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)

Specific and conditional in vivo ablation of alloreactive donor T cells after allogeneic hematopoietic stem cell transplantation could significantly contribute to preventing and treating graft-versus-host disease (GVHD). The use of donor T cells expressing a "suicide" gene such as the thymidine kinase gene of the herpes simplex virus 1 (HS-tk) has the potential of achieving such a goal. Ex vivo retroviral-mediated HS-tk gene transfer in human T cells as well as ganciclovir sensitivity of such gene-modified T cells is established. The prevention and treatment of GVHD induced by HS-tk-expressing donor T cells by ganciclovir has been demonstrated in murine models. Clinical trials involving the use of HS-tk-expressing T cells at time of transplantation in conjunction with a T-cell-depleted hematopoietic graft or subsequently for treatment of relapse or lymphoma associated with Epstein-Barr virus infection are currently underway. In vivo circulation of ganciclovir-sensitive gene-modified cells as well as the occurrence of ganciclovir-sensitive acute and chronic GVHD have been documented. If these initial exciting findings are confirmed, such an approach could significantly contribute to expanding the use of alloreactivity as a treatment modality.
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PMID:"Suicide" gene for the control of graft-versus-host disease. 981 59

Allogeneic bone marrow transplant followed by donor lymphocyte infusion (DLI) is limited by T cell-mediated graft-versus-host disease (GVHD). A potential solution to alleviate uncontrolled GVHD is to create a controllable suicidal lymphocyte using retroviral transduction of the herpes simplex virus thymidine kinase gene (HSVtk) into the T cell graft. Should GVHD arise, the administration of ganciclovir (GCV) should eliminate the causal T cells. The culture conditions and expansion protocols required to produce suicidal lymphocytes may affect the composition of the T cell product. In this report we describe how T cells from individual donor samples respond to the same culture condition in highly varied ways. Among five donors, two demonstrated predominant expansion of CD4+ cells (with a decrease of CD8+), two donors resulted in predominately CD8+ cells, and one donor developed mainly dual positive CD8+/CD56+ cells. We observed a 20-fold expansion of T cells during the 14 day protocol. The function of the T cells was not affected by the transduction procedures (as tested by 51Cr release assays). In contrast to suicidal lymphocytes prepared using entire T cell populations, T cells pre-selected into CD3+/CD4+ or CD3+/CD8+ subpopulations prior to culture maintained their initial phenotype during the 14 day culture period, with little or no drift. Results from clinical trials using suicidal lymphocytes may be confounded by variance in lymphocyte subset compositions (LSC) and optimal use of suicidal lymphocytes may require separate culture and transduction to control the LSC delivered to the patient.
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PMID:Production and culture of HSVtk transduced suicidal lymphocytes induces variable changes in the lymphocyte subset composition. 1033 46

T-cell depletion (TCD) of the bone marrow graft remains the most effective method to prevent severe graft versus host disease after allogeneic bone marrow transplantation. Early studies of HLA-identical sibling transplants showed that although T-cell depletion decreased GVHD, T-cell depleted transplants had higher risks of graft failure and leukemia relapse, leukemia free survival (LFS) was not improved compared to non-T-cell depleted transplants. In order to avoid graft failure and increased risk of relapse associated with this approach, we initiated a pilot study of T-cell depletion of the marrow graft combined with reinfusion of a fixed quantity of CD2+ peripheral blood T-cells. Depletion technique consisted in negative purging using CD2 and CD7 monoclonal antibodies (MoAbs) followed by rabbit complement cytolysis. This approach was associated with an intensified conditioning regimen using total body irradiation, high-dose cytosine arabinoside and melphalan (TAM) for all but one patient. Twenty-one patients were included with a mean age of 40 years. Only one acute severe Graft Versus Host Disease (GVHD) was observed and all patients engrafted. At 63 months, probability of survival is 42.86% with a relapse risk of 19.89%, two patients died from B-cell lymphoproliferative disease, seven other died from the procedure partially because of the use of the TAM as pretransplant regimen. This approach is being pursued by a gene therapy trial using herpes-simplex - 1 thymidine kinase gene expressing peripheral donor T-cells.
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PMID:Low dose T-cell lymphocyte infusion combined with marrow T-cell depletion as prophylaxis of acute graft vs host disease for HLA identical sibling bone marrow transplantation. 1034 50

