Peripheral Blood Gene Expression Changes Associated With Primary Graft Dysfunction After Lung Transplantation

Abstract

Recipient responses to primary graft dysfunction (PGD) after lung transplantation may have important implications to the fate of the allograft. We therefore evaluated longitudinal differences in peripheral blood gene expression in subjects with PGD. RNA expression was measured throughout the first transplant year in 106 subjects enrolled in the Clinical Trials in Organ Transplantation-03 study using a panel of 100 hypothesis-driven genes. PGD was defined as grade 3 in the first 72 posttransplant hours. Eighteen genes were differentially expressed over the first year based on PGD development, with significant representation from innate and adaptive immunity genes, with most differences identified very early after transplant. Sixteen genes were overexpressed in the blood of patients with PGD compared to those without PGD within 7 days of allograft reperfusion, with most transcripts encoding innate immune/inflammasome-related proteins, including genes previously associated with PGD. Thirteen genes were underexpressed in patients with PGD compared to those without PGD within 7 days of transplant, highlighted by T cell and adaptive immune regulation genes. Differences in gene expression present within 2 hours of reperfusion and persist for days after transplant. Future investigation will focus on the long-term implications of these gene expression differences on the outcome of the allograft.

Inflammasomes and IL-1 biology in the pathogenesis of allograft dysfunction

“…In a follow-up study, the CTOT-03 cohort was also utilized to study recipient biologic responses during PGD (40). The investigators evaluated longitudinal peripheral blood leukocyte gene expression.…”

A single-center experience of 1500 lung transplant patients

“…Experimental and clinical studies have suggested that lungs, when compared with other solid organ transplants, experience a higher incidence of ischemia-reperfusion injury. 19,20 Multiple groups have attempted to uncover the causes of PGD. There is some evidence to suggest that the type of preservation solution used might play a role.…”

Primary Graft Dysfunction (PGD) Following Lung Transplantation

“…54 Numerous studies have identified innate immune activation, likely mediated through the release of danger-associated molecular patterns (DAMPs), either based on differences in circulating proteins, changes in gene expression, or genetic polymorphisms, to be closely associated with PGD development. [55][56][57][58][59] Injury and danger signals in the donor likely also sensitize the lung for reperfusion injury in the recipient. [60][61][62][63][64] Several studies have demonstrated the utility of elevated levels of proteins integral to endothelial activation, epithelial apoptosis, and cell death and inflammation in ex vivo lung perfusate as potential markers of allografts at risk for PGD after implantation and reperfusion.…”