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

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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.

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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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Acknowledgments

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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Authors and Affiliations

  1. Department of Hematology and Oncology, University of Regensburg Medical Center, Franz-Josef-Strauß Allee 11, 93053, Regensburg, Germany

    Sandra Miklos, Gunnar Mueller, Yayi Chang, Abdellatif Bouazzaoui, Elena Spacenko, Ernst Holler, Reinhard Andreesen & Gerhard C. Hildebrandt

  2. Department of Medicine, University of Cambridge, Cambridge, UK

    David J. Grainger

  3. Institute of Pathology Frankfurt, Frankfurt, Germany

    Thomas E. O. Schubert

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  1. Sandra Miklos
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  2. Gunnar Mueller
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  10. Gerhard C. Hildebrandt
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Correspondence to Gerhard C. Hildebrandt.

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Miklos, S., Mueller, G., Chang, Y. et al. Preventive usage of broad spectrum chemokine inhibitor NR58-3.14.3 reduces the severity of pulmonary and hepatic graft-versus-host disease. Int J Hematol 89, 383–397 (2009). https://doi.org/10.1007/s12185-009-0272-y

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