The concept of replacing a defective organ with a functional one has become a reality. However, the use of non-specific immunosuppressive agents required to prevent graft rejection is associated with an increased rate of infections and malignancy. Moreover, chronic rejection remains the number one cause of late graft loss. Bone marrow chimerism confirms donor-specific transplantation tolerance for solid organ and cellular transplants. The morbidity and mortality associated with transplantation of unmodified bone marrow has limited the application of chimerism to induce tolerance in transplant recipients. Although purified stem cells engraft in syngeneic recipients, they do not engraft in MHC mismatched recipients. Over the past five years, the applicants have identified, characterized, and purified a novel facilitating cell in the bone marrow that enables engraftment of highly-purified stem cells in MHC disparate recipients without causing GVHD. In continuing studies, they will define the mechanism by which facilitating cells enable engraftment of stem cells in allogenic recipients in order to develop strategies to optimize the conditions that favor engraftment and tolerance with minimum recipient morbidity. The facilitating cell and the stem cell must be matched at the MHC, implying a receptor-ligand interaction. The investigators hypothesize at least two mechanisms by which the facilitating cell may work: 1) As a ligand to which the stem cell could anchor, providing a regulatory signal to prevent terminal differentiation or apoptosis (trophic hypothesis); or 2) As a veto type of cell that would protect the stem cell from immediate destruction by host cells, such as NK cells.
In aim 1, they will define lineage derivation of the facilitator cell. Subsequently, in aim 2, they will explore the trophic hypothesis and characterize which receptor-ligand interactions are critical to the facilitating effect. They will characterize the adhesion molecules and other cell surface molecules integral to facilitating cell-stem cell interactions. An understanding of these requirements will allow new strategies to optimize engraftment.
In aim 3, they will examine whether the facilitating effect is due to a veto mechanism.
In aim 4, they will amplify and potentiate the facilitating effect by ex-vivo expansion in a variety of cytokines. The signal overall objective of these studies is to define and optimize those components in donor marrow that will enable the application of mixed allogeneic chimerism to induce tolerance.
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