title: Lowest numbers of primary CD8(+) T cells can reconstitute protective immunity upon adoptive immunotherapy.
abstract: Patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) are threatened by potentially lethal viral manifestations like cytomegalovirus (CMV) reactivation. Because the success of today's virostatic treatment is limited by side effects and resistance development, adoptive transfer of virus-specific memory T cells derived from the stem cell donor has been proposed as an alternative therapeutic strategy. In this context, dose minimization of adoptively transferred T cells might be warranted for the avoidance of graft-versus-host disease (GVHD), in particular in prophylactic settings after T-cell-depleting allo-HSCT protocols. To establish a lower limit for successful adoptive T-cell therapy, we conducted low-dose CD8(+) T-cell transfers in the well-established murine Listeria monocytogenes (L.m.) infection model. Major histocompatibility complex-Streptamer-enriched antigen-specific CD62L(hi) but not CD62L(lo) CD8(+) memory T cells proliferated, differentiated, and protected against L.m. infections after prophylactic application. Even progenies derived from a single CD62L(hi) L.m.-specific CD8(+) T cell could be protective against bacterial challenge. In analogy, low-dose transfers of Streptamer-enriched human CMV-specific CD8(+) T cells into allo-HSCT recipients led to strong pathogen-specific T-cell expansion in a compassionate-use setting. In summary, low-dose adoptive T-cell transfer (ACT) could be a promising strategy, particularly for prophylactic treatment of infectious complications after allo-HSCT.
authors.affiliation: Institute for Medical Microbiology, Immunology and Hygiene, Technische Universität München, Munich, Germany; Focus Group "Clinical Cell Processing and Purification," Institute for Advanced Study, Technische Universität München, Munich, Germany;
authors.forename: Christian
authors.initials: C
authors.lastname: Stemberger
authors.affiliation: Institute for Medical Microbiology, Immunology and Hygiene, Technische Universität München, Munich, Germany;
authors.forename: Patricia
authors.initials: P
authors.lastname: Graef
authors.affiliation: Institute for Transfusion Medicine, German Red Cross Blood Donation Service North-East, Dresden, Germany;
authors.forename: Marcus
authors.initials: M
authors.lastname: Odendahl
authors.affiliation: Clinical Cooperation Group "Immune Monitoring," and.
authors.forename: Julia
authors.initials: J
authors.lastname: Albrecht
authors.affiliation: Institute for Medical Microbiology, Immunology and Hygiene, Technische Universität München, Munich, Germany;
authors.forename: Georg
authors.initials: G
authors.lastname: Dössinger
authors.affiliation: Institute for Medical Microbiology, Immunology and Hygiene, Technische Universität München, Munich, Germany;
authors.forename: Florian
authors.initials: F
authors.lastname: Anderl
authors.affiliation: Institute for Medical Microbiology, Immunology and Hygiene, Technische Universität München, Munich, Germany;
authors.forename: Veit R
authors.initials: VR
authors.lastname: Buchholz
authors.affiliation: Clinical Cooperation Group "Antigen-specific Immunotherapy," Helmholtz Center Munich (Neuherberg) and Technische Universität München, Munich, Germany; Institute for Virology, Technische Universität München and Helmholtz Zentrum München, Munich, Germany;
authors.forename: Georg
authors.initials: G
authors.lastname: Gasteiger
authors.affiliation: Institute for Medical Microbiology, Immunology and Hygiene, Technische Universität München, Munich, Germany; Clinical Cooperation Group "Antigen-specific Immunotherapy," Helmholtz Center Munich (Neuherberg) and Technische Universität München, Munich, Germany;
authors.forename: Matthias
authors.initials: M
authors.lastname: Schiemann
authors.affiliation: Department of Internal Medicine II, University of Würzburg, Würzburg, Germany;
authors.forename: Götz U
authors.initials: GU
authors.lastname: Grigoleit
authors.affiliation: Clinic of Paediatric Oncology, Haematology and Clinical Immunology, Centre for Child and Adolescent Health, Medical Faculty, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany;
authors.forename: Friedhelm R
authors.initials: FR
authors.lastname: Schuster
authors.affiliation: Clinic of Paediatric Oncology, Haematology and Clinical Immunology, Centre for Child and Adolescent Health, Medical Faculty, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany;
authors.forename: Arndt
authors.initials: A
authors.lastname: Borkhardt
authors.affiliation: Paediatric Blood and Marrow Transplantation Program, University Medical Center Utrecht (Wilhelmina Children´s Hospital), Utrecht, The Netherlands;
authors.forename: Birgitta
authors.initials: B
authors.lastname: Versluys
authors.affiliation: Institute for Transfusion Medicine, German Red Cross Blood Donation Service North-East, Dresden, Germany; Institute of Immunology, Medical Faculty, Dresden University of Technology, Dresden and Center for Regenerative Therapies Dresden, Dresden, Germany;
authors.forename: Torsten
authors.initials: T
authors.lastname: Tonn
authors.affiliation: Institute for Transfusion Medicine and Immunohematology, German Red Cross Blood Donor Service, Johann Wolfgang Goethe University, Frankfurt, Germany;
authors.forename: Erhard
authors.initials: E
authors.lastname: Seifried
authors.affiliation: Department of Internal Medicine II, University of Würzburg, Würzburg, Germany;
authors.forename: Hermann
authors.initials: H
authors.lastname: Einsele
authors.affiliation: Stage Cell Therapeutics, Göttingen, Germany; and.
authors.forename: Lothar
authors.initials: L
authors.lastname: Germeroth
authors.affiliation: Institute for Medical Microbiology, Immunology and Hygiene, Technische Universität München, Munich, Germany; Focus Group "Clinical Cell Processing and Purification," Institute for Advanced Study, Technische Universität München, Munich, Germany; Clinical Cooperation Group "Immune Monitoring," and Clinical Cooperation Group "Antigen-specific Immunotherapy," Helmholtz Center Munich (Neuherberg) and Technische Universität München, Munich, Germany; German Center for Infection Research, Munich, Germany.
authors.forename: Dirk H
authors.initials: DH
authors.lastname: Busch
authors.affiliation: Institute for Medical Microbiology, Immunology and Hygiene, Technische Universität München, Munich, Germany; Clinical Cooperation Group "Immune Monitoring," and Clinical Cooperation Group "Antigen-specific Immunotherapy," Helmholtz Center Munich (Neuherberg) and Technische Universität München, Munich, Germany; German Center for Infection Research, Munich, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Neuenhahn
mesh_terms: D000293:Adolescent; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002454:Cell Differentiation; D049109:Cell Proliferation; D002648:Child; D003587:Cytomegalovirus / Q000302:isolation & purification; D003586:Cytomegalovirus Infections / Q000276:immunology* / Q000378:metabolism / Q000628:therapy; D006086:Graft vs Host Disease / Q000276:immunology* / Q000378:metabolism / Q000628:therapy; D018380:Hematopoietic Stem Cell Transplantation; D018398:Homeodomain Proteins / Q000502:physiology; D006801:Humans; D007114:Immunization; D016219:Immunotherapy, Adoptive; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000502:physiology; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000276:immunology* / Q000378:metabolism / Q000628:therapy; D016511:Severe Combined Immunodeficiency / Q000276:immunology* / Q000378:metabolism / Q000628:therapy; D014184:Transplantation, Homologous; D014775:Virus Activation
chemical_list: D018398:Homeodomain Proteins; C064658:RAG-1 protein; D010047:Ovalbumin