Circulating mitochondria in organ donors promote allograft rejection.

Journal Article (Journal Article)

The innate immune system is a critical regulator of the adaptive immune responses that lead to allograft rejection. It is increasingly recognized that endogenous molecules released from tissue injury and cell death are potent activators of innate immunity. Mitochondria, ancestrally related to bacteria, possess an array of endogenous innate immune-activating molecules. We have recently demonstrated that extracellular mitochondria are abundant in the circulation of deceased organ donors and that their presence correlates with early allograft dysfunction. Here we demonstrate the ability of mitochondria to activate endothelial cells (ECs), the initial barrier between a solid organ allograft and its host. We find that mitochondria exposure leads to the upregulation of EC adhesion molecules and their production of inflammatory cytokines and chemokines. Additionally, mitochondrial exposure causes dendritic cells to upregulate costimulatory molecules. Infusion of isolated mitochondria into heart donors leads to significant increase in allograft rejection in a murine heterotopic heart transplantation model. Finally, co-incubation of human peripheral blood mononuclear cells with mitochondria-treated ECs results in increased numbers of effector (IFN-γ+ , TNF-α+ ) CD8+ T cells. These data indicate that circulating extracellular mitochondria in deceased organ donors may directly activate allograft ECs and promote graft rejection in transplant recipients.

Full Text

Duke Authors

Cited Authors

  • Lin, L; Xu, H; Bishawi, M; Feng, F; Samy, K; Truskey, G; Barbas, AS; Kirk, AD; Brennan, TV

Published Date

  • July 2019

Published In

Volume / Issue

  • 19 / 7

Start / End Page

  • 1917 - 1929

PubMed ID

  • 30761731

Pubmed Central ID

  • PMC6591073

Electronic International Standard Serial Number (EISSN)

  • 1600-6143

Digital Object Identifier (DOI)

  • 10.1111/ajt.15309


  • eng

Conference Location

  • United States