Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.1.21 (thymidine kinase)
 7,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Donor T cells have a critical role in promoting engraftment after allogeneic bone marrow transplantation (BMT), but also cause graft versus host disease (GVHD). Ex vivo T cell depletion has been an effective strategy to reduce GVHD but has been associated with impaired alloengraftment and host immunity. Using an MHC-mismatched murine model, we have examined an alternative approach to GVHD prevention whereby donor T cells are selectively eliminated in vivo after BMT using transgenic T cells in which a thymidine kinase (TK) suicide gene is targeted to the T cell. Lethally irradiated AKR/J (H-2k) mice transplanted with TCD C57BL/6 (B6)(H-2b) bone marrow (BM) plus B6 TK+ T cells and then treated with GCV post-BMT had significantly less GVHD severity and improved immune reconstitution compared to untreated mice, providing proof of principle that this strategy could mitigate GVHD. To assess the impact of GCV administration on alloengraftment, sublethally irradiated AKR mice were transplanted with TCD B6 BM alone or admixed with limiting numbers (5 x 10(5)) of B6 TK+ T cells. When tested 3-4 weeks post-transplant, control TCD BM mice all rejected their grafts. Conversely, > 80% of GCV-treated mice had sustained donor T cell engraftment comparable to what was observed in untreated animals. Notably, GCV-treated mice were more likely to have mixed T cell chimerism early post-BMT than untreated animals, however, nearly all GCV-treated mice progressed to complete donor T cell engraftment by 2-3 months post-transplant. Preservation of engraftment was critically dependent upon the GCV administration schedule and required that GCV be delayed for at least one week post-transplant. These studies demonstrate that specific incorporation of a suicide gene into donor T cells is a viable strategy that can be employed to reduce GVHD without compromising alloengraftment.
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PMID:Regulation of alloresponses after bone marrow transplantation using donor T cells expressing a thymidine kinase suicide gene. 1248

Administration of herpes simplex thymidine kinase (HSV-tk)-expressing, gene-modified T cells (GMCs) with T cell-depleted bone marrow transplantation (TCD-BMT) can allow modulation of posttransplantation alloreactivity. Twelve patients received 2 x 10(5) to 2 x 10(6) CD3+ donor GMCs per kilogram with HLA-identical sibling TCD-BMT. Despite extensive T cell depletion of bone marrow, an intensive conditioning regimen, and immunosuppressive graft-versus-host disease (GvHD) prophylaxis, infusion at the time of TCD-BMT of this low number of GMCs sufficed to induce a rapid GMC-specific immune response, as detected by interferon- enzyme- linked immunospot assay in six of eight patients, preferentially targeting HSV-tk. Maximal responses were reached early (median time, 49 [35-68] days post-BMT), with a subsequent rapid and significant decrease in five of six evaluable patients. Immune responses were negatively correlated with the maximal circulating GMC counts. However, such immune response did not result in the elimination of circulating GMCs and was not associated with measurable ex vivo cytotoxic activity against GMCs. Furthermore, alloreactive GMCs still could induce GCV-sensitive GvHD in one patient despite an ongoing immune response. Overall, infusion of HSV-tk-expressing GMCs at the time of BMT results in an early immune response. Such immune response may be altered and may not prevent persistent GCV-sensitive alloreactivity.
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PMID:Early immune response against retrovirally transduced herpes simplex virus thymidine kinase-expressing gene-modified T cells coinfused with a T cell-depleted marrow graft: an altered immune response? 1881 Jul 97