Donor T cells are beneficial for engraftment, immune reconstitution, and antileukemic effects after allogeneic marrow transplantation, but they also cause graft-versus-host disease. Treatment with ganciclovir can control graft-versus-host disease if donor T cells are genetically engineered to express viral thymidine kinase. Clinical protocols with thymidine kinase-expressing T cells currently prescribe the curative use of ganciclovir for genetic immunosuppression only after clinical manifestations of graft-versus-host disease have appeared. The aim of this work was to compare early/preventive versus delayed/curative treatment of GVHD. Here, we found that ganciclovir administered early after experimental marrow transplantation was highly effective in preventing graft-versus-host disease caused by thymidine kinase-expressing T cells, and surviving recipient mice were able to mount a T cell-dependent B cell response. In contrast, curative ganciclovir administration later after transplantation was much less effective in treating graft-versus-host disease and surviving recipients had markedly impaired immune function. These findings should be considered in the development of future clinical trials using thymidine kinase-expressing T cells; to date, such trials have envisaged the use of GCV to treat only declared graft-versus-host disease. The use of thymidine kinase-expressing T cells for conditional elimination of activated T cells after allogeneic marrow transplantation offers a promising new approach for the control of graft-versus-host disease. The versatility of the thymidine kinase/ganciclovir system offers clinical options depending on whether thymidine kinase-expressing T cells are infused at the time of bone marrow transplantation or in a delayed manner, and depending on whether GCV is administered in an early/preventive or delayed/curative manner. The rationale underlying these options is more complex than it may appear and is likely to have a profound impact on the efficacy of such treatments. In the present work, we analyze the immunological impact when GCV is administered in an early/preventive or delayed/curative manner. Our results demonstrate that the delayed/curative strategy is clearly associated with severe immunological defects. To our knowledge, this is the first report of immunodeficiency subsequent to suicide gene therapy for GVHD.
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PMID:Immunological defects after suicide gene therapy of experimental graft-versus-host disease. 1056 98

Patients with recurrent leukemia after an allogeneic hematopoietic stem cell transplant may be treated with donor lymphocyte infusions (DLI). The transfusion of lymphocytes from the original hematopoietic stem cell donor induces remission in approximately one third of relapsed AML cases and 80% of relapsed CML. DLI may be complicated by delayed and sometimes lethal graft-versus-host disease (GVHD). In an attempt to avoid this complication, several centers have initiated DLI trials in which the infused lymphocytes carry a suicide gene, herpes simplex thymidine kinase (HStk), which confers sensitivity to ganciclovir (GCV). In the event of severe GVHD, administration of GCV should terminate or ameliorate GVHD.
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PMID:Herpes simplex thymidine kinase (HStk) transgenic donor lymphocytes. 1057 53

The use of donor T cells expressing a suicide gene for destruction of graft-versus-host effector cells provides a tool for alloreactivity modulation. We describe a case of extensive vitiligo that developed after ganciclovir treatment of cutaneous chronic graft-versus-host disease in a patient who had received donor T lymphocytes expressing herpes simplex virus thymidine kinase at the time of transplantation.
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PMID:Extensive vitiligo after ganciclovir treatment of GvHD in a patient who had received donor T cells expressing herpes simplex virus thymidine kinase. 1069 89

Herpesvirus saimiri transforms human T lymphocytes to stable growth and persists episomally without genomic integration and without virus production. The transformed T cells retain essential features of their parental cells including the MHC-restricted antigen specificity which may be useful for applications in adoptive immunotherapy. In order to improve the biological safety of such vectors, the prodrug activating gene thymidine kinase of herpes simplex virus was inserted into the genome of herpesvirus saimiri by homologous recombination. After infection with wild-type or cloned recombinant viruses, T cells from tamarin monkeys and from humans were transformed to stable growth. Thymidine kinase-expressing transformed T cells were efficiently eliminated in the presence of low concentrations of ganciclovir. This elimination mechanism remained fully functional over an observation period of 12 months. The potentially immunogenic neomycin resistance gene expression cassette was deleted from the genome of established mutant viruses by using the prokaryotic Cre/LoxP recombination system. At any time during the course of a therapeutic application, thymidine kinase-expressing transformed human T cells might be eliminated after administration of ganciclovir. In principle, this function could be useful for the T cell-dependent immunotherapy of resistant blood cancer while avoiding the risk of uncontrolled graft-versus-host disease.
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PMID:Functional long-term thymidine kinase suicide gene expression in human T cells using a herpesvirus saimiri vector. 1080 89

