title: Engineering human peripheral blood stem cell grafts that are depleted of naïve T cells and retain functional pathogen-specific memory T cells.
abstract: Graft-versus-host disease (GVHD) is a frequent major complication of allogeneic hematopoietic cell transplantation (HCT). Approaches that selectively deplete T cells that cause GVHD from allogeneic stem cell grafts and preserve T cells specific for pathogens may improve HCT outcomes. It has been hypothesized that the majority of T cells that can cause GVHD reside within the naïve T cell (TN) subset, and previous studies performed in mouse models and with human cells in vitro support this hypothesis. As a prelude to translating these findings to the clinic, we developed and evaluated a novel 2-step clinically compliant procedure for manipulating peripheral blood stem cells (PBSC) to remove TN, preserve CD34(+) hematopoietic stem cells, and provide for a fixed dose of memory T cells (TM) that includes T cells with specificity for common opportunistic pathogens encountered after HCT. Our studies demonstrate effective and reproducible performance of the immunomagnetic cell selection procedure for depleting TN. Moreover, after cell processing, the CD45RA-depleted PBSC products are enriched for CD4(+) and CD8(+) TM with a central memory phenotype and contain TM cells that are capable of proliferating and producing effector cytokines in response to opportunistic pathogens.
authors: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Department of Pediatrics, University of Washington, Seattle, Washington. Electronic address: mbleakle@fhcrc.org.
authors: Marie
authors: M
authors: Bleakley
authors: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors: Shelly
authors: S
authors: Heimfeld
authors: Seattle Cancer Care Alliance, Seattle, Washington.
authors: Lori A
authors: LA
authors: Jones
authors: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Department of Medicine, University of Washington, Seattle, Washington.
authors: Cameron
authors: C
authors: Turtle
authors: Department of Laboratory Medicine, Yale University School of Medicine, New Haven, Connecticut.
authors: Diane
authors: D
authors: Krause
authors: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Department of Medicine, University of Washington, Seattle, Washington.
authors: Stanley R
authors: SR
authors: Riddell
authors: Department of Hematology, Yale School of Medicine, New Haven, Connecticut.
authors: Warren
authors: W
authors: Shlomchik
mesh_terms: D018952:Antigens, CD34 / Q000235:genetics / Q000276:immunology; D000956:Antigens, Viral / Q000276:immunology*; D015870:Gene Expression; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000276:immunology; D006801:Humans; D007156:Immunologic Memory; D018189:Immunomagnetic Separation; D016130:Immunophenotyping; D017493:Leukocyte Common Antigens / Q000235:genetics / Q000276:immunology; D008212:Lymphocyte Depletion / Q000379:methods; D019151:Peptide Library; D016176:T-Lymphocyte Subsets / Q000166:cytology* / Q000276:immunology; D013601:T-Lymphocytes / Q000145:classification / Q000166:cytology* / Q000276:immunology; D023822:Tissue Engineering / Q000379:methods*
chemical_list: D018952:Antigens, CD34; D000956:Antigens, Viral; D019151:Peptide Library; D017493:Leukocyte Common Antigens
keywords: Graft engineering; Graft-versus-host disease; Immune reconstitution; Memory T cells; Naïve T cells; Selective T cell depletion