Role of CXCL9/CXCR3 chemokine biology during pathogenesis of acute lung allograft rejection.
Acute allograft rejection is a major complication postlung transplantation and is the main risk factor for the development of bronchiolitis obliterans syndrome. Acute rejection is characterized by intragraft infiltration of activated mononuclear cells. The ELR-negative CXC chemokines CXCL9, CXCL10, and CXCL11) are potent chemoattractants for mononuclear cells and act through their shared receptor, CXCR3. Elevated levels of these chemokines in bronchoalveolar lavage fluid have been associated with human acute lung allograft rejection. This led to the hypothesis that the expression of these chemokines during an allogeneic response promotes the recruitment of mononuclear cells, leading to acute lung allograft rejection. We performed studies in a rat orthotopic lung transplantation model of acute rejection, and demonstrated increased expression of CXCL9 and CXCL10 paralleling the recruitment of mononuclear cells and cells expressing CXCR3 to the allograft. However, CXCL9 levels were 15-fold greater than CXCL10 during maximal rejection. Inhibition of CXCL9 decreased intragraft recruitment of mononuclear cells and cellular expression of CXCR3, resulting in lower acute lung allograft rejection scores. Furthermore, the combination of low dose cyclosporin A with anti-CXCL9 therapy had more profound effects on intragraft leukocyte infiltration and in reducing acute allograft rejection scores. This supports the notion that CXCL9 interaction with cells expressing CXCR3 has an important role in the recruitment of mononuclear cells, a pivotal event in the pathogenesis of acute lung allograft rejection.
Belperio
John A
JA
Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of California School of Medicine, Los Angeles, CA 90095, USA.
Keane
Michael P
MP
Burdick
Marie D
MD
Lynch
Joseph P
JP
Zisman
David A
DA
Xue
Ying Ying
YY
Li
Kewang
K
Ardehali
Abbas
A
Ross
David J
DJ
Strieter
Robert M
RM
D000208:Acute Disease; D000818:Animals; D054357:Chemokine CXCL10; D054370:Chemokine CXCL9; D019743:Chemokines, CXC / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000276:immunology / Q000502:physiology*; D006084:Graft Rejection / Q000209:etiology / Q000276:immunology*; D007106:Immune Sera / Q000008:administration & dosage; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000276:immunology / Q000502:physiology*; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000473:pathology; D008024:Ligands; D016040:Lung Transplantation / Q000276:immunology* / Q000379:methods / Q000473:pathology; D051381:Rats; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine / Q000096:biosynthesis / Q000502:physiology*; D014184:Transplantation, Homologous
C080810:CXCL9 protein, human; C515187:CXCR3 protein, human; D054357:Chemokine CXCL10; D054370:Chemokine CXCL9; D019743:Chemokines, CXC; C515189:Cxcr3 protein, rat; D007106:Immune Sera; D036341:Intercellular Signaling Peptides and Proteins; D008024:Ligands; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine