Does shining a spotlight on XIAP deficiency bring the role of allogeneic HCT into better focus?

Marsh, Rebecca

doi:10.1016/j.jaci.2022.06.003

Cited by 1 publication

(2 citation statements)

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“…The relevance of XIAP for human health is exemplified by mutations that are associated with several inflammatory diseases [14,15]. Initially, XIAP mutations were found in a relatively rare XLP-2 syndrome [12], but XIAP mutations are now correlated with a worse prognosis for GVHD patients and very early onset IBD [16][17][18][19][20][21]. These findings have prompted us to investigate novel treatment options for patients with deleterious XIAP mutations.…”

Section: Discussionmentioning

confidence: 99%

“…For patients needing hematopoietic cell transplantation (HCT), XIAP deficiency can promote graft-versus-host disease (GVHD) driven by donor T cell activation [ 17 ]. Indeed, XIAP deficiency is regarded as a high risk for allogeneic HCT and leads to suboptimal outcomes [ 16 , 18 ]. Loss-of-function XIAP mutations have also been reported in male patients with early-onset Crohn’s disease [ 19 , 20 ].…”

Section: Introductionmentioning

confidence: 99%

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XIAP deletion sensitizes mice to TNF-induced and RIP1-mediated death

Witt¹,

Goncharov²,

Lee³

et al. 2023

Cell Death Dis

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XIAP is a caspase-inhibitory protein that blocks several cell death pathways, and mediates proper activation of inflammatory NOD2-RIP2 signaling. XIAP deficiency in patients with inflammatory diseases such as Crohn’s disease, or those needing allogeneic hematopoietic cell transplantation, is associated with a worse prognosis. In this study, we show that XIAP absence sensitizes cells and mice to LPS- and TNF-mediated cell death without affecting LPS- or TNF-induced NF-κB and MAPK signaling. In XIAP deficient mice, RIP1 inhibition effectively blocks TNF-stimulated cell death, hypothermia, lethality, cytokine/chemokine release, intestinal tissue damage and granulocyte migration. By contrast, inhibition of the related kinase RIP2 does not affect TNF-stimulated events, suggesting a lack of involvement for the RIP2-NOD2 signaling pathway. Overall, our data indicate that in XIAP’s absence RIP1 is a critical component of TNF-mediated inflammation, suggesting that RIP1 inhibition could be an attractive option for patients with XIAP deficiency.

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