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

Marshall S. Baker, Xiaojuan Chen, Alizah R. Rotramel, Jeffrey J. Nelson, Bao Lu, Craig Gerard, Yashpal Kanwar, Dixon B. Kaufman

Research output: Contribution to journalArticlepeer-review

54 Scopus citations

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 (αIP-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-1α, MIP-1β, 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-1β at day 7. In comparison with untreated WT; αIP-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 α IP-10-treated WT recipients. Conclusions. CXCR3 gene deletion or αIP-10 antibody therapy modulates posttransplantation lymphocytic graft infiltration and statistically prolongs graft survival in murine islet allograft recipients.

Original languageEnglish (US)
Pages (from-to)126-133
Number of pages8
JournalSurgery
Volume134
Issue number2
DOIs
StatePublished - Aug 1 2003

ASJC Scopus subject areas

  • Surgery

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