01.03.23

Update on GVHD Biomarkers

Graft-versus-host disease (GVHD) is a potentially devastating complication of allogeneic HCT. There is an unmet need, however, for better methods of diagnosing GvHD, identifying patients at risk of GvHD, and determining which patients are at highest risk of severe GvHD and poor outcomes. This has raised interest in the study of precise and sensitive biomarkers for GvHD. 

Noncoding RNAs: from miRNAs to lncRNAs

Noncoding RNAs (ncRNAs), which are untranslated RNAs and include microRNAs (miRNAs) and long noncoding RNAs (lncRNAs), play vital roles in controlling cellular gene expression and cell function. While the majority of studies explore using proteins as diagnostic biomarkers for GVHD, ncRNAs have emerged as important for several processes such as T cell development, myeloid cell function, BCR/TCR signalling, immune cell differentiation, and others. As these processes are involved in GVHD development, this has allowed their use as potential biomarkers.

Several studies have demonstrated the importance of specific miRNAs including miR-155, miR-181a, miR-146a, and miR-17–92 in the pathophysiology of GVHD. Animal and human data have shown that, in B and T cells, miRNA-155 enhances TNF-α and Th1 development, and thereby promotes acute GVHD (aGVHD). High miRNA-155 was associated with increased risk for aGVHD and may predict aGVHD prior to onset. The miR-17–92 cluster was shown to promote T cell development, proliferation, and suppress regulatory T cells (Tregs). Conversely, high miR-181a expression was found to act as a barrier to T cell sensitivity by downregulating TCR activation. Similarly, miR-146a promotes Treg homeostasis, and transplanting miR-146a-/- T cells in mice led to increased serum levels of TNF and GVHD severity. Therefore, low expression of miR-181a or miR-146a, or high expression of miR-155, miR-17–92 may serve as potential biomarkers for GVHD in patients undergoing HCT. Additional miRNAs are also being investigated for prognostic roles in GVHD.

Other ncRNAs such as lncRNAs have been investigated as biomarkers for GVHD through their roles as immune modulators. For example, reduction in the lncRNA MAF4 resulted in the induction of Th2 and inhibition of Th1 cell production. As a prognostic marker, lnc-DC was found to be important for dendritic cell (DC) differentiation, antigen presentation, and T cell activation. This translates to a significant increase in lnc-DC in aGVHD patients compared with non-GVHD patients. A recent study that screened for lncRNAs in GVHD found NONHSAT142151, NONHSAT040475, and FR118417 as potential biomarkers given their association with BCR signalling. While promising, further research is required to establish a stronger relationship between GVHD pathogenesis and lncRNAs.

Reg3α as a biomarker for transplant-related mortality

In a recent article published in Blood Advances, researchers from the University Hospital Regensburg in Germany have found a correlation between high regenerating islet-derived 3α (Reg3α) concentrations on the day of allogeneic HCT and increased transplant-related mortality (TRM). Reg3α concentrations were also influenced by intestinal dysbiosis caused by early antibiotic use. This suggests, for the first time, a correlation between Reg3α serum concentrations on the day of transplant, TRM, and poor overall survival (OS) at one year.

Reg3α, a serum marker for aGVHD, is an antimicrobial peptide produced by Paneth cells to protect the gastrointestinal (GI) tract from gram-positive bacteria. Studies have shown that disruptions to the gut microbiome lead to poor outcomes after HCT. Therefore, the authors sought to find a biomarker for GI tract damage and HCT outcomes. This study investigated 587 patients undergoing allogeneic HCT from the Mount Sinai Acute GVHD International Consortium (MAGIC) data as a prospective assessment of clinical data and biomarkers.

The authors found that high Reg3α serum concentrations were correlated with high TRM due to GI GVHD (11.0% vs. 5.3%, P = 0.005), infectious complications (8.8% vs. 2.4%, P < 0.001), and other reasons (8.1% vs. 2.7%, P = 0.001). Interestingly, high Reg3α concentrations were correlated with early intravenous broad-spectrum antibiotic use and in older patients (over 50 years of age). By measuring microbiome diversity using 3-Indoxylsulfate (3-IS) and PCR, the authors found that high Reg3α correlates with low urinary 3-IS and low stool copy number of Clostridiales. These findings suggest an increase in microbiota disruption, which leads to Reg3α release. Overall, these findings demonstrate, for the first time, that Reg3α serum concentrations on the day of transplant correlate with TRM.   

Reference

Vajari MK, Moradinasab S, Yousefi AM, Bashash D. Noncoding RNAs in diagnosis and prognosis of graft-versus-host disease (GVHD). J Cell Physiol. 2022;237(9):3480-3495. http://doi.org/10.1002/jcp.30830

Weber DA, Weber M, Meedt E, et al. Reg3α levels at day of allogeneic stem cell transplantation predict outcome and correlate with early antibiotic use [published online ahead of print, 2022 Nov 9]. Blood Adv. 2022;bloodadvances.2022008480.

http://doi.org/10.1182/bloodadvances.2022008480

Tags: GVHD, Survival, Transplant, Mortality, Severity, graft, Biomarker, graft-versus-host disease, graft-vs-host disease, graft-versus-host

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