期刊论文详细信息
BMC Immunology
Reduced plasma levels of soluble interleukin-7 receptor during graft-versus-host disease (GVHD) in children and adults
Markus Maeurer7  Olle Ringden3  Isabelle Magalhaes1  Jacek Winiarski5  Ingemar Ernberg6  Raija Ahmed4  Nalini Kumar Vudattu2  Åsa Gustafsson-Jernberg5  Birgitta Omazic3  Mats Remberger3  Lalit Rane6  Thomas Poiret1 
[1] Division of Therapeutic Immunology, Labmed, Karolinska Institutet, Stockholm, Sweden;Department of Immunobiology and Internal Medicine, Yale University, New Haven, USA;Center for allogeneic stem cell transplantation (CAST), Karolinska University Hospital, Stockholm, Sweden;The Public Health Agency of Sweden, Sweden;Department of Pediatrics, Astrid Lindgen Barnsjukhuset, Karolinska Hospital Stockholm, Stockholm, Sweden;Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden;Therapeutic Immunology, F79, LabMed, Hälsovägen, Karolinska University Hospital Huddinge, SE-14186 Huddinge, Sweden
关键词: GVHD;    CMV;    Immune reconstitution;    Interleukin-7 receptor;    Interleukin-7;    HSCT;   
Others  :  848323
DOI  :  10.1186/1471-2172-15-25
 received in 2013-11-12, accepted in 2014-05-09,  发布年份 2014
PDF
【 摘 要 】

Background

Interleukin 7 (IL-7) signals via the IL-7 receptor (IL-7R) and drives homeostatic T-cell proliferation in patients after allogeneic hematopoietic stem cell transplantation (aHSCT).

Purpose

We performed a prospective study in adults (n = 33) and children (n = 29) undergoing aHSCT measuring plasma IL-7 and soluble IL-7R (sIL-7R) concentrations between 1 and 12 months after HSCT in order to investigate the link between sIL-7R and clinical events after aHSCT.

Results

sIL-7R, but not IL-7, increased with time after HSCT in plasma from all patients enrolled in the study. sIL-7R values were higher at 2, 3, and 6 months (p < 0.01) if the donor was a sibling as compared to an unrelated donor. Increased sIL-7R levels were also identified in plasma from patients who were not treated with anti-thymocyte globulin (ATG). Low sIL-7R was associated with any grade of acute graft-versus-host disease (GVHD) at 2 and 6 months (p = 0.02) and with a positive CMV PCR at 2 months after HSCT (p < 0.05). Patients with cytomegalovirus (CMV) reactivation had increased IL-7 values at 2 and 3 months (p = 0.02) after HSCT. In multivariate analysis, lower sIL-7R levels were associated with acute GVHD (relative hazard (RH): 0.70, p > 0.01) and sibling donors (RH: 2.23, p = 0.004). Recipients of sibling grafts showed high levels of IL-7 (RH: 1.38, p < 0.05) and bone marrow recipients had low IL-7 levels (RH: 0.73, p = 0.04).

Conclusions

Measurement of the sIL-7R/IL-7 axis will help in guided immune monitoring after HSCT and guided interference with sIL-7R may be explored in GVHD management.

【 授权许可】

   
2014 Poiret et al.; licensee BioMed Central Ltd.

【 预 览 】
附件列表
Files Size Format View
20140718065117275.pdf 664KB PDF download
Figure 5. 70KB Image download
Figure 4. 48KB Image download
Figure 3. 65KB Image download
Figure 2. 55KB Image download
Figure 1. 59KB Image download
【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