The efficacy of graft-vs.-leukemia induction to treat relapses after allogeneic progenitor cell transplant in a variety of hematologic malignancies suggest that it may be possible to use the graft versus leukemia as primary therapy for these malignancies without the need of myeloablative therapy. This type of strategy should be explored initially in patients considered ineligible for conventional myeloablative therapies either because of age or concurrent medical conditions. GVHD remains a major obstacle that needs to be overcome. Although a potentially lower level of inflammatory cytokines may be present after non-myeloablative therapies, fatal GVHD still occurs. Methods to diminish GVHD after allogeneic transplant include selective T-cell depletion (39-43) and transduction of donor T-cells with Herpes simplex virus thymidine kinase which renders these cells sensitive to ganciclovir treatment (see chapter 16). We and others have demonstrated that nonablative chemotherapy using fludarabine combinations is sufficiently immunosuppressive to allow engraftment of allogeneic blood progenitor cells. Patients could then receive graded doses of donor lymphocytes without rejection, to mediate GVL. Ideally, this therapy could be titrated to levels of residual malignant cells using sensitive detection techniques. This novel approach to therapy would reduce the toxicity of the transplant procedure, allow it to be administered more safely to debilitated patients and possibly extend the use of transplantation to older patients who are not presently eligible for BMT procedures. Other possible indications include treatment of non-malignant disorders and induction of tolerance for solid organ transplantation.
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PMID:Non myeloablative "mini transplants". 1080 Jun 46

We have initiated a phase I/II clinical trial, involving the use of herpes simplex thymidine kinase gene (HS-tk)-expressing donor primary T cells, in order to modulate the graft-versus-host disease (GvHD) occurring after allogeneic hematopoietic stem cell transplantation. The preparation of gene-modified T cells (TkTCs) required a 12-day ex vivo culture comprising an initial OKT3 and IL-2 stimulation, a retrovirus-mediated transduction, and a 7-day selection step in the presence of G418 and IL-2. The low transduction efficiency as well as the culture conditions may significantly alter the diversity of the T cell repertoire. We therefore examined the T cell repertoire of HS-tk-expressing T cell samples from 11 different donors by the Immunoscope method. This method analyzes the hypervariable region of the T cell receptor beta chain (TCRBV) by amplifying the complementarity-determining region 3 (CDR3) and determining size diversity. In all examined samples (four of which were infused into patients), all TCRBV subfamilies were represented with, however, a significant skewing within a minority of subfamilies. Kinetic studies demonstrated that this skewing appeared between day 7 and day 12, with dates of appearance variable from one subfamily to another. In addition, the repertoire analysis of two different culture products, harvested and produced at different times from the same donors, suggested that some repertoire abnormalities could be donor specific. Quantitative analysis revealed no major modifications in gene usage, even in skewed TCRBV subfamilies, with a few clonal expansions concerning a limited number of TCRBV subfamilies. Importantly, identical abnormalities were found in control cells grown in parallel under similar conditions but not transduced or selected, thus demonstrating that these abnormalities were not related to the transduction or the selection process, but rather to the ex vivo culture. The initial stimulus used for T cell activation is a major source of TCRBV perturbation, since replacing the OKT3 + IL-2 stimulus by CD3 + CD28 monoclonal antibody-coated beads prevented the occurrence of alterations. Overall, the HS-tk-expressing T cells used in our clinical trial exhibit limited TCR repertoire skewing that is not due to the transduction/selection procedure. However, future T cell gene transfer protocols for clinical trials should be designed to take into account or possibly prevent such T cell repertoire alterations.
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PMID:Retrovirus-mediated gene transfer in primary T lymphocytes: influence of the transduction/selection process and of ex vivo expansion on the T cell receptor beta chain hypervariable region repertoire. 1083 17

Generation of an efficient graft-versus-leukemia (GVL) effect in patients with hematological malignancies who relapse after allogeneic bone marrow transplantation depends in part upon the number of infused T lymphocytes. Currently, a GVL reaction cannot be achieved without inducing concomitant graft-versus-host disease (GVHD); thus, one strategy is to try to modulate this GVL/GVHD ratio. We engineered human T lymphocytes with herpes simplex virus-thymidine kinase and neomycin resistance genes, with an LXSN-derived vector that confers a ganciclovir-specific sensitivity to the transduced T cells. We analyzed proliferation, interleukin-2 production, alloreactivity in a mixed lymphocyte culture, and clonogenicity during the different stages of retroviral infection and G418 selection. Our results confirm that a sufficient number of transduced T lymphocytes can be obtained after selection for clinical studies. Their proliferative activity, alloresponsiveness, and ability to produce and respond to interleukin-2 were retained. Compared with control populations, their clonogenicity, as assessed by limiting dilution assays, was reduced after retroviral infection and G418 selection by 1.6 and 2.9 logs, respectively, with both viral supernatant incubation and coculture procedures. This study shows that infection and selection with the thymidine kinase-neomycin resistance gene retroviral vector significantly reduces the number of functional T lymphocytes. This finding should be taken into account when establishing the dose of T lymphocytes necessary to trigger a modulated GVL/GVHD effect.
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PMID:T-lymphocyte function after retroviral-mediated thymidine kinase gene transfer and G418 selection. 1088 24


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