Biomarkers for acute and chronic graft versus host disease: state of the art

ABSTRACT

Introduction

Despite significant advances in treatment and prevention, graft-versus-host disease (GVHD) still represents the main cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation. Thus, considerable research efforts have been made to find and validate reliable biomarkers for diagnosis, prognosis, and risk stratification of GVHD.

Areas covered

In this review the most recent evidences on different types of biomarkers studied for GVHD, such as genetic, plasmatic, cellular markers, and those associated with microbiome, were summarized. A comprehensive search of peer-review literature was performed in PubMed including meta-analysis, preclinical and clinical trials, using the terms: cellular and plasma biomarkers, graft-versus-host disease, cytokines, and allogeneic hematopoietic stem cell transplantation.

Expert opinion

In the near future, several validated biomarkers will be available to help clinicians in the diagnosis of GVHD, the identification of patients at high risk of GVHD development and in patients’ stratification according to its severity. Then, immunosuppressive treatment could be tailored to each patient’s real needs. However, more efforts are needed to achieve this goal. Although most of the proposed biomarkers currently lack validation with large-scale clinical data, their study led to improved knowledge of the biological basis of GVHD, and ultimately to implementation of GHVD treatment.

KEYWORDS:

• Circulating endothelial cells
• cytokines
• extracellular vesicles
• graft-versus-host disease
• microbiome
• microRNA
• natural killer
• proteomics
• regulatory T-cells
• SNPs

Article highlights box

• Considerable research efforts have been done to find and validate relevant biomarkers for graft-versus-host disease (GVHD), as new tools to tailor the use of immunosuppressive drugs and to optimize GVHD management.

• The complex pathophysiology of GVHD makes the identification of reliable biomarkers challenging.

• A combined model including clinical and genetic variables could be able to correctly predict grades III-IV acute GVHD (aGVHD) and chronic GVHD (cGVHD).

• Changes in the composition of intestinal microbiota play a pivotal role in development of GVHD.

• T, B, and Natural Killer (NK) cells are crucial in the maintenance of peripheral tolerance and impairment of their function after allogeneic transplantation can lead to GVHD onset.

• aGVHD causes endothelial injury and circulating endothelial cells (CECs) are increased in affected patients, whether these cells can be used as valid biomarker is under evaluation.

• microRNAs (miRNAs) are small non-coding RNAs, mainly involved in the regulation of gene expression. In the context of allografting, many biomarker studies have been focused on the role of miRNAs involved in T-cell function in aGVHD.

• Extracellular vesicles (EVs) play an essential role in intercellular communications and their extraction from biological fluids requires relatively non-invasive protocols, which makes them attractive as biomarkers in GVHD setting.

• The development of high throughput technologies enabling the study of an entire spectrum of molecules led to the identification of a panel of cytokines which is, at the moment, the GVHD biomarker closer to clinical application.

Despite many advances, the identification of valid GVHD biomarkers is still an unmet clinical need.

Acknowledgments

A special thanks to Rustem Aliu for graphical assistance.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was supported by Fondazione Cariplo (2015/0603 to DM), Associazione Italiana per la Ricerca sul Cancro (IG 2018-21567 to DM), and Intramural Research Funding of Istituto Clinico Humanitas (to DM). CDV was a recipient of the post-doctoral fellowships from the Fondazione Umberto Veronesi (2017-1464, 2018-1974, 2019-2563).