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

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 

Abbreviations

allo-BMT

Allogeneic bone marrow transplantation

aGVHD

Acute graft-versus-host disease

APC

Antigen presenting cell

BSCI

Broad spectrum chemokine inhibitor

Cchord

Chord compliance

CTL

Cytotoxic T lymphocyte

FEF

Forced expiratory flow

FEV

Forced expiratory volume

FITC

Fluorescein isothiocyanate

GVL

Graft-versus-leukemia

GVT

Graft-versus-tumor

ICAM-1

Intercellular adhesion molecule 1

IFN-γ

Interferon gamma

IPS

Idiopathic pneumonia syndrome

IL-8

Interleukin-8

LPS

Lipopolysaccharide

MHC

Major histocompatibility complex

PE

Phycoerythrin

PFT

Pulmonary function testing

pGVHD

Pulmonary graft-versus-host disease

SEM

Standard error of the mean

TBI

Total body irradiation

TNF-α

Tumor necrosis factor alpha

VC

Vital capacity

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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
  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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