In the setting of allogeneic bone marrow transplantation (alloBMT), donor T cells mediate a beneficial graft-versus-leukemia (GVL) effect and prevent marrow rejection; however, donor T cells can also generate graft-versus-host disease (GVHD). We have identified that donor CD8+ T cells of Tc2 phenotype, defined by their secretion of type II cytokines and their mediation of target cell lysis primarily via the perforin pathway, are capable of mediating a GVL effect and preventing marrow rejection with limited GVHD. Current efforts are evaluating the use of such Tc2 cells in murine models of non-myeloablative alloBMT. In addition, pilot clinical trials evaluating the effect of donor Tc2 cells in the setting of human alloBMT are being developed. The overall goal of this work is to improve the anti-leukemic effects of alloBMT, to reduce the morbidity and mortality associated with GVHD, and to extend the application of alloBMT to those patients lacking an HLA-matched donor.In the autologous setting, T cells may also play a role in mediating anti-leukemic effects. Murine models are being developed to evaluate the role of the fas cytolytic pathway in T cell-mediated syngeneic GVL effects. In addition, studies in CLL patients are evaluating the differential role of type I versus type II cytokines on CLL cell utilization of the fas pathway. These murine and pre-clinical human studies may provide a basis for modulation of the fas pathway for the treatment of leukemia. In addition, we have developed methodologies to purge CLL cells from peripheral T cell populations. Protocols to evaluate whether such autologous T cells might improve immune recovery after purine analog-based chemotherapy are being developed.

Agency
National Institute of Health (NIH)
Institute
Division of Clinical Sciences - NCI (NCI)
Type
Intramural Research (Z01)
Project #
1Z01SC010288-03
Application #
6433441
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
2000
Total Cost
Indirect Cost
Name
Clinical Sciences
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Granville, Courtney A; Memmott, Regan M; Balogh, Andria et al. (2009) A central role for Foxp3+ regulatory T cells in K-Ras-driven lung tumorigenesis. PLoS One 4:e5061
Mossoba, Miriam E; Walia, Jagdeep S; Rasaiah, Vanessa I et al. (2008) Tumor protection following vaccination with low doses of lentivirally transduced DCs expressing the self-antigen erbB2. Mol Ther 16:607-17
Vasu, Sumithira; Leitman, Susan F; Tisdale, John F et al. (2008) Donor demographic and laboratory predictors of allogeneic peripheral blood stem cell mobilization in an ethnically diverse population. Blood 112:2092-100
Pavletic, Steven Z; Fowler, Daniel H (2008) ""Regulating"" rheumatoid arthritis via autotransplantation. Blood 111:4838-9
Hardy, Nancy M; Hakim, Frances; Steinberg, Seth M et al. (2007) Host T cells affect donor T cell engraftment and graft-versus-host disease after reduced-intensity hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 13:1022-30
Snyder, James T; Shen, Jijia; Azmi, Hooman et al. (2007) Direct inhibition of CD40L expression can contribute to the clinical efficacy of daclizumab independently of its effects on cell division and Th1/Th2 cytokine production. Blood 109:5399-406
Sato, Takeya; Neschadim, Anton; Konrad, Manfred et al. (2007) Engineered human tmpk/AZT as a novel enzyme/prodrug axis for suicide gene therapy. Mol Ther 15:962-70
Imanguli, Matin M; Atkinson, Jane C; Harvey, Kristen E et al. (2007) Changes in salivary proteome following allogeneic hematopoietic stem cell transplantation. Exp Hematol 35:184-92
Subramaniam, D S; Fowler, D H; Pavletic, S Z (2007) Chronic graft-versus-host disease in the era of reduced-intensity conditioning. Leukemia 21:853-9
Liang, Sheng-Ben; Yoshimitsu, Makoto; Poeppl, Armando et al. (2007) Multiple reduced-intensity conditioning regimens facilitate correction of Fabry mice after transplantation of transduced cells. Mol Ther 15:618-27

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