Potential Novel Biomarkers in Chronic Graft-Versus-Host Disease

Abstract

Prognostic, diagnostic or predictive biomarkers are urgently needed for assessment of chronic graft-versus-host disease (cGvHD), a major risk for patients undergoing allogeneic hematopoietic stem cell transplantation. The main goal of this review generated within the COST Action EUROGRAFT "Integrated European Network on Chronic Graft Versus Host Disease" was to identify potential novel biomarkers for cGvHD besides the widely accepted molecular and cellular biomarkers. Thus, the focus was on cellular biomarkers, alloantibodies, glycomics, endothelial derived particles, extracellular vesicles, microbiome, epigenetic and neurologic changes in cGvHD patients. Both host-reactive antibodies in general, and particularly alloantibodies have been associated with cGvHD and require further consideration. Glycans attached to IgG modulate its activity and represent a promising predictive and/or stratification biomarker for cGVHD. Furthermore, epigenetic changes such as microRNAs and DNA methylation represent potential biomarkers for monitoring cGvHD patients and novel targets for developing new treatment approaches. Finally, the microbiome likely affects the pathophysiology of cGvHD; bacterial strains as well as microbial metabolites could display potential biomarkers for dysbiosis and risk for the development of cGvHD. In summary, although there are no validated biomarkers currently available for clinical use to better inform on the diagnosis, prognosis or prediction of outcome for cGvHD, many novel sources of potential markers have shown promise and warrant further investigation using well characterized, multi-center patient cohorts.

Keywords: alloantibodies; cellular biomarkers; chronic graft-versus-host disease (cGvHD); endothelial derived particles; epigenetic changes; extracellular vesicles; glycomics; microbiome.

Figure 1

Pathophysiology of chronic graft-versus-host disease (GvHD). The intensity and the length of GvHD is multifactorial, it depends of conditioning regimen, donor and host status including graft source, donor type, HLA match, age, and gender. APC, antigen-presenting cell; CD8⁺, cytotoxic T cells; CD4⁺, helper T cells; NKT, natural killer T cells.

Figure 2

Schematic representation of immunoglobulin G glycosyation. The IgG molecule contains a single conserved glycosylation site on each of its heavy chains that can harbor a variety of glycans. A core glycan structure contains 3 mannoses and 4 N-acetylglucosamines, which can be modified by addition of fucose, bisecting N acetylglucosamine (bisection), galactose and N-acetylneuraminic acid generating up to 30 possible glycan structures. The absence of glycans substantially affects the stability and disrupts the antibody activity. IgG, immunoglobulin G; Fab, antigen-binding fragment; Fc, crystallizable fragment; C; constant domain; V, variable domain; H, heavy chain; L, light chain, S-S, disulfide bond. Depiction according to (67) and (68).

Figure 3

Schematic representation of DNA methylation occurrence in relation to cGvHD and other conditions. In healthy condition, epigenetic changes in DNA methylation occur often on most of cellular gene promoters, resulting in the absence of gene expression. In cancer, inflammation and other conditions such as cGvHD, some relevant genes become methylated and as such, suppressed in their function. Accordingly, aberrant DNA methylation profiles can point to the diseased tissue, providing important information prior to treatment. Epigenetic drugs, such as demethylating agents (DNA methyltransferase (DNMT) inhibitors), for example azacytidine (AZAC) and decitabine (DEC), may be used to induce expression of certain genes, particularly after allogeneic hematopoietic stem cell transplantation (alloHSCT), enhancing the graft versus leukemia (GvL) effect. Thus, demethylating agents could be considered a therapy of choice for recovering from cGvHD. Hypermethylated genes are presented in red, while hypomethylated in green color.