【 参考文献 】
  • [1]Fry TJ, Mackall CL: Interleukin-7: from bench to clinic. Blood 2002, 99:3892-3904.
  • [2]Sinha ML, Fry TJ, Fowler DH, Miller G, Mackall CL: Interleukin 7 worsens graft-versus-host disease. Blood 2002, 100:2642-2649.
  • [3]Dean RM, Fry T, Mackall C, Steinberg SM, Hakim F, Fowler D, Odom J, Foley J, Gress R, Bishop MR: Association of serum interleukin-7 levels with the development of acute graft-versus-host disease. J Clin Oncol 2008, 26:5735-5741.
  • [4]Thiant S, Labalette M, Trauet J, Coiteux V, de Berranger E, Dessaint JP, Yakoub-Agha I: Plasma levels of IL-7 and IL-15 after reduced intensity conditioned allo-SCT and relationship to acute GVHD. Bone Marrow Transplant 2011, 46:1374-1381.
  • [5]Napolitano LA, Grant RM, Deeks SG, Schmidt D, De Rosa SC, Herzenberg LA, Herndier BG, Andersson J, McCune JM: Increased production of IL-7 accompanies HIV-1-mediated T-cell depletion: implications for T-cell homeostasis. Nat Med 2001, 7:73-79.
  • [6]Sorg RV, McLellan AD, Hock BD, Fearnley DB, Hart DN: Human dendritic cells express functional interleukin-7. Immunobiology 1998, 198:514-526.
  • [7]Benjamin D, Sharma V, Knobloch TJ, Armitage RJ, Dayton MA, Goodwin RG: B cell IL-7. Human B cell lines constitutively secrete IL-7 and express IL-7 receptors. J Immunol 1994, 152:4749-4757.
  • [8]Zeng M, Smith AJ, Wietgrefe SW, Southern PJ, Schacker TW, Reilly CS, Estes JD, Burton GF, Silvestri G, Lifson JD, Carlis JV, Haase AT: Cumulative mechanisms of lymphoid tissue fibrosis and T cell depletion in HIV-1 and SIV infections. J Clin Invest 2011, 121:998-1008.
  • [9]Chung B, Barbara-Burnham L, Barsky L, Weinberg K: Radiosensitivity of thymic interleukin-7 production and thymopoiesis after bone marrow transplantation. Blood 2001, 98:1601-1606.
  • [10]Vudattu NK, Kuhlmann-Berenzon S, Khademi M, Seyfert V, Olsson T, Maeurer MJ: Increased numbers of IL-7 receptor molecules on CD4+CD25-CD107a+ T-cells in patients with autoimmune diseases affecting the central nervous system. PLoS One 2009, 4:e6534.
  • [11]Bolotin E, Smogorzewska M, Smith S, Widmer M, Weinberg K: Enhancement of thymopoiesis after bone marrow transplant by in vivo interleukin-7. Blood 1996, 88:1887-1894.
  • [12]Vudattu NK, Magalhaes I, Hoehn H, Pan D, Maeurer MJ: Expression analysis and functional activity of interleukin-7 splice variants. Genes Immun 2009, 10:132-140.
  • [13]Alpdogan O, Schmaltz C, Muriglan SJ, Kappel BJ, Perales MA, Rotolo JA, Halm JA, Rich BE, van den Brink MR: Administration of interleukin-7 after allogeneic bone marrow transplantation improves immune reconstitution without aggravating graft-versus-host disease. Blood 2001, 98:2256-2265.
  • [14]Alpdogan O, Muriglan SJ, Eng JM, Willis LM, Greenberg AS, Kappel BJ, van den Brink MR: IL-7 enhances peripheral T cell reconstitution after allogeneic hematopoietic stem cell transplantation. J Clin Invest 2003, 112:1095-1107.
  • [15]Chung B, Dudl EP, Min D, Barsky L, Smiley N, Weinberg KI: Prevention of graft-versus-host disease by anti IL-7Ralpha antibody. Blood 2007, 110:2803-2810.
  • [16]Rose T, Lambotte O, Pallier C, Delfraissy JF, Colle JH: Identification and biochemical characterization of human plasma soluble IL-7R: lower concentrations in HIV-1-infected patients. J Immunol 2009, 182:7389-7397.
  • [17]Crawley AM, Faucher S, Angel JB: Soluble IL-7R alpha (sCD127) inhibits IL-7 activity and is increased in HIV infection. J Immunol 2010, 184:4679-4687.
  • [18]Lundmark F, Duvefelt K, Iacobaeus E, Kockum I, Wallstrom E, Khademi M, Oturai A, Ryder LP, Saarela J, Harbo HF, Celius EG, Salter H, Olsson T, Hillert J: Variation in interleukin 7 receptor alpha chain (IL7R) influences risk of multiple sclerosis. Nat Genet 2007, 39:1108-1113.
  • [19]Gregory SG, Schmidt S, Seth P, Oksenberg JR, Hart J, Prokop A, Caillier SJ, Ban M, Goris A, Barcellos LF, Lincoln R, McCauley JL, Sawcer SJ, Compston DA, Dubois B, Hauser SL, Garcia-Blanco MA, Pericak-Vance MA, Haines JL, Multiple Sclerosis Genetics Group: Interleukin 7 receptor alpha chain (IL7R) shows allelic and functional association with multiple sclerosis. Nat Genet 2007, 39(9):1083-1091.
