Have we made progress in the treatment of GVHD?

Abstract

One reason for the lack of progress in the treatment of acute graft versus host disease (GVHD) is the lack of reliable biomarkers. GVHD of the gastrointestinal (GI) tract is closely associated with non-relapse mortality (NRM) following hematopoietic cell transplantation (HCT). Using an unbiased, large-scale, quantitative proteomic discovery approach, we identified candidate biomarkers that were increased in plasma from HCT patients with GI GVHD. We then validated the lead candidate, REG3α, by ELISA in samples from more than 1000 HCT patients from three transplant centers. Plasma REG3α concentrations were 3-fold higher in patients at GI GVHD onset than in all other patients. REG3α concentrations correlated most closely with lower GI GVHD at GVHD onset and predicted response to therapy at 4 weeks, 1-year NRM, and 1-year survival (P ≤ 0.001). Multivariate analysis showed that advanced clinical stage, severe histologic damage, and high REG3α concentrations at the diagnosis of GVHD independently predicted 1-year NRM, which progressively increased with higher numbers of onset risk factors present. We conclude that REG3α is a plasma biomarker of GI GVHD that can be combined with clinical stage and histologic grade to improve risk stratification of patients, perhaps providing a platform for advances in the treatment of high-risk GVHD.

Figure 1. Proteomic workflow identifying REG3α as the lead candidate GI GVHD biomarker

Plasma pooled from 10 patients who never developed GVHD was compared to plasma pooled from 10 patients at the onset of GI GVHD. Of the 562 proteins initially identified, REG3α was chosen as the lead biomarker to validate because it was increased twofold in patients at the onset of GI GVHD, it is preferentially expressed in the GI tract and antibodies suitable for ELISA were commercially available.

Figure 2. REG3α concentrations in plasma samples from HCT patients of two independent validation sets

(A) University of Michigan patients (n=581) (B) Regensburg, Germany, and Kyushu, Japan (n= 94). (C) Patients from both validation sets classified by symptoms and etiology (n=1,014).

Figure 3. Proposed mechanism for elevated systemic REG3α concentrations in lower GI GVHD

At homeostasis, REG3α (red/orange dots) is concentrated in the mucous layer lining the luminal surface of the epithelium in intestinal crypts (left panel). In the setting of acute GVHD, apoptosis of enterocytes (white cells), stem cells (blue cells) and REG3α-producing Paneth cells (pink cells) are prominent. The intestinal barrier is breached and the mucous, including REG3α, readily enters systemic circulation (right panel).