Ohashi Y, Tsuchiya S et al. Prolonged secretion of IL-15 in patients with severe forms of acute graft-versus-host disease after allogeneic bone marrow transplantation in children. Int J Hematol 1998; 67: 307–312.

    Article  CAS  PubMed  Google Scholar 

  15. Sakata N, Yasui M, Okamura T, Inoue M, Yumura-Yagi K, Kawa K . Kinetics of plasma cytokines after hematopoietic stem cell transplantation from unrelated donors: the ratio of plasma IL-10/sTNFR level as a potential prognostic marker in severe acute graft-versus-host disease. Bone Marrow Transplant 2001; 27: 1153–1161.

    Article  CAS  PubMed  Google Scholar 

  16. Dulphy N, Haas P, Busson M, Belhadj S, Peffault de Latour R, Robin M et al. An unusual CD56bright CD16low NK cell subset dominates the early posttransplant period following HLA-matched hematopoietic stem cell transplantation. J Immunol 2008; 181: 2227–2237.

    Article  CAS  PubMed  Google Scholar 

  17. Dean R, Fry T, Mackall C, Steinberg SM, Hakim F, Fowler D et al. Association of serum interleukin-7 levels with the development of acute graft-versus-host disease. J Clin Oncol 2008; 26: 5735–5741.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Bolotin E, Annett G, Parkman R, Weinberg K . Serum levels of IL-7 in bone marrow transplant recipients: relationship to clinical characteristics and lymphocyte count. Bone Marrow Transplant 1999; 23: 783–788.

    Article  CAS  PubMed  Google Scholar 

  19. Micol JB, Berthon C, Tricot S, Terriou L, Darré S, Cracco P et al. Allogeneic stem-cell transplantation with fludarabine and 2-Gy TBI-based conditioning regimen for chronic hematological malignancy: a study of 25 consecutive patients and a literature review. Leuk Lymphoma 2007; 48: 321–329.

    Article  CAS  PubMed  Google Scholar 

  20. Yakoub-Agha I, Saule P, Depil S, Micol JB, Grutzmacher C, Boulanger-Villard F et al. A high proportion of donor CD4+ T cells expressing the lymph node-homing chemokine receptor CCR7 increases incidence and severity of acute graft-versus-host disease in patients undergoing allogeneic stem cell transplantation for hematological malignancy. Leukemia 2006; 20: 1557–1565.

    Article  CAS  PubMed  Google Scholar 

  21. Sallusto F, Lenig D, Forster 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 

  22. Alizadeh M, Bernard M, Danic B, Dauriac C, Birebent B, Lapart C et al. Quantitative assessment of hematopoetic chimerism after bone marrow transplantation by real-time quantitative polymerase chain reaction. Blood 2002; 99: 4618–4625.

    Article  CAS  PubMed  Google Scholar 

  23. Fuji S, Kim SW, Fukuda T, Mori S, Yamasaki S, Morita-Hoshi Y et al. Preengraftment serum C-reactive protein (CRP) value may predict acute graft-versus-host disease and nonrelapse mortality after allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2008; 14: 510–517.

    Article  CAS  PubMed  Google Scholar 

  24. Mohty M, Blaise D, Faucher C, Vey N, Bouabdallah R, Stoppa AM et al. Inflammatory cytokines and acute graft-versus-host disease after reduced-intensity conditioning allogeneic stem cell transplantation. Blood 2005; 106: 4407–4411.

    Article  CAS  PubMed  Google Scholar 

  25. Sportès C, Hakim FT, Memon SA, Zhang H, Chua KS, Brown MR et al. Administration of rhIL-7 in humans increases in vivo TCR repertoire diversity by preferential expansion of naive T cell subsets. J Exp Med 2008; 205: 1701–1714.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Petersen SL, Ryder LP, Björk P, Madsen HO, Heilmann C, Jacobsen N et al. A comparison of T-, B- and NK-cell reconstitution following conventional or nonmyeloablative conditioning and transplantation with bone marrow or peripheral blood stem cells from human leucocyte antigen identical sibling donors. Bone Marrow Transplant 2003; 32: 65–72.

