MARROW TRANSPLANT IN CANCER THERAPY T CELL RECOVERY

Summary

Principal Investigator: JULIA L contact HURWITZ
Abstract: 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.
Funding Period: 1992-08-01 - 2003-06-30
more information: NIH RePORT

Top Publications

  1. ncbi T cell epitope "hotspots" on the HIV Type 1 gp120 envelope protein overlap with tryptic fragments displayed by mass spectrometry
    Scott A Brown
    Department of Immunology, St Jude Children s Research Hospital, Memphis, Tennessee 38105, USA
    AIDS Res Hum Retroviruses 21:165-70. 2005
  2. ncbi HIV vaccine rationale, design and testing
    Karen S Slobod
    Department of Infectious Diseases, St Jude Children s Research Hospital, 332 N Lauderdale, Memphis, TN 38105, USA
    Curr HIV Res 3:107-12. 2005
  3. ncbi Multi-envelope HIV-1 vaccine devoid of SIV components controls disease in macaques challenged with heterologous pathogenic SHIV
    Xiaoyan Zhan
    Department of Infectious Diseases, St Jude Children s Research Hospital, 332 N Lauderdale, Memphis, TN 38105, USA
    Vaccine 23:5306-20. 2005
  4. ncbi A combination of 5-fluorouracil and membrane-bound antibody inhibits B-cell lymphoma growth in a mouse model system
    Mattia Bonsignori
    Leuk Lymphoma 48:406-9. 2007
  5. ncbi Epstein-Barr virus vaccine development: a lytic and latent protein cocktail
    Timothy D Lockey
    Department of Immunology, St Jude Children s Research Hospital, 332 N Lauderdale, Memphis, TN 38105, USA
    Front Biosci 13:5916-27. 2008
  6. pmc SHIV infection protects against heterologous pathogenic SHIV challenge in macaques: a gold-standard for HIV-1 vaccine development?
    Robert Sealy
    Department of Infectious Diseases, St Jude Children s Research Hospital, Memphis, TN 38105, USA
    Curr HIV Res 7:497-503. 2009

Detail Information

Publications6

  1. ncbi T cell epitope "hotspots" on the HIV Type 1 gp120 envelope protein overlap with tryptic fragments displayed by mass spectrometry
    Scott A Brown
    Department of Immunology, St Jude Children s Research Hospital, Memphis, Tennessee 38105, USA
    AIDS Res Hum Retroviruses 21:165-70. 2005
    ..Results are consistent with the suggestion that gp120 peptide location influences antigen processing, which, in turn, influences the specificity of immunodominant T cells...
  2. ncbi HIV vaccine rationale, design and testing
    Karen S Slobod
    Department of Infectious Diseases, St Jude Children s Research Hospital, 332 N Lauderdale, Memphis, TN 38105, USA
    Curr HIV Res 3:107-12. 2005
    ..Here, data relevant to the development of cocktail vaccines, designed to harness diverse, envelope-specific B-cell and T-cell responses, are reviewed...
  3. ncbi Multi-envelope HIV-1 vaccine devoid of SIV components controls disease in macaques challenged with heterologous pathogenic SHIV
    Xiaoyan Zhan
    Department of Infectious Diseases, St Jude Children s Research Hospital, 332 N Lauderdale, Memphis, TN 38105, USA
    Vaccine 23:5306-20. 2005
    ..The present report is the first to describe pathogenic SHIV disease control mediated by a heterologous HIV-1 vaccine, devoid of 89.6 or SIV derivatives...
  4. ncbi A combination of 5-fluorouracil and membrane-bound antibody inhibits B-cell lymphoma growth in a mouse model system
    Mattia Bonsignori
    Leuk Lymphoma 48:406-9. 2007
  5. ncbi Epstein-Barr virus vaccine development: a lytic and latent protein cocktail
    Timothy D Lockey
    Department of Immunology, St Jude Children s Research Hospital, 332 N Lauderdale, Memphis, TN 38105, USA
    Front Biosci 13:5916-27. 2008
    ..Results encourage further development of the cocktail vaccine strategy as a potentially powerful weapon against EBV infection and disease in humans...
  6. pmc SHIV infection protects against heterologous pathogenic SHIV challenge in macaques: a gold-standard for HIV-1 vaccine development?
    Robert Sealy
    Department of Infectious Diseases, St Jude Children s Research Hospital, Memphis, TN 38105, USA
    Curr HIV Res 7:497-503. 2009
    ..Perhaps this protective state may serve as a 'gold-standard' for HIV-1 vaccine development, as a similar degree of protection against immunodeficiency virus infections in humans would be much desired...