Mechanisms of Allogeneic Stem Cell Engraftment

University Of Louisville, Louisville KY

Investigators

Abstract

DESCRIPTION (provided by applicant): Graft-versus-host disease (GVHD) and failure of engraftment have limited the clinical application of bone marrow transplantation for patients with leukemia. Bone-marrow T-cells eliminate alloreactive host cells; however, T-cell alloreactivity may also result in the death of the host through GVHD. The facilitating cell (FC) is a rare bone-marrow CD8+TCR-cell that enhances engraftment of HSC without causing GVHD. Three independent laboratory groups have confirmed the existence of the FC, but its mechanism of action has not been defined. In preliminary analyses, CD8+TCR-FCs contain transcripts for TNFa, and TNFa-/-FC are not functional. Our central hypothesis is that FCs maintain long-term renewal of HSC through a TNFa-dependent mechanism. We will determine the role of TNFa in FC-mediated engraftment and HSC survival through the use of TNFa-/-, TNF-p55-/-, TNF-p75-/-, and TNF-p55-/-p75-/- mice as a source of FC, HSC or as recipients in allogeneic transplantation. We will directly test the role of FC in survival of HSC by 1) providing HSC with a transgenic-BCL2 survival molecule to determine if they are FC-independent, and 2) examining the cobblestone-area-forming capacity of HSC in marrow from mice defective in FC function. As we define the mechanism of action, strategies to optimize engraftment will emerge.