Patterns of gene expression among murine models of hemorrhagic shock/trauma and sepsis.

Controversy remains whether the leukocyte genomic response to trauma or sepsis is dependent upon the initiating stimulus. Previous work illustrated poor correlations between historical models of murine trauma and sepsis (i.e., trauma-hemorrhage and lipopolysaccharide injection, respectively). The aim of this study is to examine the early genomic response in improved murine models of sepsis [cecal ligation and puncture (CLP)] and trauma [polytrauma (PT)] with and without pneumonia (PT+Pp). Groups of naïve, CLP, PT, and PT+Pp mice were killed at 2 h, 1 or 3 days. Total leukocytes were isolated for genome-wide expression analysis, and genes that were found to differ from control (false discovery rate adjusted P < 0.001) were assessed for fold-change differences. Spearman correlations were also performed. For all time points combined (CLP, PT, PT+Pp), there were 10,426 total genes that were found to significantly differ from naïve controls. At 2 h, the transcriptomic changes between CLP and PT showed a positive correlation (rs) of 0.446 (P < 0.0001) but were less positive thereafter. Correlations were significantly improved when we limited the analysis to common genes whose expression differed by a 1.5 fold-change. Both pathway and upstream analyses revealed the activation of genes known to be associated with pathogen-associated and damage-associated molecular pattern signaling, and early activation patterns of expression were very similar between polytrauma and sepsis at the earliest time points. This study demonstrates that the early leukocyte genomic response to sepsis and trauma are very similar in mice.

Early Recovery of Myeloid-Derived Suppressor Cells After Allogeneic Hematopoietic Transplant: Comparison of Post-Transplantation Cyclophosphamide to Standard Graft-Versus-Host Disease Prophylaxis.

Allogeneic hematopoietic cell transplantation (alloHCT) using haploidentical donors (haploHCT) with post-transplantation cyclophosphamide (PTCy) for augmented graft-versus-host disease (GVHD) prophylaxis has emerged as a robust platform to expand donor options with acceptable levels of GVHD and graft failure. The mechanism by which PTCy mitigates GVHD risk is partly explained by preferential cytotoxicity based on aldehyde dehydrogenase levels and up-regulation of regulatory T cells, but is incompletely understood. Myeloid-derived suppressor cells are important mediators of T-cell function and are up-regulated by cyclophosphamide exposure. We hypothesized that this cell type may play a role in GVHD protection in children undergoing haploHCT/PTCy. We prospectively collected samples in the first month after alloHCT from children undergoing standard of care (SOC) alloHCT with matched donors and tacrolimus-based GVHD prophylaxis (N = 11) and PTCy recipients (N = 11). MDSC recovery was compared using flow cytometry, and MDSC suppressive function was assessed at the peak of MDSC quantitative recovery post-alloHCT. Groups were well matched for conditioning regimen and stem cell source. PTCy recipients exhibited more robust MDSC recovery, particularly polymorphonuclear-MDSCs than SOC recipients, with preservation of T-cell suppressive function. This corresponded to significantly lower incidence of Grade II to IV acute GVHD (9.1% versus 27.3%) and moderate/severe chronic GVHD (0% versus 27.3%) in PTCy recipients. Patients who developed GVHD had decreased MDSC-mediated T-cell suppression, as well as higher levels of IL-10, a cytokine closely linked to GVHD biology. Overall, these findings provide support for the role of MDSCs in mediating GVHD protection after PTCy-based haploHCT. © 2022 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.