Preventive usage of broad spectrum chemokine inhibitor NR58-3.14.3 reduces the severity of pulmonary and hepatic graft-versus-host disease.
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-alpha and IFN-gamma 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.
Miklos
Sandra
S
Department of Hematology and Oncology, University of Regensburg Medical Center, Franz-Josef-Strauß Allee 11, 93053, Regensburg, Germany.
Mueller
Gunnar
G
Department of Hematology and Oncology, University of Regensburg Medical Center, Franz-Josef-Strauß Allee 11, 93053, Regensburg, Germany.
Chang
Yayi
Y
Department of Hematology and Oncology, University of Regensburg Medical Center, Franz-Josef-Strauß Allee 11, 93053, Regensburg, Germany.
Bouazzaoui
Abdellatif
A
Department of Hematology and Oncology, University of Regensburg Medical Center, Franz-Josef-Strauß Allee 11, 93053, Regensburg, Germany.
Spacenko
Elena
E
Department of Hematology and Oncology, University of Regensburg Medical Center, Franz-Josef-Strauß Allee 11, 93053, Regensburg, Germany.
Schubert
Thomas E O
TEO
Institute of Pathology Frankfurt, Frankfurt, Germany.
Grainger
David J
DJ
Department of Medicine, University of Cambridge, Cambridge, UK.
Holler
Ernst
E
Department of Hematology and Oncology, University of Regensburg Medical Center, Franz-Josef-Strauß Allee 11, 93053, Regensburg, Germany.
Andreesen
Reinhard
R
Department of Hematology and Oncology, University of Regensburg Medical Center, Franz-Josef-Strauß Allee 11, 93053, Regensburg, Germany.
Hildebrandt
Gerhard C
GC
Department of Hematology and Oncology, University of Regensburg Medical Center, Franz-Josef-Strauß Allee 11, 93053, Regensburg, Germany. gerhard.hildebrandt@klinik.uni-regensburg.de.
D000818:Animals; D016026:Bone Marrow Transplantation / Q000009:adverse effects; D002478:Cells, Cultured; D018925:Chemokines / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006086:Graft vs Host Disease / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D008107:Liver Diseases / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D008171:Lung Diseases / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D010456:Peptides, Cyclic / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D015996:Survival Rate
D018925:Chemokines; D010456:Peptides, Cyclic; D012333:RNA, Messenger; C411952:cyclo(cysteinyl-glutaminyl-isoleucyl-tryptophyl-lysyl-glutaminyl-lysyl-prolyl-aspartyl-leucyl-cysteinyl-amide)