Application of donor lymphocytes expressing a suicide gene for early GVL induction and later control of GVH reactions after bone-marrow transplantation.
Allogeneic hematopoietic stem cell transplantation (allo-SCT) is the treatment of choice for many malignant diseases. It is recognized that the curative potential of allo-SCT relates closely to the immune advantage conferred by allogeneic T-lymphocytes. In allo-SCT donor T-lymphocytes favor engraftment, provide early immune reconstitution, and fight the underlying malignancy--the so-called graft-vs-leukemia (GVL) effect. These benefits are counterbalanced by the occurrence of a life-threatening disease: graft-vs-host disease (GVHD). A suicide gene encodes a protein able to convert a nontoxic prodrug into a toxic product. Therefore, cells expressing the suicide gene become selectively sensitive to the prodrug. The transfer of a suicide gene into donor lymphocytes could allow, upon administration of the prodrug, the in vivo selective elimination of transduced lymphocytes, resulting in the switch-off of GVHD, thus allowing full exploitation of the curative potential of donor T-lymphocytes in the context of allo-SCT. In this chapter the rationale, the materials, and the methods of the suicide-gene strategy with human T-lymphocytes are described.
Bondanza
Attilio
A
Experimental Hematology Laboratory, Cancer Immunotherapy and Gene Therapy Program, San Raffaele Scientific Institute, Milan, Italy.
Ciceri
Fabio
F
Bonini
Chiara
C
D019264:Adoptive Transfer; D016026:Bone Marrow Transplantation / Q000276:immunology*; D041722:Genes, Transgenic, Suicide / Q000235:genetics*; D015316:Genetic Therapy; D006086:Graft vs Host Disease / Q000235:genetics / Q000276:immunology*; D020544:Graft vs Leukemia Effect / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007167:Immunotherapy; D007938:Leukemia / Q000235:genetics / Q000276:immunology / Q000628:therapy; D008214:Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D012190:Retroviridae / Q000235:genetics; D014019:Tissue Donors; D014184:Transplantation, Homologous / Q000276:immunology