Article ID Journal Published Year Pages File Type
3886635 Kidney International 2008 10 Pages PDF
Abstract

The ‘injury hypothesis’ in organ transplantation suggests that ischemia–reperfusion injury is involved in the adaptative alloimmune response. We previously found that a strong immune/inflammatory response was induced by ischemia during kidney transplantation in rats. We show here that immature dendritic cells (DCs) undergo hypoxia-mediated differentiation comparable to allogeneic stimulation. Hypoxia-differentiated DCs overexpress hypoxia inducible factor-1α (HIF-1α) and its downstream target genes, such as vascular endothelial growth factor or glucose transporter-1. Rapamycin attenuated DC differentiation, HIF-1α expression, and its target gene expression in a dose-dependent manner along with downregulated interleukin-10 secretion. Coculture of hypoxia-differentiated DCs with CD3 lymphocytes induced proliferation of lymphocytes, a process also neutralized by rapamycin. Furthermore, in vivo examination of ischemia–reperfusion-injured mouse kidneys showed a clear maturation of resident DCs that was blunted by rapamycin pretreatment. Our results suggest that hypoxia is a central part of the ‘injury hypothesis’ triggering DC differentiation under hypoxic conditions. Rapamycin attenuates the hypoxic immune-inflammatory response through inhibition of the HIF-1α pathway.

Related Topics
Health Sciences Medicine and Dentistry Nephrology
Authors
, , , , , , , , , , , ,