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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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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DOI: https://doi.org/10.1007/s12185-009-0272-y