P01HL158505

Mechanisms and Therapy of Chronic Graft-vs.-Host Disease - Summary

Chronic graft-vs.-host disease (CGVHD) is the major cause of late morbidity, mortality, and compromised organ function after allogeneic hematopoietic stem cell transplant (HCT). It can affect essentially all organs and tissues, including the lungs, where the disease is termed bronchiolitis obliterans syndrome (BOS). BOS is a progressive, irreversible, and often fatal lung disease that occurs following HCT. Approximately 5-10% of HCT survivors develop BOS, which is considered the pulmonary manifestation of CGVHD. Out of CGVHD patients, about 10-15% will develop BOS, and less than 15% of BOS patients survive 5 years. The primary site of inflammation in BOS is the small airway, eventually leading to fibrosis.

CGVHD results from a failure to achieve immune tolerance after transplant. The mechanisms responsible for the failure of tolerance are complex and involve multiple cell types, but T cells are central to this process. Resting T cells preferentially use mitochondrial oxidative phosphorylation as basal energy. In acute GVHD, donor T cells exposed to host alloantigen in an inflammatory environment rapidly differentiate and proliferate, fulfilling their bioenergetic and biosynthetic needs by reprogramming metabolism and utilizing multiple energy sources. In CGVHD, the demands of metabolism are less well understood. However, with the high energy demands of proliferating immune cells in CGVHD, strategies to specifically block critical metabolic pathways may prove to be a novel treatment strategy.

In this program, we focus on the critical questions that plague the field of CGVHD. We address shortcomings in our understanding of the pathogenesis of human CGVHD and our ability to prioritize the next generation of therapeutic strategies. We aim to achieve this by defining the immune networks that characterize patients who develop CGVHD and interrogating the mechanisms of both success and failure of CGVHD treatment regimens. Additionally, we explore the unique metabolic demands in CGVHD pathogenesis and lung injury repair, with a specific focus on the most severe manifestation of CGVHD, BOS. To pinpoint the cellular and antigenic targets of BOS, we employ novel organoid cultures and immunogenomics. Our collaborative, multidisciplinary team is uniquely poised to make a significant impact in the field.

Dana-Farber Cancer Institute

THE DIVISION OF BLOOD DISEASES AND RESOURCES SUPPORTS RESEARCH AND RESEARCH TRAINING ON THE PATHOPHYSIOLOGY, DIAGNOSIS, TREATMENT, AND PREVENTION OF NON-MALIGNANT BLOOD DISEASES, INCLUDING ANEMIAS, SICKLE CELL DISEASE, THALASSEMIA, LEUKOCYTE BIOLOGY, PRE-MALIGNANT PROCESSES SUCH AS MYELODYSPLASIA AND MYELOPROLIFERATIVE DISORDERS, HEMOPHILIA AND OTHER ABNORMALITIES OF HEMOSTASIS AND THROMBOSIS, AND IMMUNE DYSFUNCTION. FUNDING ENCOMPASSES A BROAD SPECTRUM OF HEMATOLOGIC INQUIRY, RANGING FROM STEM CELL BIOLOGY TO MEDICAL MANAGEMENT OF BLOOD DISEASES AND TO ASSURING THE ADEQUACY AND SAFETY OF THE NATION'S BLOOD SUPPLY. PROGRAMS ALSO SUPPORT THE DEVELOPMENT OF NOVEL CELL-BASED THERAPIES TO BRING THE EXPERTISE OF TRANSFUSION MEDICINE AND STEM CELL TECHNOLOGY TO THE REPAIR AND REGENERATION OF HUMAN TISSUES AND ORGANS. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, USE SMALL BUSINESS TO MEET FEDERAL RESEARCH AND DEVELOPMENT NEEDS, FOSTER AND ENCOURAGE PARTICIPATION IN INNOVATION AND ENTREPRENEURSHIP BY SOCIALLY AND ECONOMICALLY DISADVANTAGED PERSONS, AND INCREASE PRIVATE-SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT FUNDING. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, FOSTER TECHNOLOGY TRANSFER THROUGH COOPERATIVE R&D BETWEEN SMALL BUSINESSES AND RESEARCH INSTITUTIONS, AND INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL R&D.

93.837 - Cardiovascular Diseases Research

National Heart Lung and Blood Institute (NHLBI) [HHS - NIH]

Boston, Massachusetts 022155418 United States

Single Zip Code

NHLBI Program Project Applications (P01 Clinical Trials Optional) (PAR-21-088)

Amendment Since initial award the End Date has been extended from 08/30/27 to 08/31/27 and the total obligations have increased 287% from $2,665,095 to $10,320,200.