Donor liver quality is critical to avoid primary non-function or dysfunction after transplantation. Previously, our lab developed a model of Non-human Primate (NHP) Brain death (BD) that recapitulates clinical human brain death by placing a balloon catheter in the cranial subdural space that causes brain-stem herniation (anesthetized animals). Using this model, we have been able to demonstrate statistical up-regulation of innate immunity pathways, NFΚB targets and regulatory proteins (NFΚB1,IL-1IB,RelB) and apoptosis (CASP 1,3,4,8,10), and genes associated with metabolism of lipids and carbohydrates in liver samples from BD donors compared to NBD controls. We propose administration of IL-1 Receptor Antagonist (IL-1RA) as a donor management strategy to reduce activation of the inflammation response.

Results: Liver infiltration of CD45+ and CD68+ cells was significantly reduced in the BD+IL-1RA animals compared to untreated BD animals, as were markers of oxidative stress. There was also a significant reduction in circulating IL-6 in the IL-1RA-treated BD animals compared to untreated. We observed a reduction of AST and Troponin 1 values in the blood plasma in the presence of IL-1RA treatment. By microarray, IL-1RA treatment conferred an intermediate phenotype in terms of expression differences between BD and Control, likely through modulation of NFΚB signaling: 15% of the identified NFΚB targets on the array were significantly different between Control and Brain Death (1.5 threshold, t-test, Benjamini and Hochberg correction), whereas only the 8% of these targets were significantly different between Control and BD+IL-1RA. IL-1RA-treatment dampened BD-induced expression of genes involved in innate immunity, stress response, lymphocyte activation, cytokine production, and apoptosis. By qPCR we saw a significant difference in gene expression for markers of inflammation, including IL-1Β, IL-6, and TNFΑ. These results together suggest that IL-1RA produces an intermediate phenotype that mitigates the effect of Brain Death-induced inflammation in the liver.

Conclusion: Intervention with IL-1RA resulted in down-regulation of pathways associated with inflammation and provided a protective effect to the liver of pre-treated BD donors. Donor intervention with IL-1RA constitutes a promising therapeutic strategy to modulate the inflammatory response in BD organ donors potentially improving pre-transplant organ quality.

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