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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
7R01DK052294-07
Application #
2856814
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Badman, David G
Project Start
1991-07-01
Project End
2000-12-31
Budget Start
1999-01-01
Budget End
1999-12-31
Support Year
7
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Louisville
Department
Type
Organized Research Units
DUNS #
City
Louisville
State
KY
Country
United States
Zip Code
40292
Leventhal, J; Miller, J; Abecassis, M et al. (2013) Evolving approaches of hematopoietic stem cell-based therapies to induce tolerance to organ transplants: the long road to tolerance. Clin Pharmacol Ther 93:36-45
Ding, Chuanlin; Cai, Yihua; Marroquin, Jose et al. (2009) Plasmacytoid dendritic cells regulate autoreactive B cell activation via soluble factors and in a cell-to-cell contact manner. J Immunol 183:7140-9
Xu, Hong; Huang, Yiming; Chilton, Paula M et al. (2008) Strategic nonmyeloablative conditioning: CD154:CD40 costimulatory blockade at primary bone marrow transplantation promotes engraftment for secondary bone marrow transplantation after engraftment failure. J Immunol 181:6616-24
Ildstad, Suzanne T; Chilton, Paula M; Xu, Hong et al. (2005) Preconditioning of NOD mice with anti-CD8 mAb and costimulatory blockade enhances chimerism and tolerance and prevents diabetes, while depletion of alpha beta-TCR+ and CD4+ cells negates the effect. Blood 105:2577-84
Huang, Yiming; Rezzoug, Francine; Xu, Hong et al. (2005) NK cells play a critical role in the regulation of class I-deficient hemopoietic stem cell engraftment: evidence for NK tolerance correlates with receptor editing. J Immunol 175:3753-61
Huang, Yiming; Rezzoug, Francine; Chilton, Paula M et al. (2004) Matching at the MHC class I K locus is essential for long-term engraftment of purified hematopoietic stem cells: a role for host NK cells in regulating HSC engraftment. Blood 104:873-80
Xu, Hong; Exner, Beate G; Chilton, Paula M et al. (2004) CD45 congenic bone marrow transplantation: evidence for T cell-mediated immunity. Stem Cells 22:1039-48
Grimes, H Leighton; Schanie, Carrie L; Huang, Yiming et al. (2004) Graft facilitating cells are derived from hematopoietic stem cells and functionally require CD3, but are distinct from T lymphocytes. Exp Hematol 32:946-54
Mueller, Yvonne M; Cramer, Daniel E; Huang, Yiming et al. (2002) Hematopoietic stem cells from the marrow of mice treated with Flt3 ligand are significantly expanded but exhibit reduced engraftment potential. Transplantation 73:1177-85
Huang, Y; Cramer, D E; Ray, M B et al. (2001) The role of alphabeta- and gammadelta-T cells in allogenic donor marrow on engraftment, chimerism, and graft-versus-host disease. Transplantation 72:1907-14

Showing the most recent 10 out of 15 publications