  • [20]Hafler DA, Compston A, Sawcer S, Lander ES, Daly MJ, De Jager PL, de Bakker PI, Gabriel SB, Mirel DB, Ivinson AJ, Pericak-Vance MA, Gregory SG, Rioux JD, McCauley JL, Haines JL, Barcellos LF, Cree B, Oksenberg JR, Hauser SL, International Multiple Sclerosis Genetics C: Risk alleles for multiple sclerosis identified by a genomewide study. N Engl J Med 2007, 357:851-862.
  • [21]Santiago JL, Alizadeh BZ, Martinez A, Espino L, de la Calle H, Fernandez-Arquero M, Figueredo MA, de la Concha EG, Roep BO, Koeleman BP, Urcelay E: Study of the association between the CAPSL-IL7R locus and type 1 diabetes. Diabetologia 2008, 51:1653-1658.
  • [22]O'Doherty C, Alloza I, Rooney M, Vandenbroeck K: IL7RA polymorphisms and chronic inflammatory arthropathies. Tissue Antigens 2009, 74:429-431.
  • [23]Shamim Z, Ryder LP, Heilmann C, Madsen H, Lauersen H, Andersen PK, Svejgaard A, Jacobsen N, Muller K: Genetic polymorphisms in the genes encoding human interleukin-7 receptor-alpha: prognostic significance in allogeneic stem cell transplantation. Bone Marrow Transplant 2006, 37:485-491.
  • [24]Azarpira N, Dehghani M, Aghdaie MH, Darai M: Interleukin-7 receptor-alpha gene polymorphisms in bone marrow transplant recipients. Mol Biol Rep 2010, 37:27-31.
  • [25]Schaffer M, Aldener-Cannava A, Remberger M, Ringden O, Olerup O: Roles of HLA-B, HLA-C and HLA-DPA1 incompatibilities in the outcome of unrelated stem-cell transplantation. Tissue Antigens 2003, 62:243-250.
  • [26]Ringden O, Ruutu T, Remberger M, Nikoskelainen J, Volin L, Vindelov L, Parkkali T, Lenhoff S, Sallerfors B, Ljungman P, Lotta Mellander, Niels Jacobsen for the Nordic Bone Marrow Transplantation Group: A randomized trial comparing busulfan with total body irradiation as conditioning in allogeneic marrow transplant recipients with leukemia: a report from the Nordic Bone Marrow Transplantation Group. Blood 1994, 83:2723-2730.
  • [27]Ringden O, Remberger M, Dahllof G, Garming-Legert K, Karlsson H, Svenberg P, Uhlin M, Uzunel M, Mattsson J: Sirolimus and tacrolimus as immune prophylaxis compared to cyclosporine with or without methotrexate in patients undergoing allogeneic haematopoietic stem cell transplantation for non-malignant disorders. Eur J Haematol 2011, 87:503-509.
  • [28]Remberger M, Svahn BM, Mattsson J, Ringden O: Dose study of thymoglobulin during conditioning for unrelated donor allogeneic stem-cell transplantation. Transplantation 2004, 78:122-127.
  • [29]Ljungman P, Perez-Bercoff L, Jonsson J, Avetisyan G, Sparrelid E, Aschan J, Barkholt L, Larsson K, Winiarski J, Yun Z, Ringden O: Risk factors for the development of cytomegalovirus disease after allogeneic stem cell transplantation. Haematologica 2006, 91:78-83.
  • [30]Avetisyan G, Aschan J, Hagglund H, Ringden O, Ljungman P: Evaluation of intervention strategy based on CMV-specific immune responses after allogeneic SCT. Bone Marrow Transplant 2007, 40:865-869.
  • [31]Svahn BM, Remberger M, Myrback KE, Holmberg K, Eriksson B, Hentschke P, Aschan J, Barkholt L, Ringden O: Home care during the pancytopenic phase after allogeneic hematopoietic stem cell transplantation is advantageous compared with hospital care. Blood 2002, 100:4317-4324.
  • [32]Maeurer MJ, Hurd S, Martin DM, Storkus WJ, Lotze MT: Cytolytic T-cell clones define HLA-A2-restricted human cutaneous melanoma peptide epitopes: correlation with T-cell receptor usage. Cancer J Sci Am 1995, 1:162-170.
  • [33]Kreft KL, Verbraak E, Wierenga-Wolf AF, van Meurs M, Oostra BA, Laman JD, Hintzen RQ: The IL-7Ralpha pathway is quantitatively and functionally altered in CD8 T cells in multiple sclerosis. J Immunol 2012, 188:1874-1883.
  • [34]Rajasuriar R, Booth D, Solomon A, Chua K, Spelman T, Gouillou M, Schlub TE, Davenport M, Crowe S, Elliott J, Hoy J, Fairley C, Stewart G, Cameron P, Lewin SR: Biological determinants of immune reconstitution in HIV-infected patients receiving antiretroviral therapy: the role of interleukin 7 and interleukin 7 receptor alpha and microbial translocation. J Infect Dis 2010, 202:1254-1264.
