Altered heme-mediated modulation of dendritic cell function in sickle cell alloimmunization

Emmanuelle Godefroy, Yunfeng Liu, Patricia Shi, W. Beau Mitchell, Devin Cohen, Stella T. Chou, Deepa Manwani, Karina Yazdanbakhsh

Research output: Contribution to journalArticle

15 Scopus citations

Abstract

Transfusions are the main treatment for patients with sickle cell disease. However, alloimmunization remains a major life-threatening complication for these patients, but the mechanism underlying pathogenesis of alloimmunization is not known. Given the chronic hemolytic state characteristic of sickle cell disease, resulting in release of free heme and activation of inflammatory cascades, we tested the hypothesis that anti-inflammatory response to heme is compromised in alloimmunized sickle patients, increasing their risk of alloimmunization. Heme-exposed monocyte-derived dendritic cells from both non-alloimmunized sickle patients and healthy donors inhibited priming of proinflammatory CD4+ type 1 T cells, and exhibited significantly reduced levels of the maturation marker CD83. In contrast, in alloimmunized patients, heme did not reverse priming of pro-inflammatory CD4+ cells by monocyte-derived dendritic cells or their maturation. Furthermore, heme dampened NF-kB activation in non-alloimmunized, but not in alloimmunized monocyte-derived dendritic cells. Heme-mediated CD83 inhibition depended on Toll-like receptor 4 but not heme oxygenase 1. These data suggest that extracellular heme limits CD83 expression on dendritic cells in non-alloimmunized sickle patients through a Toll-like receptor 4-mediated pathway, involving NF-kB, resulting in dampening of pro-inflammatory responses, but that in alloimmunized patients this pathway is defective. This opens up the possibility of developing new therapeutic strategies to prevent sickle cell alloimmunization.

Original languageEnglish (US)
Pages (from-to)1028-1038
Number of pages11
JournalHaematologica
Volume101
Issue number9
DOIs
StatePublished - Jan 1 2016

ASJC Scopus subject areas

  • Hematology

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