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.
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