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Genetic engineering of virus-specific T cells with T-cell receptors recognizing minor histocompatibility antigens for clinical application
- Source :
- Haematologica. 93:1535-1543
- Publication Year :
- 2008
- Publisher :
- Ferrata Storti Foundation (Haematologica), 2008.
-
Abstract
- Background Donor lymphocyte infusion is an effective form of adoptive immunotherapy for hematologic malignancies after allogeneic stem cell transplantation. Graft-versus-host disease, however, often develops due to recognition of ubiquitously-expressed minor histocompatibility antigens. Transfer of T-cell receptors recognizing hematopoiesis-restricted minor histocompatibility antigens to virus-specific T cells may be a powerful anti-tumor therapy with a low risk of graft-versus-host disease. The purpose of this study was to develop an optimal T-cell receptors-encoding multi-cistronic retroviral vector and an efficient method for generating T-cell receptors-engineered virus-specific T cells.Design and Methods Retroviral vectors encoding the T-cell receptors for the hematopoiesis-restricted minor histocompatibility antigen HA-2 with and without selection markers were compared for T-cell receptors surface expression and HA-2-specific lysis. In addition, two different methods, i.e. peptide stimulation of CD8+ cells and Pro5® MHC pentamer-based isolation of antigen-specific T cells, were investigated for their efficiency to generate T-cell receptors-transduced virus-specific T cells.Results Bi-cistronic vectors without selection markers most efficiently mediated T-cell receptors surface expression and HA-2-specific lysis. Furthermore, both methods were useful for generating gene-modified cells, but the purity of virus-specific T cells was higher after pentamer isolation. Finally, the capacity of gene-modified cells to express the transgenic T-cell receptors at the cell surface markedly differed between virus-specific T cells and was correlated with lysis of relevant target cells.Conclusions Our data support T-cell receptors gene transfer to pentamer-isolated virus-specific T cells using bi-cistronic retroviral vectors and illustrate the relevance of selection of gene-modified T cells with appropriate transgenic T-cell receptors surface expression for clinical gene therapy.
- Subjects :
- biology
T-Lymphocytes
Genetic Vectors
Antigen presentation
Receptors, Antigen, T-Cell
CD1
Hematology
Streptamer
Protein Engineering
Major histocompatibility complex
Natural killer T cell
Cell biology
Minor Histocompatibility Antigens
Retroviridae
Immunology
biology.protein
Minor histocompatibility antigen
Humans
Cytotoxic T cell
Antigen-presenting cell
Cells, Cultured
Subjects
Details
- ISSN :
- 15928721 and 03906078
- Volume :
- 93
- Database :
- OpenAIRE
- Journal :
- Haematologica
- Accession number :
- edsair.doi.dedup.....bc8896faa43a432803a160e77fab5e51