  • [35]Marks DI, Cullis JO, Ward KN, Lacey S, Syzdlo R, Hughes TP, Schwarer AP, Lutz E, Barrett AJ, Hows JM, Batchelor JR, Goldman JM: Allogeneic bone marrow transplantation for chronic myeloid leukemia using sibling and volunteer unrelated donors. A comparison of complications in the first 2 years. Ann Intern Med 1993, 119:207-214.
  • [36]Grundy JE, Shanley JD, Shearer GM: Augmentation of graft-versus-host reaction by cytomegalovirus infection resulting in interstitial pneumonitis. Transplantation 1985, 39:548-553.
  • [37]Cantoni N, Hirsch HH, Khanna N, Gerull S, Buser A, Bucher C, Halter J, Heim D, Tichelli A, Gratwohl A, Stern M: Evidence for a bidirectional relationship between cytomegalovirus replication and acute graft-versus-host disease. Biol Blood Marrow Transplant 2010, 16:1309-1314.
  • [38]Paulin T, Ringden O, Nilsson B: Immunological recovery after bone marrow transplantation: role of age, graft-versus-host disease, prednisolone treatment and infections. Bone Marrow Transplant 1987, 1:317-328.
  • [39]Noel DR, Witherspoon RP, Storb R, Atkinson K, Doney K, Mickelson EM, Ochs HD, Warren RP, Weiden PL, Thomas ED: Does graft-versus-host disease influence the tempo of immunologic recovery after allogeneic human marrow transplantation? An observation on 56 long-term survivors. Blood 1978, 51:1087-1105.
  • [40]Paulin T, Ringden O, Lonnqvist B: Faster immunological recovery after bone marrow transplantation in patients without cytomegalovirus infection. Transplantation 1985, 39:377-384.
  • [41]Paulin T, Ringden O, Nilsson B, Lonnqvist B, Gahrton G: Variables predicting bacterial and fungal infections after allogeneic marrow engraftment. Transplantation 1987, 43:393-398.
  • [42]Ringden O, Remberger M, Persson U, Ljungman P, Aldener A, Andstrom E, Aschan J, Bolme P, Dahllof G, Dalianis T, Gahrton G, Hägglund H, Lönnqvist B, Olerup O, Shanwell A, Sparrelid E, Winiarski J, Möller E, Öberg M: Similar incidence of graft-versus-host disease using HLA-A, -B and -DR identical unrelated bone marrow donors as with HLA-identical siblings. Bone Marrow Transplant 1995, 15:619-625.
  • [43]Dreger P, Haferlach T, Eckstein V, Jacobs S, Suttorp M, Loffler H, Muller-Ruchholtz W, Schmitz N: G-CSF-mobilized peripheral blood progenitor cells for allogeneic transplantation: safety, kinetics of mobilization, and composition of the graft. Br J Haematol 1994, 87:609-613.
  • [44]Ringden O, Remberger M, Runde V, Bornhauser M, Blau IW, Basara N, Holig K, Beelen DW, Hagglund H, Basu O, Ehninger G, Fauser AA: Peripheral blood stem cell transplantation from unrelated donors: a comparison with marrow transplantation. Blood 1999, 94:455-464.
  • [45]Park JH, Yu Q, Erman B, Appelbaum JS, Montoya-Durango D, Grimes HL, Singer A: Suppression of IL7Ralpha transcription by IL-7 and other prosurvival cytokines: a novel mechanism for maximizing IL-7-dependent T cell survival. Immunity 2004, 21:289-302.
  • [46]Rubinstein MP, Lind NA, Purton JF, Filippou P, Best JA, McGhee PA, Surh CD, Goldrath AW: IL-7 and IL-15 differentially regulate CD8+ T-cell subsets during contraction of the immune response. Blood 2008, 112:3704-3712.
  • [47]Unsinger J, McGlynn M, Kasten KR, Hoekzema AS, Watanabe E, Muenzer JT, McDonough JS, Tschoep J, Ferguson TA, McDunn JE, Morre M, Hildeman DA, Caldwell CC, Hotchkiss RS: IL-7 promotes T cell viability, trafficking, and functionality and improves survival in sepsis. J Immunol 2010, 184:3768-3779.
  • [48]Kasten KR, Prakash PS, Unsinger J, Goetzman HS, England LG, Cave CM, Seitz AP, Mazuski CN, Zhou TT, Morre M, Hotchkiss RS, Hildeman DA, Caldwell CC: Interleukin-7 (IL-7) treatment accelerates neutrophil recruitment through gamma delta T-cell IL-17 production in a murine model of sepsis. Infect Immun 2010, 78:4714-4722.
  文献评价指标  
  下载次数:70次 浏览次数:26次