Allogeneic stem cell transplantation is a standard treatment for patients with high-risk relapsed leukemia, aplastic anemia, congenital bone marrow failure syndromes, and relapsed or recurrent lymphoid malignancies. Over 20,000 allogeneic transplants are conducted annually worldwide, confirming its effectiveness as a treatment for patients with otherwise lethal malignancies. Although an effective treatment, acute graft-versus-host disease (aGvHD) occurs in 30-70% of transplant recipients. aGvHD is syndrome characterized by selective epithelial damage to target organs and is mediated by mature T lymphocytes present in the donor marrow or stem cell inoculums. While GvHD is a significant complication of allo-SCT it is very closely associated with the immune-mediated destruction of host tumor cells termed the graft-versus- leukemia (GvL) response. As allo-SCT remains the only treatment for many diseases, eliminating complications from aGvHD while retaining the beneficial effects of the GvL response is imperative. My long-term goal is to eliminate aGvHD in allogeneic stem cell transplant recipients while maintaining GvL response, decreasing morbidity and mortality in transplant recipients. Migration of donor T cells to initial sites of activation is required for the pathogenesis of aGvHD. Both extracellular and intracellular components are responsible for the migration of T cells. Coronins (Coro) are a family of actin-binding proteins that function in cell motility, migration, and cytoskeleton organization. Coro 1A is found predominantly in hematopoietic tissue while Coro 1B is ubiquitously expressed. Both Coro 1A and Coro 1B are expressed in T cells leading me to the hypothesis that elimination of Coro 1A or Coro 1B will attenuated aGvHD in transplant recipients. In this research training plan we will first determine the effects of T cells deficient in Coro 1A or Coro 1B on aGvHD. Additionally the effects on the closely related GvL response will be investigated. Next we will determine how Coro 1A and Coro 1B alter steady state actin dynamics that lead to chemotaxis and migration dysfunction. Lastly, the ability of Coro 1A or Coro 1B deficient cells to clear viral pathogens will be determined. A combination of genetics, molecular biology, cell biology and immunology techniques will be used to determine the effects of Coro 1A and Coro 1B on aGvHD and viral pathogens, and determine how Coronins alter steady state actin dynamics.
Allogeneic stem cell transplantation is a standard treatment for patients with high-risk relapsed leukemia, aplastic anemia, congenital bone marrow failure syndromes, and relapsed or recurrent lymphoid malignancies. Although an effective treatment, acute graft-versus-host disease (aGvHD), a syndrome characterized by selective epithelial damage to target organs, occurs in 30-70% of transplant recipients. As allo-SCT remains the only treatment for many diseases, eliminating complications from aGvHD is imperative.
|Fulton, LeShara M; Taylor, Nicholas A; Coghill, James M et al. (2014) Altered T-cell entry and egress in the absence of Coronin 1A attenuates murine acute graft versus host disease. Eur J Immunol 44:1662-71|