International Journal of Hematology

, Volume 89, Issue 3, pp 383–397 | Cite as

Preventive usage of broad spectrum chemokine inhibitor NR58-3.14.3 reduces the severity of pulmonary and hepatic graft-versus-host disease

  • Sandra Miklos
  • Gunnar Mueller
  • Yayi Chang
  • Abdellatif Bouazzaoui
  • Elena Spacenko
  • Thomas E. O. Schubert
  • David J. Grainger
  • Ernst Holler
  • Reinhard Andreesen
  • Gerhard C. HildebrandtEmail author
Original Article


Pulmonary graft-versus-host disease (pGVHD) is a major complication after allogeneic bone marrow transplantation (BMT), which involves donor leukocyte migration into the lung along chemokine gradients, leading to pulmonary dysfunction and respiratory insufficiency. As broad spectrum chemokine inhibitor (BSCI) NR58-3.14.3 suppresses leukocyte migration in response to various chemokines, including CCL2, CCL3, CCL5, we investigated the effects of NR58-3.14.3 on the evolution of pGVHD. Lethally irradiated B6D2F1 mice received BMT from syngeneic (B6D2F1) or allogeneic (C57BL/6) donors, and animals were treated with either NR58-3.14.3 or vehicle control from day −1 to day +14. At week 6, in allogeneic recipients that received BSCI, inflammatory cell infiltrates in the lung were decreased, and reduced histopathologic changes translated into improved pulmonary function when compared to allo-controls. Acute GVHD of the liver was also diminished, whereas no differences were seen in the gut. Alloantigen-dependent splenic T cell expansion and systemic TNF-α and IFN-γ levels were comparable in NR58-3.14.3-treated animals and allo-controls. No suppressive effect of NR58-3.14.3 on CTL cytotoxicity was found, and diminished cellular infiltrates in lung and liver were most likely due to decreased migration of mononuclear cells. Therefore, novel approaches involving BSCIs may provide a promising tool in the management of pGVHD.


Lung Allogeneic bone marrow transplantation Chemokine Graft-versus-host disease Idiopathic pneumonia syndrome 



Allogeneic bone marrow transplantation


Acute graft-versus-host disease


Antigen presenting cell


Broad spectrum chemokine inhibitor


Chord compliance


Cytotoxic T lymphocyte


Forced expiratory flow


Forced expiratory volume


Fluorescein isothiocyanate






Intercellular adhesion molecule 1


Interferon gamma


Idiopathic pneumonia syndrome






Major histocompatibility complex




Pulmonary function testing


Pulmonary graft-versus-host disease


Standard error of the mean


Total body irradiation


Tumor necrosis factor alpha


Vital capacity



We would like to thank Funxional Therapeutics (Cambridge, UK) for generously providing NR58-3.14.3. DJG is a Director and acts as consultant CSO for Funxional Therapeutics Ltd (Cambridge, UK), who own and develop BSCIs for various indications, with an initial focus on asthma. GCH is a Max Eder Research Fellow of the Deutsche Krebshilfe e.V. and this work was supported by the German Cancer Foundation (Deutsche Krebshilfe e.V.), Project #106647.


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Copyright information

© The Japanese Society of Hematology 2009

Authors and Affiliations

  • Sandra Miklos
    • 1
  • Gunnar Mueller
    • 1
  • Yayi Chang
    • 1
  • Abdellatif Bouazzaoui
    • 1
  • Elena Spacenko
    • 1
  • Thomas E. O. Schubert
    • 3
  • David J. Grainger
    • 2
  • Ernst Holler
    • 1
  • Reinhard Andreesen
    • 1
  • Gerhard C. Hildebrandt
    • 1
    Email author
  1. 1.Department of Hematology and OncologyUniversity of Regensburg Medical CenterRegensburgGermany
  2. 2.Department of MedicineUniversity of CambridgeCambridgeUK
  3. 3.Institute of Pathology FrankfurtFrankfurtGermany

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