Targeting Neovascularization in Graft-Versus-Host Disease
Allogeneic bone marrow transplantation (allo-BMT) is a widely-used treatment for leukemias and lymphomas. For many children with these malignancies, allo-BMT represents the only treatment with the potential for cure. Graft-versus-host disease (GVHD), however, afflicts between 30-80% of patients following transplant and remains a major cause of death. The primary cause of GVHD is known to be linked to donor T cells, which can recognize host cells as foreign and attack indiscriminately, often targeting both cancer cells and normal tissues.
Our recent preclinical studies in mouse models have demonstrated a previously unknown association between growth of new blood vessels and development of GVHD. We found that organs involved with GVHD have evidence of new vessel growth, and that mice with GVHD have increased numbers of circulating cells called endothelial progenitor cells (EPCs), which are recruited in the formation of new vessels. Treating mice with the antibody E4G10 to reduce numbers of EPCs resulted in decreased growth of new vessels as well as decreased GVHD. Transplanted mice treated with this antibody were significantly healthier and had improved survival after allo-BMT. Interestingly, the ability of donor T cells to attack cancer cells was not compromised by antibody treatment.
In this grant, we propose studies in mouse models to characterize the link between the growth of new vessels and GVHD, as well as experiments to designed to answer important preclinical questions necessary prior to starting clinical trials, including safety and determining how to combine this therapy with other forms of immune suppression.