Baker Marshall S, Chen Xiaojuan, Rotramel Alizah R, Nelson Jeffrey J, Lu Bao, Gerard Craig, Kanwar Yashpal, Kaufman Dixon B
Departments of Surgery and Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
Surgery. 2003 Aug;134(2):126-33. doi: 10.1067/msy.2003.213.
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.
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.
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.
CXCR3 gene deletion or alphaIP-10 antibody therapy modulates posttransplantation lymphocytic graft infiltration and statistically prolongs graft survival in murine islet allograft recipients.
趋化因子受体CXCR3与其配体IP - 10的相互作用介导效应细胞向全器官同种异体移植小鼠模型中的同种异体移植排斥部位迁移。我们假设阻断CXCR3/IP - 10相互作用会损害移植后白细胞向胰岛同种异体移植物的迁移，并延迟排斥反应。
将A/J品系小鼠胰岛植入H - 2不同、经链脲佐菌素诱导的糖尿病野生型（WT）、CXCR3缺陷型（CXCR3(-/-)）或经IP - 10抗体处理的WT（αIP - 10）C57BL/6受体的肾包膜。每组在第7天收获代表性移植物。采用核糖核酸酶保护试验确定细胞标志物F4/80（巨噬细胞）、CD8（I型T细胞）、CD4（II型T细胞）和CD19（自然杀伤细胞）以及趋化因子IP - 10、MIP - 1α、MIP - 1β、MCP - 1和RANTES的基因表达。免疫组织化学用于确认核糖核酸酶保护试验的浸润数据。移植物部位趋化因子基因表达和细胞浸润与功能性移植物排斥时间相关。
未经处理的WT受体在第7天显示出大量移植物部位细胞浸润，细胞标志物F4/80、CD8、CD4和CD19以及趋化因子RANTES、IP - 10和MIP - 1β的移植物部位基因表达增加。与未经处理的WT相比，αIP - 10处理的WT和CXCR3(-/-)受体显示出相同程度的趋化因子基因表达，但淋巴细胞浸润较少。未经处理的WT同种异体移植物平均存活时间为12.7±3.1天，而CXCR3(-/-)受体为20.2±2.7天（P<.05），αIP - 10处理的WT受体为19.7±2.3天（P<.05）。
CXCR3基因缺失或αIP - 10抗体治疗可调节移植后淋巴细胞移植物浸润，并在统计学上延长小鼠胰岛同种异体移植受体的移植物存活时间。
