Preparation of genetically homogeneous antigen-specific thymidine kinase positive T-lymphocyte clones for the control of alloreactivity post-bone marrow transplantation

Hum Gene Ther. 2004 Jun;15(6):542-52. doi: 10.1089/104303404323141999.

Abstract

We have previously proposed the use of HLA-specific T-cell clones transduced with a suicide gene to produce an allogeneic effect that can be controlled after allogeneic bone marrow transplantation. Procedures described so far to obtain specific T-cells transduced with a suicide gene have led to the recovery of heterogeneous polyclonal T-cells with a limited level of purity. We have therefore developed an approach to select specific T-cell clones in which the suicide transgene is inserted at a unique site of the genome, and used it to produce CD(+)-cytotoxic HLA-DP-specific T-cell clones. Immunization was performed by a one-way mixed lymphocyte culture and responder T lymphocytes were transduced at day 16, 6 days after the second stimulation. Transductions were carried out using gibbon ape leukemia virus (GALV)-pseudotyped retroviral particles harboring a bicistronic Thy-1/TK vector produced by TEFLY GA16-pKM4 clone 34 packaging cells. Three to 5 days later, CD90 immunomagnetic selection and cloning were performed on the transduced T cells. Our results demonstrate that this procedure led to the recovery of T-cell clones, the majority of which had the expected specificity and a single site of transgene insertion. Such clonotransgenic T-cell populations represent suitable tools to drive a defined alloreaction that can be controlled after bone marrow transplantation.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, CD / immunology
  • Antigens, CD / metabolism
  • Bone Marrow Transplantation*
  • Cells, Cultured / transplantation
  • Clone Cells
  • Genes, Transgenic, Suicide / physiology*
  • HLA-DP Antigens / genetics
  • HLA-DP Antigens / immunology*
  • Humans
  • Immunization*
  • Immunomagnetic Separation
  • Immunotherapy
  • Leukemia Virus, Gibbon Ape / genetics
  • Lymphocyte Activation
  • Retroviridae / genetics
  • T-Lymphocytes / enzymology*
  • T-Lymphocytes / immunology
  • Thy-1 Antigens / immunology
  • Thy-1 Antigens / metabolism
  • Thymidine Kinase / metabolism*
  • Transduction, Genetic

Substances

  • Antigens, CD
  • HLA-DP Antigens
  • Thy-1 Antigens
  • Thymidine Kinase