Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018133 (graft-versus-host disease)
 18,032 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Graft-versus-host disease (GvHD), a major complication of allogeneic bone marrow transplantation, has been ascribed to mature T cells in the graft. Because T cells play an important role in engraftment of the bone marrow and decrease the probability of relapse of leukemia, a treatment strategy was developed to preserve the benefits of T cells in the graft and to control the severe complications of GvHD. This can be accomplished by the genetic modification of donor T cells with a suicide gene that allows their selective in vivo elimination and subsequently the abrogation of GvHD. For clinical benefit the alloreactivity of herpes simplex virus thymidine kinase (HSV-TK) gene-transduced T cells should be retained. Therefore, we investigated the influence of gene transduction and the selection procedure on T cells. We demonstrated that activation and culturing of T cells reduce their capacity to induce lethal GvHD in an allogeneic rat bone marrow transplantation model. Furthermore, positive immunomagnetic selection of gene-transduced T cells resulted in loss of the GvHD-inducing capacity of HSV-TK(+) T cells directly after MACS (magnetic cell sorting) selection; this loss could be recovered by a 1-day expansion of the selected T cells. No effect on alloreactivity was observed to be caused by the gene transduction procedure. Our study resulted in the development of an optimized culture and gene transduction protocol with preservation of T cell alloreactivity. Treatment of transplanted rats with ganciclovir resulted in a rapid reduction in the number of HSV-TK(+) T cells in the peripheral blood and in increased survival of the animals.
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PMID:Reduced graft-versus-host disease-inducing capacity of T cells after activation, culturing, and magnetic cell sorting selection in an allogeneic bone marrow transplantation model in rats. 1181 76

The immunosuppressive drug cyclosporin A (CsA) represents the standard preventive treatment of graft-versus-host disease (GVHD), the main complication of allogeneic hematopoietic stem cell transplantation (HSCT). However, its efficacy is only partial and many patients develop lethal GVHD despite CsA. A strategy of genetic immunosuppression based on conditional elimination of donor T cells expressing the Herpes simplex type 1 thymidine kinase (TK) suicide gene was recently developed. In this system, ganciclovir (GCV) selectively kills dividing but not quiescent TK T cells. Since CsA is known to have a cytostatic effect on T cells, it could negatively interfere with the division-dependent TK gene therapy. We thus tested whether administration of CsA would antagonize elimination of alloreactive donor TK T cells mediated by GCV in a murine model of GVHD. In vivo experiments revealed that, contrary to GCV, CsA only transiently controlled alloactivation-induced T cell proliferation, and likewise could not prevent lethal GVHD. When T cells resumed proliferation under CsA, they were however still sensitive to GCV. Survival, as well as immune reconstitution, was excellent in mice treated with GCV alone or in combination with CsA. These observations should help to design improved suicide gene therapy trials in the field of allogeneic HSCT.
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PMID:Effect of combined cytostatic cyclosporin A and cytolytic suicide gene therapy on the prevention of experimental graft-versus-host disease. 1185 23

Retroviral transfer of Herpes simplex virus thymidine kinase to T cells has been used to confer sensitivity to the antiviral agent ganciclovir. This has allowed therapeutic approaches to be developed in which T cells mediating graft-versus-host disease after bone marrow transplantation can be selectively eliminated by the administration of ganciclovir. Although the strategy has been shown to be generally successful in early clinical trials, there are concerns about possible resistance to ganciclovir and the risk of myelosuppressive side-effects at the doses required to induce T cell suicide. We have incorporated the enhanced mutant HSV-TKSR39 into retroviral vectors tailored to exhibit high levels of expression in T cells and have used protocols optimized for the transduction and selection of primary lymphocytes. We demonstrate that leukemic and primary T cells can be efficiently transduced and highly enriched under conditions that should be readily adaptable for clinical use. T cells carrying HSV-TKSR39 were inhibited by exposure to ganciclovir at concentrations an order of magnitude below those required for wild-type HSV-TK. The less toxic agent aciclovir also eliminated T cells transduced with HSV-TKSR39 (but not HSV-TK), underlining the increased therapeutic potential of the mutant suicide gene system in the bone marrow transplantation setting.
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PMID:T cell transduction and suicide with an enhanced mutant thymidine kinase. 1204 Apr 65

