title: Cytotoxic minor histocompatibility antigen HA-1-specific CD8+ effector memory T cells: artificial APCs pave the way for clinical application by potent primary in vitro induction.
abstract: Induction of cytotoxic T lymphocytes (CTLs) for treatment of relapsed leukemia after allogeneic stem-cell transplantation is hindered by the laborious and time-consuming procedure of generating dendritic cells for antigen presentation. Artificial antigen-presenting cells (aAPCs) offer the advantage of being readily available in sufficient numbers, thus allowing for a highly standardized in vitro induction of CTLs. We generated aAPCs coated with anti-CD28 antibody (Ab) and either high-density (HD) or low-density (LD) major histocompatibility complex (MHC) class I molecules loaded with HA-1(H), a nonapeptide derived from the hematopoiesis-restricted minor histocompatibility antigen HA-1. HD- and LD-aAPCs potently induced HA-1(H)-specific CD8+ CTLs from untouched CD8+ T cells of healthy donors. CTLs were subsequently purified by magnetic-activated cell sorting. HD- as well as LD-aAPC-induced CTLs exerted high HA-1H-specific cytotoxicity, resembled T(c)1 effector memory cells, survived a long time in vitro, and were expanded by a factor varying between 8.2 x 10(4) and 51 x 10(4). The T-cell receptor (TCR) repertoire of HA-1H tetramer-positive CTLs was oligoclonal with a prominent usage of Vbeta6. The TCR repertoire of tetramer-positive CTLs was distinct from and more restricted than that of tetramer-negative cells. These findings indicate that aAPCs are attractive tools for the ex vivo generation of HA-1H-specific CTLs suitable for immunotherapy of relapsed leukemia.
authors.affiliation: University Children's Hospital Tübingen, Hoppe-Seyler-Str 1, D-72076 Tübingen, Germany. knschilb@med.unituebingen.de
authors.forename: Karin
authors.initials: K
authors.lastname: Schilbach
authors.forename: Gunter
authors.initials: G
authors.lastname: Kerst
authors.forename: Steffen
authors.initials: S
authors.lastname: Walter
authors.forename: Matthias
authors.initials: M
authors.lastname: Eyrich
authors.forename: Dorothee
authors.initials: D
authors.lastname: Wernet
authors.forename: Rupert
authors.initials: R
authors.lastname: Handgretinger
authors.forename: Weidong
authors.initials: W
authors.lastname: Xie
authors.forename: Hans-Georg
authors.initials: HG
authors.lastname: Rammensee
authors.forename: Ingo
authors.initials: I
authors.lastname: Müller
authors.forename: Hans-Jörg
authors.initials: HJ
authors.lastname: Bühring
authors.forename: Dietrich
authors.initials: D
authors.lastname: Niethammer
mesh_terms: D019264:Adoptive Transfer / Q000379:methods*; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000637:transplantation*; D001402:B-Lymphocytes / Q000166:cytology; D001782:Blood Donors; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000637:transplantation; D002461:Cell Line, Transformed; D002648:Child; D005260:Female; D006801:Humans; D007156:Immunologic Memory / Q000276:immunology; D066298:In Vitro Techniques; D008297:Male; D015778:Minor Histocompatibility Antigens / Q000276:immunology*; D009842:Oligopeptides / Q000276:immunology*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000276:immunology* / Q000628:therapy*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000637:transplantation
chemical_list: C110615:HA-1 antigen; D015778:Minor Histocompatibility Antigens; D009842:Oligopeptides