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

doi:10.1007/s12185-009-0272-y

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

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22 Scopus citations

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.

Original language	English
Pages (from-to)	383-397
Number of pages	15
Journal	International Journal of Hematology
Volume	89
Issue number	3
DOIs	https://doi.org/10.1007/s12185-009-0272-y
State	Published - Apr 2009

Bibliographical note

Funding Information:
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.

Keywords

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

ASJC Scopus subject areas

Hematology

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10.1007/s12185-009-0272-y

Cite this

Miklos, S., Mueller, G., Chang, Y., Bouazzaoui, A., Spacenko, E., Schubert, T. E. O., Grainger, D. J., Holler, E., Andreesen, R., & Hildebrandt, G. C. (2009). Preventive usage of broad spectrum chemokine inhibitor NR58-3.14.3 reduces the severity of pulmonary and hepatic graft-versus-host disease. International Journal of Hematology, 89(3), 383-397. https://doi.org/10.1007/s12185-009-0272-y

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

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

author = "Sandra Miklos and Gunnar Mueller and Yayi Chang and Abdellatif Bouazzaoui and Elena Spacenko and Schubert, {Thomas E.O.} and Grainger, {David J.} and Ernst Holler and Reinhard Andreesen and Hildebrandt, {Gerhard C.}",

note = "Funding Information: 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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doi = "10.1007/s12185-009-0272-y",

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Miklos, S, Mueller, G, Chang, Y, Bouazzaoui, A, Spacenko, E, Schubert, TEO, Grainger, DJ, Holler, E, Andreesen, R & Hildebrandt, GC 2009, 'Preventive usage of broad spectrum chemokine inhibitor NR58-3.14.3 reduces the severity of pulmonary and hepatic graft-versus-host disease', International Journal of Hematology, vol. 89, no. 3, pp. 383-397. https://doi.org/10.1007/s12185-009-0272-y

TY - JOUR

T1 - Preventive usage of broad spectrum chemokine inhibitor NR58-3.14.3 reduces the severity of pulmonary and hepatic graft-versus-host disease

AU - Miklos, Sandra

AU - Mueller, Gunnar

AU - Chang, Yayi

AU - Bouazzaoui, Abdellatif

AU - Spacenko, Elena

AU - Schubert, Thomas E.O.

AU - Grainger, David J.

AU - Holler, Ernst

AU - Andreesen, Reinhard

AU - Hildebrandt, Gerhard C.

N1 - Funding Information: 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.

PY - 2009/4

Y1 - 2009/4

N2 - 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.

AB - 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.

KW - Allogeneic bone marrow transplantation

KW - Chemokine

KW - Graft-versus-host disease

KW - Idiopathic pneumonia syndrome

KW - Lung

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JO - International Journal of Hematology

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ER -

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

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

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