Department of Surgery, Section of Transplantation Surgery, University of Michigan Medical Center, Ann Arbor, MI 48109, USA.
J Surg Res. 2012 May 1;174(1):166-75. doi: 10.1016/j.jss.2010.12.014. Epub 2011 Jan 8.
CC chemokine receptor 5 (CCR5) plays an important role in mediating inflammation. We examined the effect of CCR5 on the immune response to adenovirus vectors and graft function in islet transplant model.
Syngeneic wild-type (WT) or CCR5-deficient (KO) mouse islets transduced with adenovirus encoding β-gal were transplanted under the renal capsule. After transplant, blood glucose, glucose tolerance, graft cellular infiltration, transgene and chemokine/receptor expression, and systemic anti-adenoviral/-β-gal immune response were evaluated.
Diabetes was reversed in 1 d in both WT and KO untransduced recipients, while islets transduced with adenovirus failed to reverse diabetes until 10 d post-transplant in WT recipients or even longer (>15 d) in KO recipients (P < 0.05). A profound infiltration of CD4(+), CD8(+) cells and macrophages was observed in both WT and KO transduced grafts at 25 d. Though transgene expression was significantly reduced, insulin and β-gal expression persisted over 3 mo. Glucose tolerance was impaired in all grafts in KO recipients compared with untransduced grafts in WT recipients at 25 d post-transplant, but was equivalent at 3 mo. Early expression of CCR2 mRNA was increased in transduced grafts in both WT and KO recipients. No systemic antivector immunity was demonstrated in any recipient group.
Transduction of islets with adenovirus causes significant local inflammation in islet grafts and impairs early graft function in CCR5-deficient recipients, but long-term graft function is preserved. Thus, CCR5 absence does not prevent the local immune response to adenovirus transduction, and vector-associated graft dysfunction is not mediated by CCR5.
CC 趋化因子受体 5（CCR5）在介导炎症中发挥重要作用。我们研究了 CCR5 对胰岛移植模型中腺病毒载体免疫反应和移植物功能的影响。
用腺病毒编码β-半乳糖苷转导同基因野生型（WT）或 CCR5 缺陷型（KO）小鼠胰岛，然后将胰岛移植到肾包膜下。移植后，评估血糖、葡萄糖耐量、移植物细胞浸润、转导基因和趋化因子/受体表达以及全身抗腺病毒/-β-半乳糖苷免疫反应。
WT 和 KO 未转导受者在 1 天内糖尿病均得到逆转，而在 WT 受者中，用腺病毒转导的胰岛直到移植后 10 天（P < 0.05）甚至更长时间（> 15 天）才逆转糖尿病，而在 KO 受者中则更长时间。在 WT 和 KO 转导的移植物中，在 25 天观察到 CD4(+)、CD8(+)细胞和巨噬细胞的严重浸润。尽管转导基因表达显著降低，但胰岛素和β-半乳糖苷表达持续 3 个月。与 WT 受者未转导移植物相比，在 KO 受者中所有移植物的葡萄糖耐量在移植后 25 天受损，但在 3 个月时则相同。在 WT 和 KO 受者的转导移植物中，CCR2 mRNA 的早期表达增加。在任何受者组中均未显示出针对载体的系统免疫反应。
腺病毒转导胰岛会导致胰岛移植物中发生显著的局部炎症，并损害 CCR5 缺陷受者的早期移植物功能，但长期移植物功能得以保留。因此，CCR5 缺失不能阻止腺病毒转导的局部免疫反应，载体相关的移植物功能障碍不是由 CCR5 介导的。
