The major goal in organ transplantation is to prevent rejection yet preserce recipient immunocompetence. Bone marrow (BM) chimerism, resulting from engraftment of the donor BM stem cell (SC), is associated with long-term donor-specific tolerance, associated with the infusion of unmodified BM into ablated recipients has excluded the potential use of chimerism in the induction of transplantation tolerance. The incidence and severity of graft vs. host disease (GVHD) is directly related to the antigenic disparity between the donor and the recipient. T-cell depletion (TCD) of donor BM significantly reduces GVHD, but is associated with a concurrent rise in the incidence of engraftment failure. Recently, we have identified a rare BM-derived cell population, of unknown lineage, which we call the facilitating cell (FC), that is sufficient to permit engraftment of highly purified murine SC in completely MHC-disparate recipients, without GVHD. The global aim in this proposal is to characterize cell surface molecules on the FC population which are responsible for the unique property of SC facilitation in vivo. The FC is inadvertently removed by some techniques of TCD, because it does express CD8alphabeta and CD3epsilon, however, it can be isolated in a subpoplulation distinct from conventional T cells due to the absence of the alpha beta or gamma delta T cell receptor (TCR) complex, CD3 expression without the conventional TCR heterodimers has been described on immature thymocytes. In all cases, CD3epsilon was associated with a TCR-surrogate or chaperone protein, in a functional CD3 receptor complex. Therefore, we have focused our search for a marker of FC function on the identification of CD3epsilon-associated molecules (CD3AMs) on the FC cell surface. We have now identified at least two CD3AMs on the FC, which are not found on conventional T cells.
In Aim I, we will Characterized the CD3AMs on the FC Population: Is CD3AM Expression Independent of the T Cell Receptor? CD3 expression in the absence of TCR heterodimers, suggest that the FC is not a T cell, and therefore, the FC (and CD3AM expression) should be present, and capable of SC facilitation, in mice deficient of T cells. Therefore, in Aim II, we will Determine the Mechanistic Role of CD3AMs on the Ability of the FC Population to Facilitate Engraftment of the Allogeneic SC. Failure of a viable SC to engraft in an allogeneic environment is likely to be secondary to the inability of the foreign environment to foster SC differentiation and self-renewal.
In Aim III, we will Determine the Mechanism by Which The FC Facilitates SC Survival: Are CD3AMs Necessary for SC Rescue?
|Colson, Yolonda L; Shinde Patil, Vivek R; Ildstad, Suzanne T (2007) Facilitating cells: novel promoters of stem cell alloengraftment and donor-specific transplantation tolerance in the absence of GVHD. Crit Rev Oncol Hematol 61:26-43|
|Colson, Y L; Schuchert, M J; Ildstad, S T (2000) The abrogation of allosensitization following the induction of mixed allogeneic chimerism. J Immunol 165:637-44|