The goal of this application is to test the hypothesis that the T cells in bone marrow are qualitatively different than those in peripheral blood of normal mice and that after treatment with G-CSF, marrow T cells are mobilized into the blood. Preliminary data have suggested that marrow T cells have a markedly reduced capacity to induce lethal graft-versus-host disease after allogeneic marrow transplantation as compared to blood T cells but retain graft-versus-leukemia activity and an ability to facilitate engraftment. In order to test this hypothesis, the applicant will compare the surface markers, migration pathways, cytokine secretion patterns and capacity to induce lethal graft-versus-host disease, mediate graft-versus-leukemia effects and facilitate engraftment by using highly purified T cell subsets from the bone marrow and blood of normal mice and from mice treated with G-CSF. Purified donor T cell subsets will be obtained by flow cytometry and injected together with T cell-depleted marrow in lethally irradiated MHC matched or mismatched recipients. Graft-versus-leukemia activity will be measured with the use of the BCL1 B cell leukemia, and graft facilitation will be measured using purified stem cells. Results of this study should help the design of clinical protocols of allogeneic marrow or mobilized blood cell transplantation in attempts to reduce the risks of graft-versus-host disease and recurrent malignancy.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL058250-04
Application #
6139252
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Project Start
1997-01-01
Project End
2001-12-31
Budget Start
2000-01-01
Budget End
2000-12-31
Support Year
4
Fiscal Year
2000
Total Cost
$299,549
Indirect Cost
Name
Stanford University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
800771545
City
Stanford
State
CA
Country
United States
Zip Code
94305
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Dutt, Suparna; Baker, Jeanette; Kohrt, Holbrook E et al. (2011) CD8+CD44(hi) but not CD4+CD44(hi) memory T cells mediate potent graft antilymphoma activity without GVHD. Blood 117:3230-9
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Dutt, Suparna; Tseng, Diane; Ermann, Joerg et al. (2007) Naive and memory T cells induce different types of graft-versus-host disease. J Immunol 179:6547-54
Pillai, A; Teo, P; George, T et al. (2007) Alloantigen recognition is critical for CD8 T cell-mediated graft anti-tumor activity against murine BCL1 lymphoma after myeloablative bone marrow transplantation. Bone Marrow Transplant 40:487-97
Pillai, Asha B; George, Tracy I; Dutt, Suparna et al. (2007) Host NKT cells can prevent graft-versus-host disease and permit graft antitumor activity after bone marrow transplantation. J Immunol 178:6242-51
Takahashi, Tsuyoshi; Dejbakhsh-Jones, Sussan; Strober, Samuel (2006) Expression of CD161 (NKR-P1A) defines subsets of human CD4 and CD8 T cells with different functional activities. J Immunol 176:211-6

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