Hematopoietic stem cell transplantation (HCT) is a life-saving therapy, but one that is still plagued with complications, the most deadly of which is graft-versus-host disease (GVHD). Acute GVHD (AGVHD) occurs in as many as 70% of transplant recipients, despite their treatment with multiple immunosuppressive drugs. Moreover, Grade III-IV GVHD, especially involving the GI system, is often untreatable, leading to high rates of post-HCT morbidity and mortality. These issues give rise to three central challenges in the field. They are: (1) What are the mechanisms that drive breakthrough T cell allo-immunity and tissue damage despite current immune suppression strategies? (2) Can we design treatment strategies to directly target these mechanisms? and (3) What are the necessary components of a GVHD-prevention strategy that will safely produce long-term immune tolerance? To address these questions, we have developed and refined the only non-human primate (NHP) model of GVHD, and have used this model to discover a series of new insights into the immunology of this disease. These include: (1) That a systems biology approach can be applied to GVHD to uncover central mechanisms and targetable pathways. (2) That AGVHD can be divided into ?primary? and ?breakthrough? mechanisms: with primary GVHD driven by Th/Tc1 pathways, while breakthrough GVHD is driven by IL17- predominant pathways. (3) That primary AGVHD can be successfully controlled by calcineurin Inhibitor-free CD28:CD80/86 blockade + rapamycin. These discoveries form the core of our new understanding of AGVHD and inform the next phase of our work. This work is based on the overarching hypothesis that the tissue- specific molecular mechanisms controlling GVHD can be identified, and that by targeting these mechanisms, an evidence-based approach to the prevention and treatment of this disease can be achieved. We will test this hypothesis through the following Specific Aims:
Aim 1 : Evidence-based GVHD Prevention:
This Aim will determine strategies by which immune escape pathways, identified through transcriptome analysis, can be targeted to prevent GVHD.
Aim 2 : Tissue-Specific GVHD Diagnostics: In this Aim, we will establish a transcriptomic map comparing blood- liver, and GI-specific immune activation during NHP GVHD, using both population- and single-cell techniques.
Aim 3 : Evidence-based GVHD Treatment: In this Aim we will determine the mechanisms controlling breakthrough GVHD in both NHP and patients and test novel treatment strategies in our newly-developed NHP GVHD Treatment Model.
Every year, thousands of patients undergo hematopoietic stem cell transplant. While this procedure is potentially lifesaving for patients with hematologic malignancies and non-malignant hematologic disease, it is still plagued with complications, the most deadly of which is graft-versus-host disease (GVHD). The proposed research is highly relevant to public health because it aims to improve clinical outcomes for patients that are undergoing hematopoietic stem cell transplantation, by discovering new strategies to prevent and treat graft- versus-host disease.
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