Clinical data indicate that after allogeneic hematopoietic stem cell transplantation (HSCT) for hematological malignancies, the graft-versus-leukemia (GVL) effect is in large part mediated by the graft-versus-host reaction (GVHR), which also often leads to graft-versus-host disease (GVHD). Controlling alloreactivity to prevent GVHD while retaining GVL poses a true dilemma for the successful treatment of such malignancies. We reasoned that suicide gene therapy, which kills dividing cells expressing the thymidine kinase (TK) "suicide" gene using time-controlled administration of ganciclovir (GCV), might solve this dilemma. We have previously shown that after infusion of allogeneic TK T cells along with HSCT to an irradiated recipient, an early and short GCV treatment efficiently prevents GVHD by selectively eliminating alloreactive T cells while sparing nonalloreactive T cells, which can then contribute to immune reconstitution. Nevertheless, it remained to be established that this therapeutic strategy retained the desired GVL effect. Hypothesizing that a contained GVHR would be essential, we evaluated the GVL effect using different protocols of GCV administration. We were able to show that when the GCV treatment is initiated at, or close to, the time of grafting, GVHD is controlled but GVL is lost. In contrast, when the onset of GCV administration is delayed until day 6, a potent GVL effect is retained while GVHD is still controlled. These data emphasize that, by a time-optimized scheduling of the administration of GCV, this TK/GCV strategy can be tuned to efficiently treat malignant hemopathies.
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PMID:Graft-versus-leukemia effect after suicide-gene-mediated control of graft-versus-host disease. 1220 Mar 61

We have previously shown that the infusion of donor lymphocytes expressing the herpes simplex virus thymidine kinase (HSV-tk) gene is an efficient tool for controlling graft-versus-host disease (GVHD) while preserving the graft-versus-leukemia (GVL) effect. In addition to the GVL effect, the administration of donor HSV-tk(+) cells could have a clinical impact in promoting immune reconstitution after T-cell-depleted stem cell transplantation (SCT). To explore this hypothesis, we have investigated whether in vitro polyclonal activation, retroviral transduction, immunoselection, and expansion affect the immune competence of donor T cells. We have observed that, after appropriate in vitro manipulation, T cells specific for antigens relevant in the context of SCT are preserved in terms of frequency, expression of T-cell receptor, proliferation, cytokine secretion, and lytic activity. A reduction in the frequency of allospecific T-cell precursors is observed after prolonged T-cell culture, suggesting that cell manipulation protocols involving a short culture time and high transduction efficiency are needed. Finally, the long-term persistence of HSV-tk(+) cells was observed in a patient treated in the GVL clinical trial, and a reversion of the phenotype of HSV-tk(+) cells from CD45RO(+) to CD45RA(+) was documented more than 2 years after the infusion. Based on all this evidence, we propose a clinical study of preemptive infusions of donor HSV-tk(+) T cells after SCT from haploidentical donors to provide early immune reconstitution against infection and potential immune protection against disease recurrence.
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PMID:Immunologic potential of donor lymphocytes expressing a suicide gene for early immune reconstitution after hematopoietic T-cell-depleted stem cell transplantation. 1239 8

In allogeneic hematopoietic cell transplantation, donor lymphocytes play a central therapeutic role in both graft-versus-leukemia and immune reconstitution. However, their use is limited by the risk of severe graft-versus-host disease (GVHD). Different strategies have been investigated to obtain all the benefits derived from donor lymphocytes while avoiding the risk of GVHD. Infusions of donor lymphocytes transduced with the herpes simplex virus thymidine kinase (HSV-tk) suicide gene resulted in anti-tumor activity in a substantial number of patients. Acute GVHD could be effectively controlled by ganciclovir-induced elimination of the transduced cells. Haplo-identical stem cell transplantation (haplo-SCT) is a promising therapeutic option for patients with high-risk hematologic malignancies lacking an HLA-matched donor. However, the intensive T-cell depletion required to overcome the risk of lethal GVHD has been associated with a delayed immune recovery with a prolonged risk of posttransplantation viral, fungal, and other opportunistic infections. Donor lymphocyte infusions of HSV-tk represent a promising tool for preventing disease relapse and promoting immune reconstitution after haplo-SCT, and a unique tool for the control of GVHD. The genetic manipulation of donor lymphocytes with a suicide gene is a promising strategy to increase feasibility and safety of allogeneic bone marrow transplantation.
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PMID:Suicide-gene-Transduced donor T-cells for controlled graft-versus-host disease and graft-versus-tumor. 1246 92

