Engineering patient avatars of hematopoietic stem cell transplantation to study GvHD

About This Grant

PROJECT SUMMARY Total transplantation of the immune system via bone marrow transplantation is a critical treatment for various conditions, yet it faces significant challenges, most notably Graft versus Host Disease (GVHD). This project proposes a transformative approach to understand and mitigate GVHD, especially in pediatric patients. We aim to develop a groundbreaking multi-tissue Organotypic Culture Model (OCM) that integrates gut, liver, and blood components to replicate the complex immune interactions occurring during acute GVHD with intestinal and hepatic involvement. This model will provide a physiologically relevant platform to study donor-recipient immune responses in bone marrow transplantation, overcoming the limitations of current in vitro models. Central to our approach is the creation of patient-specific OCMs using tissues from pediatric bone marrow transplant recipients. This personalized methodology allows for an in-depth understanding of individual GVHD responses and the potential for tailored therapeutic strategies, thus advancing precision medicine in transplant immunology. Specifically, we will first develop a gut-liver-immune OCM platform to study the impact of HLA- mismatched donor-recipient immune interactions using HLA-matched and mismatched “donor” blood and characterizing the recipient's acute immune response to simulated transplantation and gut ulceration. Second, we will develop a gut OCM of pediatric bone marrow transplantation and rejection by performing deep multi- omics profiling of gut and liver biopsies and peripheral blood from patient undergoing bone marrow transplantation samples and then develop OCM models of pediatric aGvHD to replicate salient features of immune activation and tissue damage. Finally, we will develop a computational model of the donor-recipient immune networks to create “immunologic digital twins” and characterize the drivers of successful transplantation and GvHD. These models will integrate multi-omic data, including single-cell RNA sequencing, to simulate and predict transplant outcomes, including the risk and severity of GVHD. This approach represents a significant stride in preclinical translation modeling, offering a powerful tool for preemptive intervention and personalized treatment planning. The project is underpinned by a unique and transformative interdisciplinary team comprising experts in OCM technology, computational modeling, and clinicians specializing in pediatric GVHD. This collaboration ensures a comprehensive, bench-to-bedside approach, facilitating rapid translation of our findings into clinical practice. Our work promises to not only deepen the understanding of GVHD pathophysiology but also to revolutionize the management and treatment of this condition in bone marrow transplantation. By integrating innovative OCM platforms with advanced computational modeling and patient-centric research, we aim to deliver a new approach available for the studies of transplant immunology and the potential to improve patient outcomes significantly.