- Emmanuelle Godefroy1,
- Yunfeng Liu1,
- Patricia Shi1,
- W. Beau Mitchell1,
- Devin Cohen2,
- Stella T. Chou3,
- Deepa Manwani4 and
- Karina Yazdanbakhsh1,*
- 1 New York Blood Center;
- 2 Childrens Hospital of Philadelphia;
- 3 The Childrens Hospital of Philadelphia;
- 4 Albert Einstein College of Medicine
- ↵* Corresponding author; email:
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. Because of chronic hemolytic state in 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, heightening their risk of alloimmunization. Heme-exposed monocyte-derived dendritic cells from both non-alloimmunized sickle patients and healthy donors inhibited priming of pro-inflammatory 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-kappaB 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-kappaB, resulting in dampening of pro-inflammatory responses, but that in alloimmunized patients this pathway is defective, opening up new therapeutic strategies to prevent sickle cell alloimmunization.
- Received March 30, 2016.
- Accepted May 19, 2016.
- Copyright © 2016, Ferrata Storti Foundation