Original Article

International Journal of Hematology

, Volume 89, Issue 3, pp 383-397

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

  • Sandra MiklosAffiliated withDepartment of Hematology and Oncology, University of Regensburg Medical Center
  • , Gunnar MuellerAffiliated withDepartment of Hematology and Oncology, University of Regensburg Medical Center
  • , Yayi ChangAffiliated withDepartment of Hematology and Oncology, University of Regensburg Medical Center
  • , Abdellatif BouazzaouiAffiliated withDepartment of Hematology and Oncology, University of Regensburg Medical Center
  • , Elena SpacenkoAffiliated withDepartment of Hematology and Oncology, University of Regensburg Medical Center
  • , Thomas E. O. SchubertAffiliated withInstitute of Pathology Frankfurt
  • , David J. GraingerAffiliated withDepartment of Medicine, University of Cambridge
  • , Ernst HollerAffiliated withDepartment of Hematology and Oncology, University of Regensburg Medical Center
  • , Reinhard AndreesenAffiliated withDepartment of Hematology and Oncology, University of Regensburg Medical Center
    • , Gerhard C. HildebrandtAffiliated withDepartment of Hematology and Oncology, University of Regensburg Medical Center Email author 

Rent the article at a discount

Rent now

* Final gross prices may vary according to local VAT.

Get Access

Abstract

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.

Keywords

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