Amid Search for Biomarkers in oGVHD, Research Focuses on Cytokine Profile of Tears

Amidst an evolving understanding of indicators for prognosis, diagnosis, and treatment of ocular graft-vs-host disease (oGVHD), researchers of a systematic review are offering a current understanding of potential biomarkers in the disease.

Close-up image of a tear | Image Credit: Laura Pashkevich-stock.adobe.com

Across studies included in their review, tears were the most commonly used source for analysis, a noninvasive and easily accessible approach for determining biomarkers in oGVHD, which affects approximately half of patients post stem cell transplant.

“The ophthalmic manifestations of this disease occur in more than half of all allo-HSCT [allogeneic hematopoietic stem cell transplantationpatients], which may present as severe dry eye disease, foreign body sensation, corneal scarring, decreased visual acuity, and, in severe cases, corneal perforation,” explained the researchers in Biomolecules. “In clinical settings, the limited specificity and consistency of these indicators highlight the challenges associated with diagnosing and characterizing oGVHD, which are necessary to optimize treatment and identify patients at risk for the development of the most severe forms of oGVHD. As such, validated biomarkers are a critical tool for objective diagnostics and monitoring tools for this disease.”

With the need for biomarkers to differentiate the disease from other dry eye diseases (DED) and subsequently improve diagnosis and treatment, the researchers underscore the value of their findings, which they say provide valuable insights into how the microbiome of the ocular surface plays into the pathogenesis of oGVHD.

Nineteen studies were included in the analysis, and they were identified from the Scopus, PubMed, and Embase databases. The researchers cautioned the potential of language bias, publication bias, and sampling bias among the studies, as well as a lack of appropriate controls included in the study cohorts.

Across biomarkers assessed in the studies, cytokines were the most common, with a primary focus on which cytokines have an impact on disease severity. Elevations in interleukin (IL)-6 and IL-8, and decreases in IL-7 have been identified in tear analysis.

“In areas of inflammation, IL-6 functions to regulate immune responses while IL-8 (specifically) activates neutrophils. IL-7 induces T-cell maturation and homeostasis; thus, a reduced level is expected in oGVHD patients via thymic injury from HSCT,” detailed the researchers. “Likewise, decreased amounts of EGF [epidermal growth factor], which increases cell growth, may indicate an inflammatory state susceptible to both GVHD and oGVHD. Additionally, numerous studies were identified showing the correlation between cytokines MMP-9, granulocyte-macrophage colony-stimulating factor (GM-CSF), B-cell activating factor (BAFF), and ICAM in the tears of patients with oGVHD.”

For example, one study included in the analysis found that compared with patients with DED, patients with oGVHD had elevated levels of IL-6, IL-8, and ICAM-1, as well as decreased levels of IL-7 and EGF. In another study comparing cytokine levels among patients with oGVHD and healthy controls, researchers found that in addition to elevations of the aforementioned cytokines, BAFF and GM-CSF were elevated in patients with oGVHD.

The decreased levels of IL-7 and EGF in patients with oGVHD may suggest a protective effect of these cytokines against the disease, although the researchers note further research is required.

The studies also characterized potential implications of newer biomarkers, including lymphotoxin-α (LT-α), oncostatin M (OSM), and LIGHT/TNFSF14. One study showed that levels of LT-α were significantly lower in patients with oGVHD compared with healthy controls. The cytokine had negative correlations with Ocular Surface Disease Index score and positive correlations with tear breakup time.

Outside of cytokines, proteins such as lactotransferrin, lipocalin-1, and lysozyme C, and proline-rich proteins 1 and 4 in patient tears have been assessed. Additionally, the leukocyte profile in tears and the microflora profile on the ocular surface have been explored.

Reference

Bohlen J, Gomez C, Zhou J, Guasch FM, Wandvik C, Sunshine SB. Molecular biomarkers in ocular graft-versus-host disease: a systematic review. Biomolecules. 2024;14(1):102. doi:10.3390/biom14010102