Blockade of CXCR3 receptor:ligand interactions reduces leukocyte recruitment to the lung and the severity of experimental idiopathic pneumonia syndrome.
Idiopathic pneumonia syndrome (IPS) is a frequently fatal complication after allogeneic stem cell transplantation (allo-SCT) that responds poorly to standard immunosuppressive therapy. The pathophysiology of IPS involves the secretion of inflammatory cytokines including IFN-gamma and TNF-alpha along with the recruitment of donor T cells to the lung. CXCR3 is a chemokine receptor that is expressed on activated Th1/Tc1 T cell subsets and the expression of its ligands CXCL9 (monokine induced by IFN-gamma (Mig)) and CXCL10 (IFN-gamma-inducible protein 10 (IP-10)) can be induced in a variety of cell types by IFN-gamma alone or in combination with TNF-alpha. We used a lethally irradiated murine SCT model (B6 --> bm1) to evaluate the role of CXCR3 receptor:ligand interactions in the development of IPS. We found that Mig and IP-10 protein levels were significantly elevated in the bronchoalveolar lavage fluid of allo-SCT recipients compared with syngeneic controls and correlated with the infiltration of IFN-gamma-secreting CXCR3(+) donor T cells into the lung. The in vivo neutralization of either Mig or IP-10 significantly reduced the severity of IPS compared with control-treated animals, and an additive effect was observed when both ligands were blocked simultaneously. Complementary experiments using CXCR3(-/-) mice as SCT donors also resulted in a significant decrease in IPS. These data demonstrate that interactions involving CXCR3 and its primary ligands Mig and IP-10 significantly contribute to donor T cell recruitment to the lung after allo-SCT. Therefore, approaches focusing on the abrogation of these interactions may prove successful in preventing or treating lung injury that occurs in this setting.
Hildebrandt
Gerhard C
GC
Department of Pediatrics, Blood and Marrow Transplantation Program, University of Michigan, Ann Arbor, MI 48109, USA.
Corrion
Leigh A
LA
Olkiewicz
Krystyna M
KM
Lu
Bao
B
Lowler
Kathleen
K
Duffner
Ulrich A
UA
Moore
Bethany B
BB
Kuziel
William A
WA
Liu
Chen
C
Cooke
Kenneth R
KR
D000818:Animals; D001854:Bone Marrow Cells; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002478:Cells, Cultured / Q000276:immunology; D054357:Chemokine CXCL10; D054370:Chemokine CXCL9; D019743:Chemokines, CXC / Q000037:antagonists & inhibitors / Q000502:physiology*; D002634:Chemotaxis, Leukocyte / Q000187:drug effects*; D003433:Crosses, Genetic; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects*; D007371:Interferon-gamma / Q000096:biosynthesis / Q000097:blood; D008024:Ligands; D008168:Lung / Q000473:pathology*; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011014:Pneumonia / Q000209:etiology / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D019713:Receptors, CCR5 / Q000172:deficiency / Q000235:genetics; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D013154:Spleen / Q000166:cytology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism; D014184:Transplantation, Homologous / Q000009:adverse effects*; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
D054357:Chemokine CXCL10; D054370:Chemokine CXCL9; D019743:Chemokines, CXC; C485969:Cxcl9 protein, mouse; C515188:Cxcr3 protein, mouse; D008024:Ligands; D019713:Receptors, CCR5; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma