A novel CXCL8 protein-based antagonist in acute experimental renal allograft damage.
Acute renal allograft damage is caused by early leukocyte infiltration which is mediated in part by chemokines presented by glycosaminoglycan (GAG) structures on endothelial surfaces. CXCL8 can recruit neutrophils and induce the firm arrest of monocytes on activated endothelial cells. A human CXCL8-based antagonist (dnCXCL8) designed to generate a dominant-negative mutant protein with enhanced binding to GAG structures and reduced CXCR1/2 receptor binding ability was tested in models of early allograft injury. The agent displayed enhanced binding to GAG structures in vitro and could antagonize CXCL8-induced firm adhesion of monocytes as well as neutrophils to activated microvascular endothelium in physiologic flow assays. In a rat model of acute renal damage, dnCXCL8 treatment limited proximal tubular damage and reduced granulocyte infiltration. In a Fischer 344 (RT1(lvl)) to Lewis (RT1(l)) rat acute renal allograft model, dnCXCL8 was found to reduce monocyte and CD8+ T-cell infiltration into glomeruli and to limit tubular interstitial inflammation and tubulitis in vivo. Early treatment of allografts with agents like dnCXCL8 may help reduce acute allograft damage and preserve renal morphology and thereby help limit chronic dysfunction.
Bedke
Jens
J
Department of Cellular and Molecular Pathology, German Cancer Research Center, Heidelberg, Germany. bedke@live.com
Nelson
Peter J
PJ
Kiss
Eva
E
Muenchmeier
Niklas
N
Rek
Angelika
A
Behnes
Carl-Ludwig
CL
Gretz
Norbert
N
Kungl
Andreas J
AJ
Gröne
Hermann-Josef
HJ
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D004195:Disease Models, Animal; D006025:Glycosaminoglycans / Q000235:genetics / Q000276:immunology*; D006084:Graft Rejection / Q000188:drug therapy* / Q000276:immunology; D006801:Humans; D016209:Interleukin-8 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology / Q000494:pharmacology*; D016030:Kidney Transplantation / Q000276:immunology*; D009000:Monocytes / Q000276:immunology; D009504:Neutrophils / Q000276:immunology; D051381:Rats; D011916:Rats, Inbred F344; D011917:Rats, Inbred Lew; D023062:Receptors, Interleukin-8A / Q000235:genetics / Q000276:immunology; D023063:Receptors, Interleukin-8B / Q000235:genetics / Q000276:immunology; D014184:Transplantation, Homologous
C508606:CXCL8 protein, human; D006025:Glycosaminoglycans; D016209:Interleukin-8; D023062:Receptors, Interleukin-8A; D023063:Receptors, Interleukin-8B