Immunohistochemical staining of mouse ileum using anti-Reg3γ antibody, showing loss of Reg3γ expression in GVHD (left image) in comparison to normal small intestine (right image).
The current projects in the Ferrara Laboratory investigate graft versus host disease (GVHD) using two different approaches:
Biomarkers of GVHD
In these projects, we aim to use novel and established proteomic techniques to identify and validate biomarkers of GVHD, and subsequently combine these into predictive algorithms. Such algorithms will further be tested in innovative clinical trials, to prospectively assess their capacity to help diagnose and treat acute GVHD. Specific projects include:
- The development of a biomarker algorithm to identify patients at high risk of developing acute GVHD prior to the onset of clinical symptoms. Such an algorithm would then facilitate a clinical trial of pre-emptive treatment of acute GVHD for high-risk patients.
- The use of biomarkers in real-time to stratify patients with diagnosed acute GVHD into those at high risk for severe disease. These patients are then eligible for a trial of monoclonal antibody therapy in addition to high dose steroids as primary treatment.
Our biomarker projects are collaborative, using patient data and samples from twenty-five bone marrow transplant centers across the USA, Europe and Asia. Together, these centers comprise MAGIC (Mount Sinai Acute GVHD International Consortium), under the leadership of Dr. Ferrara.
Mechanisms of GVHD Pathophysiology
These projects aim to dissect the biological pathways of GVHD at the cellular and molecular levels, using both in vitro assays and in vivo murine models. There is synergy to be found with the biomarker work, since biomarkers of GVHD may play an active role in the pathophysiology of GVHD and may represent potential therapeutic targets. Current projects include:
- Paneth cells, an important epithelial component of the intestinal stem cell niche, are targets of GVHD. Interestingly, serum Reg3α and its murine orthologue Reg3γ, produced by the Paneth cells, are strong predictive biomarkers of intestinal acute GVHD. We are exploring the role of Reg3γ in mouse models of GVHD.
- Soluble ST2, a decoy receptor for IL-33, represents a powerful predictor of acute GVHD. We are aiming to further understand the pleiotropic roles of IL-33 signalling in acute GVHD.