    Article  CAS  PubMed  Google Scholar 

  27. Scholl S, Mügge LO, Issa MC, Kasper C, Pachmann K, Höffken K et al. Impact of early NK cell recovery on development of GvHD and CMV reactivation in dose-reduced regimen prior to allogeneic PBSCT. Bone Marrow Transplant 2005; 35: 183–190.

    Article  CAS  PubMed  Google Scholar 

  28. O’Brien S, Kantarjian H, Beran M, Smith T, Koller C, Estey E et al. Results of fludarabine and prednisone therapy in 264 patients with chronic lymphocytic leukemia with multivariate analysis-derived prognostic model for response to treatment. Blood 1993; 82: 1695–1700.

    PubMed  Google Scholar 

  29. Yakoub-Agha I, Saule P, Magro L, Cracco P, Duhamel A, Coiteux V et al. Immune reconstitution following myeloablative allogeneic hematopoietic stem cell transplantation: the impact of expanding CD28negative CD8+ T cells on relapse. Biol Blood Marrow Transplant 2009; 15: 496–504.

    Article  PubMed  Google Scholar 

  30. Reddy V, Winer AG, Eksioglu E, Meier-Kriesche HU, Schold JD, Wingard JR . Interleukin 12 is associated with reduced relapse without increased incidence of graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2005; 11: 1014–1021.

    Article  CAS  PubMed  Google Scholar 

  31. Lozza L, Rivino L, Guarda G, Jarrossay D, Rinaldi A, Bertoni F et al. The strength of T cell stimulation determines IL-7 responsiveness, secondary expansion, and lineage commitment of primed human CD4+ IL-7Rhi T cells. Eur J Immunol 2008; 38: 30–39.

    Article  CAS  PubMed  Google Scholar 

  32. Sereti I, Dunham RM, Spritzler J, Aga E, Proschan MA, Medvik K et al. IL-7 administration drives T cell-cycle entry and expansion in HIV-1 infection. Blood 2009; 113: 6304–6314.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Moxham VF, Karegli J, Phillips RE, Brown KL, Tapmeier TT, Hangartner R et al. Homeostatic proliferation of lymphocytes results in augmented memory-like function and accelerated allograft rejection. J Immunol 2008; 180: 3910–3918.

    Article  CAS  PubMed  Google Scholar 

  34. Miller JS, Weisdorf DJ, Burns LJ, Slungaard A, Wagner JE, Verneris MR et al. Lymphodepletion followed by donor lymphocyte infusion (DLI) causes significantly more acute graft-versus-host disease than DLI alone. Blood 2007; 110: 2761–2763.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Gendelman M, Hecht T, Logan B, Vodanovic-Jankovic S, Komorowski R, Drobyski W . Host conditioning is a primary determinant in modulating the effect of IL-7 on murine graft-versus-host disease. J Immunol 2004; 172: 3328–3336.

    Article  CAS  PubMed  Google Scholar 

  36. Levy Y, Lacabaratz C, Weiss L, Viard JP, Goujard C, Lelièvre JD et al. Enhanced T cell recovery in HIV-1-infected adults through IL-7 treatment. J Clin Invest 2009; 119: 997–1007.

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This study was supported by the French Ministère de la Recherche, the University of Lille 2, and CHRU de Lille (EA 2686). ST is the recipient of a PhD Ministère de la Recherche scholarship. We thank all the patients who agreed to be enrolled in this study. We are grateful to the staff of the BMT unit, Service des Maladies du Sang and the staff of the cellular immunology unit.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to I Yakoub-Agha.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Thiant, S., Labalette, M., Trauet, J. et al. Plasma levels of IL-7 and IL-15 after reduced intensity conditioned allo-SCT and relationship to acute GVHD. Bone Marrow Transplant 46, 1374–1381 (2011). https://doi.org/10.1038/bmt.2010.300

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/bmt.2010.300

Keywords

This article is cited by

Search

Quick links