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

Allogeneic donor T lymphocytes manipulated genetically to express the herpes simplex virus thymidine kinase (HSV-TK) gene have emerged as promising tools to alter the balance between graft versus host disease and graft versus leukemia after allogeneic stem cell transplantation, since they can be eliminated selectively in vivo with ganciclovir. Recently, it was reported that in SFCMM-3, an HSV-TK-encoding retroviral vector, two cryptic splice sites in the HSV-TK sequence led to the generation of an HSV-TK splice variant (deltaHSV-TK) that encodes a ganciclovir-resistant gene product. In order to quantify wtHSV-TK and deltaHSV-TK RNA levels we have developed two real time Taqman PCR assays. We demonstrate that the sensitivity of both PCR assays is 10(-4). It was found that the splice variant is generated in the packaging cell line and results in approximately 4.8+/-1.9% of virions that contain deltaHSV-TK RNA. After transduction of human T cells no significant increase in deltaHSV-TK RNA could be detected. Thus, at maximum 4.2+/-1.2% of T cells transduced with SFCMM-3 will be resistant to ganciclovir due to this mechanism only. Together, these assays provide a powerful method to monitor patients in future clinical trials.
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PMID:Development and application of quantitative real time PCR and RT-PCR assays that discriminate between the full-length and truncated herpes simplex virus thymidine kinase gene. 1271 Oct 61

Clinical trials evaluating the herpes simplex virus thymidine kinase (HSV-tk)/ganciclovir (GCV) suicide gene therapy system for the control of graft-versus-host disease (GVHD) have been limited by low transduction efficiencies and inefficient selection procedures. In this study, we designed and evaluated a novel chimeric suicide gene consisting of the extracellular and transmembrane domains of human CD34 and full-length HSV-tk (DeltaCD34-tk). High-efficiency transfer of DeltaCD34-tk to primary human T cells was accomplished after a single exposure to VSV-G-pseudotyped, Moloney murine leukemia virus-based retrovirus 48 h after activation of human PBMCs with anti-CD3 and anti-CD28 antibodies immobilized on magnetic beads. Using an optimized 5-day transduction and selection procedure, transduction efficiencies averaged 71%, with isolation purities greater than 95% and yields exceeding 90%. The immunoselected T cells were selectively eliminated by GCV (IC(50) approximately 3 nM), maintained a normal subset composition, exhibited a polyclonal TCR Vbeta family repertoire, and contained 5 or 6 vector copies per transduced cell when optimally transduced. No increase in GCV sensitivity was observed upon incorporation of highly active mutant HSV-tk enzymes into the DeltaCD34-tk suicide gene. T cells modified with the DeltaCD34-tk gene using the optimized protocol should improve the overall efficacy of the HSV-tk/GCV suicide gene therapy method of GVHD control.
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PMID:Transduction and selection of human T cells with novel CD34/thymidine kinase chimeric suicide genes for the treatment of graft-versus-host disease. 1284 26

Engineering donor T lymphocytes with inducible 'suicide genes', such as herpes simplex virus thymidine kinase, has potential to improve safety and efficacy in allogeneic transplantation by facilitating management of graft-versus-host disease. Elective administration of a relatively nontoxic pro-drug would induce in vivo negative selection of engineered lymphocytes specifically, sparing other donor hematopoietic cells. The engineered cells must retain immunologic function, and undergo negative selection in response to clinically attainable plasma concentrations of pro-drug. The cell engineering process itself, typically involving activation, transduction, ex vivo expansion, and selection, must produce clinically useful numbers of genetically modified cells at high purity. We discuss development of a cellular engineering manufacturing process that yields transduced, expanded T lymphocytes meeting these requirements.
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PMID:Cellular engineering of HSV-tk transduced, expanded T lymphocytes for graft-versus-host disease management. 1458 72


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