The long-term objective of this research is to develop immunotherapies for preventing viral infections among recipients of allogeneic bone marrow transplants. The growing use of matched unrelated-donor and mismatched related-donor bone marrow transplantation has increased the risk of graft-versus-host disease (GVHD), in which the donor T cells respond to recipient human leukocyte antigens (HLA). Such allogeneic grafts are routinely depleted of mature T cells to prevent GVHD, rendering recipients vulnerable to viral infections until the T-cell response has been reconstituted. Viral infections and disease could be prevented if memory T cells from donor peripheral blood mononuclear cells (PBMC) could be made safe for transfer to BMT recipients. Previous funding has allowed the development of a novel depletion strategy in which T cells responsive to host HLA are selectively removed from donor PBMC. Donor cells are co-cultivated in vitro with host-derived antigen presenting cells, and donor cells responding to this stimulation are removed based on cell size and phenotype. Fluorescence-activated cell sorting stringently depletes host-reactive T cells, including those that express activation antigens only weakly. Studies proposed here test the hypothesis that allogeneic donor T cells can be depleted of GVHD potential while preserving virus-specific activity.
Specific aims to test this hypothesis are to: 1. Implement host-specific T-cell depletion (HSTD) technology for clinical application. 2. Determine the safety of administering escalating doses of HSTD cells to allogeneic bone marrow transplant recipients. 3. Characterize T cell function transferred to BMT recipients following HSTD infusions. Safe delivery of mature T cells with broad anti-viral specificities may protect recipients of allogeneic BMT from the morbidity and mortality of viral infections. Ultimately, clinical availability of donor T cells free of GVHD potential may enhance the success and applicability of bone marrow transplantation. The PI and co-PI have demonstrated their ability to translate basic laboratory studies into testable clinical hypotheses at St. Jude Children's Research Hospital (SJCRH), predicting successful implementation of the proposed studies.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA057419-07
Application #
2907993
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Program Officer
Mccarthy, Susan A
Project Start
1992-08-01
Project End
2002-06-30
Budget Start
1999-07-19
Budget End
2000-06-30
Support Year
7
Fiscal Year
1999
Total Cost
Indirect Cost
Name
St. Jude Children's Research Hospital
Department
Type
DUNS #
067717892
City
Memphis
State
TN
Country
United States
Zip Code
38105
Sealy, Robert; Zhan, Xiaoyan; Lockey, Timothy D et al. (2009) SHIV infection protects against heterologous pathogenic SHIV challenge in macaques: a gold-standard for HIV-1 vaccine development? Curr HIV Res 7:497-503
Lockey, Timothy D; Zhan, Xiaoyan; Surman, Sherri et al. (2008) Epstein-Barr virus vaccine development: a lytic and latent protein cocktail. Front Biosci 13:5916-27
Bonsignori, Mattia; D'Costa, Sybil; Surman, Sherri et al. (2007) A combination of 5-fluorouracil and membrane-bound antibody inhibits B-cell lymphoma growth in a mouse model system. Leuk Lymphoma 48:406-9
Brown, Scott A; Lockey, Timothy D; Slaughter, Clive et al. (2005) T cell epitope ""hotspots"" on the HIV Type 1 gp120 envelope protein overlap with tryptic fragments displayed by mass spectrometry. AIDS Res Hum Retroviruses 21:165-70
Slobod, Karen S; Coleclough, Chris; Bonsignori, Mattia et al. (2005) HIV vaccine rationale, design and testing. Curr HIV Res 3:107-12
Zhan, Xiaoyan; Martin, Louis N; Slobod, Karen S et al. (2005) Multi-envelope HIV-1 vaccine devoid of SIV components controls disease in macaques challenged with heterologous pathogenic SHIV. Vaccine 23:5306-20
D'Costa, Sybil S; Hurwitz, Julia L (2003) Phytohemagglutinin inhibits lymphoid tumor growth in vitro and in vivo. Leuk Lymphoma 44:1785-91
Zhan, Xiaoyan; Brown, Brita; Slobod, Karen S et al. (2003) Inhibition of ex vivo-expanded cytotoxic T-lymphocyte function by high-dose cyclosporine. Transplantation 76:739-40
D'Costa, Sybil; Hurwitz, Julia L (2003) Customized mitogen or antibody treatments enhance the sensitivity of lymphoid tumors to 5-fluorouracil in vitro and in vivo. Leuk Lymphoma 44:841-7
D'Costa, Sybil; Slobod, Karen S; Hurwitz, Julia L (2003) Do the immunosuppressive drugs used as treatment for graft-versus-host disease directly inhibit lymphoid tumor cell growth? Leuk Lymphoma 44:139-42

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