title: Suicide gene therapy of graft-versus-host disease induced by central memory human T lymphocytes.
abstract: In allogeneic hematopoietic cell transplantation (allo-HCT), the immune recognition of host antigens by donor T lymphocytes leads to a beneficial graft-versus-leukemia (GvL) effect as well as to life-threatening graft-versus-host disease (GvHD). Genetic modification of T lymphocytes with a retroviral vector (RV) expressing the herpes simplex virus-thymidine kinase (TK) suicide gene confers selective sensitivity to the prodrug ganciclovir (GCV). In patients, the infusion of TK+ lymphocytes and the subsequent administration of GCV resulted in a time-wise modulation of antihost reactivity for a GvL effect, while controlling GvHD. Because activation required for genetic modification with RV may reduce antihost reactivity, we investigated the requirements for maximizing the potency of human TK+ lymphocytes. Whereas T-cell receptor triggering alone led to effector memory (EM) TK+ lymphocytes, the addition of CD28 costimulation through cell-sized beads resulted in the generation of central memory (CM) TK+ lymphocytes. In a quantitative model for GvHD using nonobese diabetic/severely combined immunodeficient mice, CM TK+ lymphocytes were more potent than EM TK+ lymphocytes. GCV administration efficiently controlled GvHD induced by CM TK+ lymphocytes. These results warrant the clinical investigation of CM suicide gene-modified human T lymphocytes for safe and effective allo-HCT.
authors.affiliation: Experimental Hematology Laboratory, Cancer Immunotherapy and Gene Therapy Program, Università Vita-Salute S. Raffaele, Pathology Unit, Telethon Institute for Gene Therapy, Milan, Italy.
authors.forename: Attilio
authors.initials: A
authors.lastname: Bondanza
authors.forename: Veronica
authors.initials: V
authors.lastname: Valtolina
authors.forename: Zulma
authors.initials: Z
authors.lastname: Magnani
authors.forename: Maurilio
authors.initials: M
authors.lastname: Ponzoni
authors.forename: Katharina
authors.initials: K
authors.lastname: Fleischhauer
authors.forename: Mark
authors.initials: M
authors.lastname: Bonyhadi
authors.forename: Catia
authors.initials: C
authors.lastname: Traversari
authors.forename: Francesca
authors.initials: F
authors.lastname: Sanvito
authors.forename: Salvatore
authors.initials: S
authors.lastname: Toma
authors.forename: Marina
authors.initials: M
authors.lastname: Radrizzani
authors.forename: Simona
authors.initials: S
authors.lastname: La Seta-Catamancio
authors.forename: Fabio
authors.initials: F
authors.lastname: Ciceri
authors.forename: Claudio
authors.initials: C
authors.lastname: Bordignon
authors.forename: Chiara
authors.initials: C
authors.lastname: Bonini
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage; D018106:CD28 Antigens / Q000276:immunology; D005260:Female; D015774:Ganciclovir / Q000008:administration & dosage; D041722:Genes, Transgenic, Suicide / Q000235:genetics / Q000276:immunology*; D015316:Genetic Therapy; D006086:Graft vs Host Disease / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D020544:Graft vs Leukemia Effect / Q000235:genetics / Q000276:immunology; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007156:Immunologic Memory; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D012190:Retroviridae; D018139:Simplexvirus / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology* / Q000637:transplantation; D013937:Thymidine Kinase / Q000235:genetics / Q000276:immunology*; D014184:Transplantation, Homologous; D014764:Viral Proteins / Q000235:genetics / Q000276:immunology*
chemical_list: D000998:Antiviral Agents; D018106:CD28 Antigens; D011948:Receptors, Antigen, T-Cell; D014764:Viral Proteins; D013937:Thymidine Kinase; D015774:Ganciclovir