Treatment of Cytomegalovirus Diseases

Vogel, Jens-Owe; Scholz, Martin; Cinatl, Jindrich

doi:10.1159/000150568

Cited by 27 publications

(15 citation statements)

References 52 publications

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“…11 The drug used to trigger suicide in the Fas system is AP1903, a synthetic, small-molecule compound that was specifically designed to interact with the engineered F36V-FKBP but not with endogenous FKBP12. 16 In contrast, the HSV-tk system requires GCV, an antiviral drug with a low therapeutic index because of myelotoxicity 42 and moreover a drug broadly used for treatment of cytomegalovirus infection. 43 Our experiments provide information that will be useful in defining the dosing regimen for use in GVHD applications.…”

Section: Discussionmentioning

confidence: 99%

A Fas-based suicide switch in human T cells for the treatment of graft-versus-host disease

Thomis

Marktel

Bonini

et al. 2001

Blood

178

124

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Graft-versus-host disease (GVHD) is a major complication of allogeneic bone marrow transplantation. One strategy to treat GVHD is to equip donor T cells with a conditional suicide mechanism that can be triggered when GVHD occurs. The herpes simplex virus thymidine kinase (HSV-tk)/ganciclovir system used clinically has several limitations, including immunogenicity and cell cycle dependence. An alternative switch based on chemically inducible apoptosis was designed and evaluated. A chimeric human protein was expressed comprising an extracellular marker (⌬LNGFR), the Fas intracellular domain, and 2 copies of an FK506-binding protein (FKBP). Primary human T lymphocytes retrovirally transduced with this construct could be purified to homogeneity using immunomagnetic beads. Genetic integrity of the construct was ensured by redesigning repetitive sequences. Transduced T cells behaved indistinguishably from untransduced cells, retaining the ability to mount a specific antiallogeneic immune response. However, they rapidly underwent apoptosis with the addition of subnanomolar concentrations of AP1903, a bivalent "dimerizer" drug that binds FKBP and induces Fas cross-linking. A single 2-hour treatment eliminated approximately 80% of T cells, and multiple exposures induced further apoptosis. T cells were eliminated regardless of their proliferation state, suggesting that the AP1903/ Fas system, which contains only human components, is a promising alternative to HSV-tk for treating GVHD. IntroductionIn allogeneic bone marrow transplantation (BMT), the delayed infusion of donor lymphocytes plays a central therapeutic role in the control of disease relapse (graft-versus-leukemia effect [GVL]) 1 and in the induction of immune reconstitution, 2,3 the latter especially in the subset of T-depleted matched transplants and in the context of partially mismatched transplants. 4 However, graft-versushost-disease (GVHD) represents a frequent and often lethal complication of delayed lymphocyte infusions. 1 Managing the threat of GVHD while maximizing the beneficial GVL effect would broaden the scope and usefulness of allogeneic BMT procedures.We and others have previously demonstrated that ex vivo genetic manipulation of donor lymphocytes to insert a conditional, drug-inducible suicide gene provides a means for the specific elimination of donor T cells with the onset of GVHD while maximizing the therapeutic benefit of the GVL effect. 2,5,6 Although a number of suicide genes have been proposed, 7,8 the herpes simplex virus thymidine kinase (HSV-tk)/ganciclovir (GCV)-based suicide strategy appears to be the most effective and specific and has been widely adopted. 9,10 Cells are engineered to express HSV-tk; the addition of ganciclovir leads to cell death through tk-catalyzed metabolism of the drug to a lethal product. In the current clinical trial, 6 HSV-tk-engineered-donor T cells demonstrated an effective antileukemic effect, and GVHD could be successfully treated through GCV administration. 2,11 Despite this demonstration of efficacy, ...

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Section: Discussionmentioning

confidence: 99%

A Fas-based suicide switch in human T cells for the treatment of graft-versus-host disease

Thomis

Marktel

Bonini

et al. 2001

Blood

178

124

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“…A range of regimens for CMV disease management have evolved, encompassing the identification of risk factors, the early detection of CMV infection followed by the initiation of specific antiviral therapy, prophylactic antiviral strategies, reduction in immunosuppression, prophylaxis and treatment of superinfection, selective use of intravenous immunoglobulin, and surveillance viral detection to monitor the response to therapy (248,450,485). Surveillance viral monitoring may include serial CMV cultures (blood, urine) and biopsy with viral culture of tissue specimens whenever clinically indicated.…”

Section: Treatmentmentioning

confidence: 99%

New Strategies for Prevention and Therapy of Cytomegalovirus Infection and Disease in Solid-Organ Transplant Recipients

Sia¹,

Patel²

2000

Clinical Microbiology Reviews

220

181

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“…GCV, PFA and HPMPC, exert their actions by preventing viral DNA replication, and the subsequent synthesis of HCMV late proteins [34]. These drugs efficiently prevent virus replication, but have no influence on events (IE expression) that occur before viral DNA synthesis [35].…”

Section: Isis 2922 Combined With Antioxidants: a Novel Anti-cmv Treatmentioning

confidence: 99%

Proinflammatory Potential of Cytomegalovirus Infection

Činátl

Vogel²,

Kotchetkov³

et al. 1999

Intervirology

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We observed the effects of antiviral therapy on CMV and/or oxidative-stress-induced stimulation of proinflammatory molecules including interleukin-8 (IL-8), melanoma growth stimulatory activity-α (GRO-α) and intercellular adhesion molecule 1 (ICAM-1) using human foreskin fibroblasts. Ganciclovir, foscarnet or cidofovir completely suppressed virus replication, as demonstrated by CMV late (L) antigen production. These drugs did not influence CMV immediate-early (IE) antigen expression and had no effects on CMV-induced cellular changes in IL-8, GRO-α and ICAM-1 levels. Phosphorothioate oligonucleotide (ISIS 2922) suppressed both CMV IE and L antigen by 99%. ISIS 2922 completely suppressed CMV-induced upregulation of both chemokines and ICAM-1. Induction of oxidative stress by H₂O₂ upregulated IL-8 expression. Oxidative stress and CMV infection showed synergistic effects on IL-8 expression. ISIS 2922 only partially inhibited the upregulation of IL-8 in infected cells treated with H₂O₂, whereas cotreatment with ISIS 2922 and antioxidants inhibited the upregulation almost completely. The results showed that inhibition of CMV IE expression alone or in combination with antioxidants is promising for the treatment of CMV disease.

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Treatment of Cytomegalovirus Diseases

Cited by 27 publications

References 52 publications

A Fas-based suicide switch in human T cells for the treatment of graft-versus-host disease

A Fas-based suicide switch in human T cells for the treatment of graft-versus-host disease

New Strategies for Prevention and Therapy of Cytomegalovirus Infection and Disease in Solid-Organ Transplant Recipients

Proinflammatory Potential of Cytomegalovirus Infection

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