Suicide gene therapy of graft-versus-host disease induced by central memory human T lymphocytes.
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.
Bondanza
Attilio
A
Experimental Hematology Laboratory, Cancer Immunotherapy and Gene Therapy Program, Università Vita-Salute S. Raffaele, Pathology Unit, Telethon Institute for Gene Therapy, Milan, Italy.
Valtolina
Veronica
V
Magnani
Zulma
Z
Ponzoni
Maurilio
M
Fleischhauer
Katharina
K
Bonyhadi
Mark
M
Traversari
Catia
C
Sanvito
Francesca
F
Toma
Salvatore
S
Radrizzani
Marina
M
La Seta-Catamancio
Simona
S
Ciceri
Fabio
F
Bordignon
Claudio
C
Bonini
Chiara
C
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*
D000998:Antiviral Agents; D018106:CD28 Antigens; D011948:Receptors, Antigen, T-Cell; D014764:Viral Proteins; D013937:Thymidine Kinase; D015774:Ganciclovir