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Ganciclovir treatment of herpes simplex thymidine kinase-transduced primary T lymphocytes: an approach for specific in vivo donor T-cell depletion after bone marrow transplantation?
| Content Provider | Semantic Scholar |
|---|---|
| Author | Tiberghien, Pierre Reynolds, Craig W. Keller, Joan Spence, Sally Deschaseaux, M. L. Certoux, Jean Marie Contassot, Emmanuel Murphy, William J. Lyons, Ruth G. Chiang, Yawen |
| Copyright Year | 1994 |
| Abstract | Allogeneic bone marrow transplantation (BMT) is associated with a severe complication--graft-versus-host disease (GVHD). Although effectively preventing GVHD, ex vivo T-lymphocyte marrow depletion unfortunately increases graft rejection and reduces the graft-versus-leukemia (GVL) effect. The ex vivo transfer of the herpes simplex thymidine kinase (HS-tk) suicide gene into T cells before their infusion with hematopoietic stem cells could allow for selective in vivo depletion of these T cells with ganciclovir (GCV) if subsequent GVHD was to occur. Thus, one could preserve the beneficial effects of the T cells on engraftment and tumor control in patients not experiencing severe GVHD. To obtain T cells specifically depleted by GCV, we transduced primary T cells with a retroviral vector containing the HS-tk and neomycin resistance (NeoR) genes. Gene transfer was performed by coculturing PHA +/- CD3- or alloantigen-stimulated purified T cells on an irradiated retroviral vector producer cell line or by incubating the T cells in supernatant from the producer. Subsequent culture in G418 for 1 week allowed for the selection of transduced cells. GCV treatment of interleukin-2-responding transduced and selected cells resulted in greater than 80% growth inhibition, whereas GCV treatment of control cells had no effect. Similarly, the allogeneic reactivity of HS-tk-transduced cells was specifically inhibited by GCV. Combining transduced and nontransduced T cells did not show a bystander effect, thus implying that all of the cells inhibited by GCV were indeed transduced. Lastly, studies involving the transduction of the HUT-78 (T-lymphoma) cell line suggest that stable expression of HS-tk can be maintained over 3 months in vitro in the absence of G418. In summary, we have established the feasibility of generating HS-tk-transduced T cells for subsequent in vivo transfer with hematopoietic stem cells and, if GVHD occurs, specific in vivo GCV-induced T-cell depletion in allogeneic BMT recipients. |
| File Format | PDF HTM / HTML |
| DOI | 10.1182/blood.V84.4.1333.1333 |
| PubMed reference number | 8049449 |
| Journal | Medline |
| Volume Number | 84 |
| Issue Number | 4 |
| Alternate Webpage(s) | http://www.bloodjournal.org/content/bloodjournal/84/4/1333.full.pdf?sso-checked=true |
| Alternate Webpage(s) | https://doi.org/10.1182/blood.V84.4.1333.1333 |
| Journal | Blood |
| Language | English |
| Access Restriction | Open |
| Content Type | Text |
| Resource Type | Article |
