title: Genetic deletion of chemokine receptor CXCR3 or antibody blockade of its ligand IP-10 modulates posttransplantation graft-site lymphocytic infiltrates and prolongs functional graft survival in pancreatic islet allograft recipients.
abstract: BACKGROUND
  Interaction of chemokine receptor CXCR3 with its ligand IP-10 mediates effector cell trafficking to sites of allograft rejection in murine models of whole organ allotransplantation. We hypothesized that blocking the CXCR3/IP-10 interaction would impair posttransplantation leukocyte trafficking to and delay rejection of pancreatic islet allografts.
  
  
  METHODS
  A/J strain murine islets were implanted to the kidney capsule of H-2 disparate, streptozotocin-induced diabetic wild type (WT), CXCR3 deficient (CXCR3(-/-)) or IP-10 antibody-treated WT (alphaIP-10) C57BL/6 recipients. Representative grafts from each group were harvested at day 7. Ribonuclease protection assay was used to determine gene expression for cell markers F4/80 (macrophages), CD8 (type I T cells), CD4 (type II T cells), and CD 19 (natural killer cells), and for chemokines IP-10, MIP-1alpha, MIP-1beta, MCP-1, and RANTES. Immunohistochemistry was used to confirm ribonuclease protection assay infiltrate data. Graft-site chemokine gene expression and cellular infiltrate were correlated with time to functional graft rejection.
  
  
  RESULTS
  Untreated WT recipients demonstrated heavy graft-site cell infiltrates and increased graft-site gene expression for cell markers F4/80, CD8, CD4, and CD19, and for chemokines RANTES, IP-10, and MIP-1beta at day 7. In comparison with untreated WT, alphaIP-10-treated WT and CXCR3(-/-) recipients demonstrated the same degree of chemokine gene expression but less lymphocytic infiltrate. The mean length of allograft survival was 12.7 +/- 3.1 days in untreated WT versus 20.2 +/- 2.7 days (P <.05) for CXCR3(-/-)- and 19.7 +/- 2.3 days (P <.05) for alphaIP-10-treated WT recipients.
  
  
  CONCLUSIONS
  CXCR3 gene deletion or alphaIP-10 antibody therapy modulates posttransplantation lymphocytic graft infiltration and statistically prolongs graft survival in murine islet allograft recipients.
authors.affiliation: Departments of Surgery and Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
authors.forename: Marshall S
authors.initials: MS
authors.lastname: Baker
authors.forename: Xiaojuan
authors.initials: X
authors.lastname: Chen
authors.forename: Alizah R
authors.initials: AR
authors.lastname: Rotramel
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Nelson
authors.forename: Bao
authors.initials: B
authors.lastname: Lu
authors.forename: Craig
authors.initials: C
authors.lastname: Gerard
authors.forename: Yashpal
authors.initials: Y
authors.lastname: Kanwar
authors.forename: Dixon B
authors.initials: DB
authors.lastname: Kaufman
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology*; D054357:Chemokine CXCL10; D018925:Chemokines / Q000378:metabolism; D019743:Chemokines, CXC / Q000276:immunology*; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000601:surgery*; D017353:Gene Deletion; D006085:Graft Survival; D007515:Islets of Langerhans / Q000378:metabolism / Q000473:pathology; D016381:Islets of Langerhans Transplantation; D008024:Ligands; D008214:Lymphocytes / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine / Q000235:genetics*; D014184:Transplantation, Homologous
chemical_list: D000906:Antibodies; D054357:Chemokine CXCL10; D018925:Chemokines; D019743:Chemokines, CXC; C515188:Cxcr3 protein, mouse; D008024:Ligands; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine