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

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.
 ...
PMID: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? 804 49

Herpes simplex virus (HSV) infections are common in bone marrow transplantation patients. Unusual sites may be involved, however colonic disease with HSV is rare. We report a successfully treated case of colitis due to HSV, cytomegalovirus, Clostridium difficile and graft-versus-host disease in an allogeneic marrow recipient.
 ...
PMID:Herpes simplex virus (HSV) colitis in a bone marrow transplant recipient. 864 Jan 81

Allogeneic bone marrow transplantation is still limited by the morbidity and mortality caused by graft-versus-host disease (GVHD), resulting from host recognition by donor T lymphocytes. It is possible to drastically reduce the T-cell content of the graft. However, transplanted T cells can also have a beneficial effect by graft enhancement and the graft-versus-leukemia effect. How can we keep the beneficial GVL effect while protecting the patient from possible GVHD? A recent report proposed the ex vivo transfer of the herpes simplex thymidine kinase (HSv-tk) gene into donor T cells before their infusion with hematopoietic stem cells. This procedure is expected to allow selective donor T-cell depletion with ganciclovir should GVHD occur, but it has two major drawbacks: reinjection of a fraction of untransfected T cells cannot be avoided and heterogeneity of the transfected population results in increased risks such as HSv-tk gene instability or dysfunction of some of the transfected T cell. Alternative approaches must be considered. We demonstrate here the feasibility of generating HSv-tk transfected HLA-specific CD4+ cytotoxic T-cell clonal populations, in which 100% of the cells have the HSv-tk gene inserted at a single site within their genome. These clones retained their specificity, their function, and their sensitivity to ganciclovir treatment. Our approach is not limited to bone marrow transplantation. Indeed, this procedure represents a useful alternative to retroviral gene transduction and is applicable to every circumstance where clinical use of gene modified T-cell clones is to be considered.
 ...
PMID:Human HLA-specific T-cell clones with stable expression of a suicide gene: a possible tool to drive and control a graft-versus-host- graft-versus-leukemia reaction? 870 20

Oropharyngeal shedding of herpes viruses (herpes simplex, cytomegalovirus) was assessed in patients on standard acyclovir prophylaxis during bone marrow transplantation (BMT) to determine the frequency of viral shedding and to assess possible oropharyngeal complications that may be associated with viral reactivation in these patients. We conducted a prospective assessment of 83 patients receiving BMT. Patients were evaluated weekly and oral surveillance cultures were completed. Shedding of herpes simplex virus (HSV) was detected in the oropharynx of 2.9% of seropositive patients on prophylactic acyclovir, and only one case of clinical oral herpetic infection was seen. Cytomegalovirus (CMV) was cultured from the oropharynx in 13.3% of CMV seropositive patients provided with prophylactic acyclovir, but no oropharyngeal lesions were attributed to CMV reactivation. No correlation was seen between HSV and CMV pretransplant serology and severity of oral mucositis and acute graft versus host disease. No effect on time to engraftment was detected. This study supports the continuing use of acyclovir prophylaxis in HSV seropositive patients receiving BMT. Acyclovir prophylaxis was effective in preventing viral shedding in all but 2.9% of patients, and only one case of clinical infection was diagnosed. The frequency of CMV shedding was approximately four times that of HSV; however, no oral lesions were attributed to CMV.
 ...
PMID:Acyclovir prophylaxis of oral herpes virus during bone marrow transplantation. 876 72

To investigate the presence of nondiagnosed viral lung infections in patients who developed acute respiratory failure and diffuse pulmonary infiltrates after bone marrow transplantation (BMT), we studied necropsy-obtained lung specimens with features of diffuse alveolar damage (DAD) where no other specific histological diagnosis could be established, by using in situ hybridization and immunohistochemistry. Lung tissue samples obtained at necropsy from 19 patients (12 males and 7 females; 31 +/- 11 yrs mean +/- SD age) who died 56 +/- 36 days after BMT (12 allogeneic and 7 autologous), were studied retrospectively using specific deoxyribonucleic acid (DNA) probes to detect cytomegalovirus (CMV), herpes simplex virus (HSV), Epstein-Barr virus (EBV), and adenovirus genomes. Tissue samples were additionally processed with antibodies to CMV and HSV antigens. Cells infected by CMV were detected by in situ hybridization in five cases, and by immunohistochemistry in four cases. Combining the results of both procedures, a previously undiagnosed CMV infection was found in six patients. All of them had received an allogeneic BMT and had developed graft-versus-host disease (GVHD). No evidence of cells infected by HSV, EBV, or adenovirus was found in any case. No viral infection was detected either in recipients of autologous marrow or in recipients of allogeneic BMT without GVHD. These results indicate that pulmonary cytomegalovirus infection not detected by conventional histological examinations may be present in patients with diffuse alveolar damage associated with bone marrow transplantation, especially in recipients of allogeneic marrow who develop graft-versus-host disease. Furthermore, the use of in situ hybridization and/or immunohistochemistry on pulmonary histology might improve the diagnosis of viral lung infections in patients receiving bone marrow transplantation.
 ...
PMID:Undetected viral infection in diffuse alveolar damage associated with bone marrow transplantation. 880 24

A number of diverse gene therapy strategies are being evaluated in the search for novel therapeutic approaches to leukemia. Antisense oligonucleotides, ribozymes and retroviral vectors are approaches directed at the molecular mechanisms of cancer. Transfer of genes encoding cytokines and human leukocyte antigens (HLAs) could also be used to elicit immunity against tumor cells. Gene marking strategies have been useful in elucidating the biology of disease relapse after autologous bone marrow transplantation. Suicide genes, such as the herpes simplex thymidine kinase gene, have been used to modulate graft-versus-host disease after allogeneic bone marrow transplantation. Although gene delivery remains a major challenge to gene therapy, some modifications have been implemented to overcome this issue. This review will summarize these gene therapy strategies aimed at increasing the survival of patients with leukemia.
 ...
PMID:Gene therapy strategies for leukemia. 902 41

In allogeneic bone marrow transplantation (allo-BMT), donor lymphocytes play a central therapeutic role in both graft-versus-leukemia (GvL) and immune reconstitution. However, their use is limited by the risk of severe graft-versus-host disease (GvHD). Eight patients who relapsed or developed Epstein-Barr virus-induced lymphoma after T cell-depleted BMT were then treated with donor lymphocytes transduced with the herpes simplex virus thymidine kinase (HSV-TK) suicide gene. The transduced lymphocytes survived for up to 12 months, resulting in antitumor activity in five patients. Three patients developed GvHD, which could be effectively controlled by ganciclovir-induced elimination of the transduced cells. These data show that genetic manipulation of donor lymphocytes may increase the efficacy and safety of allo-BMT and expand its application to a larger number of patients.
 ...
PMID:HSV-TK gene transfer into donor lymphocytes for control of allogeneic graft-versus-leukemia. 920 27

Alloreactive T cells present in a bone marrow transplant are responsible for graft-versus-host disease (GVHD), but their depletion is associated with impaired engraftment, immunosuppression, and loss of the graft-versus-leukemia effect. We developed a therapeutic strategy against GVHD based on the selective destruction of these alloreactive T cells, while preserving a competent T-cell pool of donor origin. We generated transgenic mice expressing in their T lymphocytes the Herpes simplex type 1 thymidine kinase (TK) suicide gene that allows the destruction of dividing T cells by a ganciclovir treatment. T cells expressing the TK transgene were used to generate GVHD in irradiated bone marrow grafted mice. We show that a short 7-day ganciclovir treatment, initiated at the time of bone marrow transplantation, efficiently prevented GVHD in mice receiving TK-expressing T cells. These mice were healthy and had a normal survival. They maintained a T-cell pool of donor origin that responded normally to in vitro stimulation with mitogens or third party alloantigens, but were tolerant to recipient alloantigens. Our experimental system provides the proof of concept for a therapeutic strategy of GVHD prevention using genetically engineered T cells.
 ...
PMID:Prevention of graft-versus-host disease in mice using a suicide gene expressed in T lymphocytes. 919 90

Bone marrow transplantation, once regarded as experimental, has evolved into a standard treatment for a variety of malignancies. Considerable advances have been made in histocompatibility typing, pretransplantation chemotherapy, and posttransplantation immunosuppressive therapy as well as prophylaxis and treatment of infections. Oral complications develop in almost all patients, and their early recognition may result in the institution of prompt treatment and prolonged survival. Mucositis, often severe and extremely painful, develops in more than three quarters of bone marrow transplant recipients, and its prevention, unfortunately, remains unsatisfactory. Herpes simplex virus and Candida albicans account for most oral infections, although their incidence has been dramatically reduced by the institution of prophylactic agents. Graft versus host disease continues to be a significant complication of marrow transplantation, and the detection of commonly occurring oral changes may support its diagnosis.
 ...
PMID:Oral cavity complications of bone marrow transplantation. 942 Dec 17

This study will evaluate the safety and efficacy of allogenic donor lymphocyte infusions in patients who have relapsed hematologic malignancies after allogeneic bone marrow transplantation (BMT). Donor lymphocyte transfusions have resulted in the cure of some patients with relapsed leukemia or lymphoproliferative disorder after allogeneic BMT, but has been complicated by the development of graft versus host disease (GvHD). We hypothesize that a retroviral vector containing the Herpes simplex thymidine kinase (HStk) gene will allow for retention of the anti-leukemia response of transfused donor lymphocytes while allowing for the adverse effects of GVHD to be mitigated. Patients with relapsed hematologic malignancies after allogeneic BMT will be infused with ex vivo gene modified donor lymphocytes. The Herpes Simplex thymidine kinase (HStk) gene will be transduced into the cells ex vivo using LTKOSN. 1 vector supernate. Insertion of the HStk gene into lymphocytes confers a sensitivity to the anti-herpes drug ganciclovir (GCV). This selective destruction of donor lymphocytes in situ will be used to abrogate the effect of graft versus host disease, if it develops.
 ...
PMID:Adoptive immunotherapy for leukemia: donor lymphocytes transduced with the herpes simplex thymidine kinase gene for remission induction. HGTRI 0103. 945 47


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>