Hypoxia stimulus: An adaptive immune response during dendritic cell maturation

I. Rama, B. Bruene, J. Torras, R. Koehl, J. M. Cruzado, O. Bestard, M. Franquesa, N. Lloberas, A. Weigert, I. Herrero-Fresneda, O. Gulias, J. M. Grinyó

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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.

Idioma originalAnglès
Pàgines (de-a)816-825
Nombre de pàgines10
RevistaKidney International
Estat de la publicacióPublicada - d’abr. 2008
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