Tumor necrosis factor-driven cell death in donor organ as a barrier to immunological toleranceAng, Rosalind L.; Ting, Adrian T.Current Opinion in Organ Transplantation: February 2019 - Volume 24 - Issue 1 - p 12–19 doi: 10.1097/MOT.0000000000000599 TRANSPLANT IMMUNOLOGY: REJECTION, TOLERANCE AND HISTOCOMPATIBILITY: Edited by Paolo Cravedi Abstract Author InformationAuthors Article MetricsMetrics Purpose of review Regulated cell death (RCD) is likely to play a role in organ rejection but it is unclear how it may be invoked. A well-known trigger of regulated cell death is tumor necrosis factor-alpha (TNF), which activates both caspase-dependent apoptosis and caspase-independent necroptosis. TNF is best known as a pro-inflammatory cytokine because it activates NFκB and MAPK signaling to induce expression of pro-inflammatory genes. Recent findings Emerging data from animal models now suggest that TNF-induced cell death can also be inflammatory. Therefore, the role of cellular demise in regulating immunity should be considered. In transplantation, TNF could have a role in cellular injury or death from ischemia reperfusion (IR) injury and this may dictate organ survival. The default response to TNF in most cells is survival, rather than death, because of the presence of cell death checkpoints. However, cells succumb to TNF-driven death when these checkpoints are disrupted, and sensitivity to death likely reflects a reduction in molecules that fortify these checkpoints. We propose that a cell's propensity to die in response to TNF may underlie allograft rejection. Summary Genetic, epigenetic, and posttranslational control of death checkpoint regulators in donor tissues may determine graft survival. Therapeutically, drugs that prevent donor cell demise could be useful in preventing organ rejection. Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, USA Correspondence to Adrian T. Ting, PhD, Precision Immunology Institute, Box 1630, Icahn School of Medicine at Mount Sinai, 1 Gustave L Levy Place, NY 10029, USA. Tel: +212 659 9410; e-mail: email@example.com Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.