This project is focused on studies of the mechanism of transplantation tolerance induced by mixed allogeneic and syngeneic bone marrow transplantation in a murine model. The major goal is to examine the influence of various genetic barriers on the induction of mixed chimerism and to determine the mechanism of tolerance induction. Experiments are designed to evaluate the role of T cell subsets and NK cells in resisting engraftment across selected MHC and non-MHC barriers, to determine the mechanism whereby tolerance is maintained by persistence of allogeneic lymphohematopoietic elements, to determine the ability of tolerance to withstand challenge with normal non-tolerant recipient strain T cells, to evaluate the susceptibility of chimeras prepared by a non-myeloablative conditioning regimen to the induction of GVHD by administration of donor T cells, and, to evaluate clonal deletion of the specific allo-reactive T cells by in vitro assays of cellular immunity and by detection of recipient T cells bearing donor reactive V-beta by flow cytometry. It is hoped that these studies will provide insight into the mechanisms of tolerance induced by a new non-lethal preparative regimen as well as into the potential application of this method for induction of specific transplantation tolerance across histocompatibility barriers.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Experimental Immunology Study Section (EI)
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Massachusetts General Hospital
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Sykes, M (2015) Immune tolerance in recipients of combined haploidentical bone marrow and kidney transplantation. Bone Marrow Transplant 50 Suppl 2:S82-6
Haspot, F; Li, H W; Lucas, C L et al. (2014) Allospecific rejection of MHC class I-deficient bone marrow by CD8 T cells. Am J Transplant 14:49-58
Strober, Samuel; Spitzer, Thomas R; Lowsky, Robert et al. (2011) Translational studies in hematopoietic cell transplantation: treatment of hematologic malignancies as a stepping stone to tolerance induction. Semin Immunol 23:273-81
Lucas, Carrie L; Workman, Creg J; Beyaz, Semir et al. (2011) LAG-3, TGF-?, and cell-intrinsic PD-1 inhibitory pathways contribute to CD8 but not CD4 T-cell tolerance induced by allogeneic BMT with anti-CD40L. Blood 117:5532-40
Hermanrud, Christina E; Lucas, Carrie L; Sykes, Megan et al. (2011) Expression and purification of soluble murine CD40L monomers and polymers in yeast Pichia pastoris. Protein Expr Purif 76:115-20
Levesque, V; Bardwell, P D; Shimizu, I et al. (2011) B-cell-dependent memory T cells impede nonmyeloablative mixed chimerism induction in presensitized mice. Am J Transplant 11:2322-31
Mollov, J L; Lucas, C L; Haspot, F et al. (2010) Recipient dendritic cells, but not B cells, are required antigen-presenting cells for peripheral alloreactive CD8+ T-cell tolerance. Am J Transplant 10:518-526
Nikolic, Boris; Onoe, Takashi; Takeuchi, Yasuo et al. (2010) Distinct requirements for achievement of allotolerance versus reversal of autoimmunity via nonmyeloablative mixed chimerism induction in NOD mice. Transplantation 89:23-32
Fehr, Thomas; Lucas, Carrie L; Kurtz, Josef et al. (2010) A CD8 T cell-intrinsic role for the calcineurin-NFAT pathway for tolerance induction in vivo. Blood 115:1280-7
Sykes, Megan (2009) Mechanisms of transplantation tolerance in animals and humans. Transplantation 87:S67-9

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