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)

Genetically modified lymphocytes have been successfully used for correction of ADA deficiency in children and in controlling graft-versus-host disease (GvHD) after allogeneic bone marrow transplantation. Low transduction efficiencies are, however, limiting for gene therapeutic strategies based on lymphocytes. In this study we compared protocols for highly efficient gene transfer into human T cells using retroviral vector-containing supernatant. We showed that infection of both human primary T cells and CD4+ Jurkat cells is most efficient on the matrix component fibronectin. Transduction was carried out with a retroviral vector encoding both the human intracytoplasmatically truncated low-affinity nerve growth factor receptor (deltaLNGFR) as a gene transfer marker and the Herpes simplex virus thymidine kinase for negative selection. Based on LNGFR expression genetically modified cells were enriched to near purity by magnetic cell sorting (MACS). Enriched cells could be shown to be highly sensitive to ganciclovir.
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PMID:Highly-efficient gene transfer with retroviral vectors into human T lymphocytes on fibronectin. 969 74

To gain further insights in the pathogenesis of herpesvirus pneumonia in allogeneic bone marrow transplant recipients, transplanted mice (B10.BR --> CBA) with graft-versus-host disease (GVHD) and control mice (transplanted mice without GVHD and normal CBA mice) were infected intranasally with herpes simplex virus type 1 (HSV-1). When compared with infected control mice, infected allogeneic transplant recipients with GVHD showed increased periluminal mononuclear cell infiltrates. However, infected allogeneic transplant recipients with GVHD showed lower virus content in the lung tissue than infected control mice. High concentrations of transforming growth factor-beta 1 (TGF-beta1) were detected in the bronchoalveolar lavage (BAL) fluid of mock-infected allogeneic transplant recipients with GVHD, which increased slightly after infection. Anti-TGF-beta treatment of allogeneic transplant recipients with GVHD significantly decreased the histological evidence of pneumonitis at day 4 after HSV-1 infection. We conclude that allogeneic transplant recipients with GVHD have (1) increased pneumonia, (2) highly elevated levels of TGF-beta1 in the BAL fluid, and (3) reduced pulmonary virus content after HSV-1 infection. Our data suggest that the newly recognized dysregulation of cytokine (TGF-beta1) production may be more important than the viral load for the increased severity of HSV-1 pneumonia in allogeneic transplant recipients with GVHD.
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PMID:A role for transforming growth factor-beta1 in the increased pneumonitis in murine allogeneic bone marrow transplant recipients with graft-versus-host disease after pulmonary herpes simplex virus type 1 infection. 974

We previously demonstrated that severe graft-versus-host disease (GvHD), associated with the therapeutic infusion of donor lymphocytes after allogeneic marrow transplantation (BMT), can be efficiently controlled by the SFCMM-2-mediated expression of the herpes simplex virus thymidine kinase (HSV-tk) suicide gene into the allogeneic lymphocytes. This was achieved by selective elimination of transduced lymphocytes by ganciclovir (GCV) infusion. Despite the positive results of the pilot clinical trial, two vector-related limitations were observed. The induction of a strong immune response against genetically modified cells was observed in two patients. In addition, the only patient who developed chronic GvHD showed only partial response to ganciclovir treatment. In an attempt to overcome these limitations, we developed a new generation of vectors. The neomycin resistance (neoR) gene was removed from the SFCMM-3 and SFCMM-4 retroviral vectors. These vectors are less immunogenic and able to confer higher ganciclovir sensitivity to transduced human lymphocytes. All the vectors carry a modified form of the low-affinity nerve growth factor receptor cDNA, as cell surface selectable marker (deltaLNGFR). The vectors were compared in terms of gene transfer efficiency, and ability to confer high and specific sensitivity to ganciclovir. The SFCMM-3 vector, carrying the entire HSV-tk gene driven by the LTR promoter, allows efficient transduction of human T lymphocytes and confers the highest GCV sensitivity to transduced lymphocytes with a high and a low proliferation index. The expression of the deltaLNGFR marker allows an easier in vitro manipulation and a faster immune selection of transduced cells compared with neoR selection. Finally, the elimination of the neoR gene removes a potent immunogen from transduced lymphocytes.
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PMID:Herpes simplex virus thymidine kinase gene transfer for controlled graft-versus-host disease and graft-versus-leukemia: clinical follow-up and improved new vectors. 979 8

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

Posttransplant infection associated with host immune deficiency is the major cause of nonrelapse mortality of human bone marrow transplant recipients. In a new murine model of posttransplant infection, allogeneic bone marrow transplant recipients were infected with herpes simplex virus-1 (HSV-1) via intraperitoneal inoculation 12 weeks after transplantation. Allogeneic transplant recipients with graft-versus-host disease (GVHD) had significantly increased mortality from HSV-1 encephalitis, with deficiencies of both specific anti-HSV-1 antibody and total serum IgG2a. GVHD mice displayed a Th2 cytokine profile (increased interleukin-4 [IL-4] and decreased interferon-gamma) and decreased lipopolysaccharide (LPS) responses, suggesting that both T-cell and B-cell defects contributed to the impaired production of antibody. Because passive transfer of hyperimmune serum protected mice from HSV-1 infection, we hypothesized that CD40 ligand (CD40L), which induces B-cell maturation, would protect mice from HSV-1 infection. CD40L-treated GVHD mice showed elevated IgG2a levels and increased survival compared with vehicle-treated transplant recipients.
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PMID:Recombinant CD40L treatment protects allogeneic murine bone marrow transplant recipients from death caused by herpes simplex virus-1 infection. 983 55

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

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

We examined the incidence of herpes varicella-zoster virus (VZV) infection in 151 patients undergoing allogeneic BMT between August 1990 and September 1997 and who survived at least 3 months. Median follow-up was 17 (range 3.3-80.7) months. Herpes simplex virus antibody positive (HSV+) patients received aciclovir 1200 mg p.o. daily or 750 mg i.v. daily, in divided doses from day 0 to engraftment. Ganciclovir (5 mg/kg i.v. three times per week) was given in CMV+ patients (or if the donor was CMV+) from engraftment to day 84. Ganciclovir was continued or recommenced if a dose of greater than 20 mg of prednisone was used for the treatment of GVHD otherwise aciclovir was recommenced. In HSV+ patients not receiving ganciclovir, aciclovir 600 mg p.o. daily in divided doses was given until at least 6 months after BMT. Thirty-two patients developed VZV infection from 4.1 to 28 months after transplant. The estimated cumulative incidence of VZV was 13% (95% confidence interval 6-19%) at 12 months, 32% (22-42%) at 24 months and 38% (27-50%) at 28 months, with no further cases beyond that time. No patient developed VZV whilst receiving aciclovir or ganciclovir (P < 0.0001). However, there was a rapid onset of VZV following cessation of antiviral therapy (33% (20-46%) at 1 year post cessation). The presence of GVHD and the prior duration of antiviral prophylaxis were significant and independent risk factors for the development of VZV. Age, underlying disease, conditioning therapy or donor type were not. We conclude that 3-6 months of low-dose aciclovir and ganciclovir are effective at delaying the onset of VZV after allogeneic BMT, but may not affect the overall incidence of infection. Prolonged prophylaxis may be warranted in patients at high risk of infection, for example those patients with GVHD.
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PMID:Varicella-zoster infection after allogeneic bone marrow transplantation: incidence, risk factors and prevention with low-dose aciclovir and ganciclovir. 1073 1

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


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