Table 5.

Gaps in knowledge and proposed priority research studies for chronic GVHD biology

Gaps and questions	Proposed research studies
Links between clinical manifestations and biology of cGVHD
What is the effect of the different type of outcomes identified in Table 1 on immune responses after HCT?	Evaluate late vaccine and immune responses in humans with resolved, active, no, and inactive chronic GVHD (Table 1).
Do different clinical manifestations of chronic GVHD have distinct biology?	Study biological characteristics of the clinically annotated models proposed herein.
Are there distinct disease biology clusters that occur independently across various clinical key manifestations?	Study clustering of biological characteristics in patients independent of clinical manifestations.
How does previous chronic GVHD increase the risk of late effects including stroke, myocardial infarction, infections, and subsequent malignancies?	Conduct human and murine studies evaluating the role of immune dysregulation and chronic inflammation in the development of late effects
Gaps in understanding cGVHD biology
What are the specific contributions of donor and recipient immunity to inflammatory pathways involved in chronic GVHD induction for each pair?	Conduct in-depth clinical studies of HLA and non-HLA encoded polymorphisms for donor:recipient pairs.
What are the target antigens of chronic GVHD in humans?	Perform large analyses to expand on current miHA target antigens recognized in humans and develop murine models based on these miHAs.
T-cell and B-cell repertoire analyses in peripheral blood, lymphoid tissues, and target organs are needed to better understand clonal responses of T cells and antigen identification, and are underexplored in preclinical models and in clinical studies.	Detailed analyses of T-cell and B-cell repertoire on humans that develop within the different types GVHD defined in Table 1. Develop murine GVHD models that reflect human repertoire development.
What is the role of tissue DCs in inducing and propagating chronic GVHD?	Evaluate the role of DCs in murine chronic GVHD models.
Is there a mechanistic link between early injurious events that occur early after transplant and the subsequent development of chronic GVHD?	Study whether targeted protection of early vascular and epithelial injury may reduce subsequent target organ dysfunction associated with chronic GVHD.
Do the fibrotic manifestations involve distinct pathways in various organs or do they have a singular, inciting, pathway that unifies different clinical phenotypes?	Conduct longitudinal clinical studies of target tissue immuno-biology.
Are fibrotic manifestations end-stage changes or are they reversible? If so, What are the mechanisms involved in functional wound healing after tolerance has been established?	Conduct longitudinal observational and therapy studies of fibrotic manifestations in mice and humans
What are the mechanisms responsible for collagen deposition and target organ fibrosis during end stages of chronic GVHD?	Develop novel approaches to target fibrinogenic pathways in order to treat patients with evolving organ fibrosis and dysfunction.
Gaps in understanding functional immunity and tolerance
What are the molecular pathways underpinning development of functional immunity (and tolerance)?	Study immune function in murine models of transplant tolerance (in mice on GVHD prophylaxis and after medication wean) and conduct studies of patients with chronic GVHD who then have full resolution of clinical manifestations and are weaned off immune suppression.
How do current GVHD prophylaxes regiments influence the development of immune tolerance? Decipher mechanisms of chronic GVHD prevention with PT/Cy?	Use of GVHD prophylaxis in mouse models to decipher their role in preventing tolerance induction and/or promotion of chronic GVHD.
How does an aged immune system versus a juvenile immune system (where all animal studies are focused) respond differently to the development of acute and chronic GVHD?	Improve our understanding of the effect of both donor and recipient age on immune tolerance.
Development of new animal models
Can steroid-refractory animal models be developed?	Study new agents for steroid-refractory disease.
A robust, large animal model of chronic GVHD is a gap in the field and would be useful for testing human reagents prior to clinical trials.	Expand the current primate and dog models to better evaluate chronic GVHD.
The specific anti-pathogen and anti-tumor effects of therapeutic agents on chronic GVHD therapy in preclinical models have been largely unexplored and deserve further consideration for testing.	Perform murine chronic GVHD model-based studies focused on the ability to respond to pathogens and malignancy in the presence of chronic GVHD.
Biomarkers and disease pathogenesis
What specific biomarkers and pre-clinical animal model would be most useful for exploring disease pathogenesis and therapy?	Perform large HCT population-based studies evaluating how a number of identified covariates influence biomarker concordance with chronic GVHD and evaluate these factors in murine GVHD models.