9-(1-3-Dihydroxy-2-propoxymethyl)guanine prevents death but not immunity in murine cytomegalovirus-infected normal and immunosuppressed BALB/c mice

Wilson, Eileen J.; Medearis, Donald N.; Hansen, Lawrence A.; Rubin, Robert H.

doi:10.1128/aac.31.7.1017

Cited by 22 publications

(6 citation statements)

References 14 publications

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“…Thus, therapy was effective with the combined regimen even when it was begun relatively late in the course of the lethal infection. These results confirm and extend our previously reported preliminary findings (19), and they are consistent with findings on bone marrow transplant recipients who had CMV pneumonia (5,11). In the report by Emmanuel et al, when DHPG and immunoglobulin were both administered, 7 of 10 patients survived, whereas none of 11 treated with either alone survived (5).…”

Section: Discussionsupporting

confidence: 82%

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Combined antibody and ganciclovir treatment of murine cytomegalovirus-infected normal and immunosuppressed BALB/c mice

Rubin

Lynch

Pasternack

et al. 1989

Antimicrob Agents Chemother

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The efficacy of treatment with ganciclovir (DHPG) and antibody activity-containing ascitic fluid (AF) separately and in combination was studied in normal and immunosuppressed BALB/c mice challenged intraperitoneally with a lethal dose (106 PFU) of murine cytomegalovirus (CMV). With combination therapy, lower doses of both DHPG and AF were often as effective as a higher dose of either agent given singly. For instance, the survival rate of murine CMV-challenged inmunosuppressed mice was doubled when 4 mg of DHPG per kg and a 1:16 dilution of AF were both administered in contrast to when each was used alone. In both groups of animals, combination therapy was shown to be more effective than either therapy individually, even when initiation of therapy was delayed as long as 48 h. Such an approach holds promise for decreasing the expense associated with antibody use and the dose-related toxicity associated with DHPG use while maintaining or possibly increasing the efficacy of prophylaxis and therapy of serious CMV disease in humans.Cytomegalovirus (CMV) has been the single most important cause of infectious disease morbidity and mortality in human transplantation for the past 2 decades, and it is often a significant problem in patients with the acquired immune deficiency syndrome (1,6,9,12). Clinical findings indicated that hyperimmune immunoglobulin preparations directed against this virus might prevent its clinical effects (17,20) and that the antiviral drug ganciclovir [9-(1,3-dihydroxy-2-propoxymethyl)guanine; DHPG] might have utility in the treatment of clinical CMV disease (8, 16), but the efficacy of both of these approaches was limited. Moreover, immunoglobulin prophylaxis is expensive and may vary in efficacy from lot to lot, while DHPG carries the risk of significant bone marrow toxicity. Therefore, alternative approaches are needed.Recently, we reported preliminary data suggesting that the combination of antibody therapy with DHPG might be more effective than either modality individually in mice (19). Findings on human bone marrow transplant recipients with CMV pneumonia also suggest that this approach has merit (5,6,11 Virus assay. Secondary cell cultures were prepared from 12-to 15-day CD-1 mouse embryos with Dulbecco medium plus 10% fetal bovine serum; cultures were plated onto six-well Costar plates. Plaque assays used these secondary mouse embryo cell cultures overlaid with a 1.5% methylcellulose solution as previously described (13). Samples (0.2 ml) of serial 10-fold dilutions of 10% (wt/vol) homogenates of infected tissues served as inocula.Preparation of AF with antibody activity. Latently infected BALB/c mice produced as previously described (14)

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Section: Discussionsupporting

confidence: 82%

“…Recently, we reported preliminary data suggesting that the combination of antibody therapy with DHPG might be more effective than either modality individually in mice (19). Findings on human bone marrow transplant recipients with CMV pneumonia also suggest that this approach has merit (5,6,11 (3).…”

mentioning

confidence: 92%

Combined antibody and ganciclovir treatment of murine cytomegalovirus-infected normal and immunosuppressed BALB/c mice

Rubin

Lynch

Pasternack

et al. 1989

Antimicrob Agents Chemother

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“…Use of GCV prophylaxis did not seem to impact the priming of the adaptive response in this model, suggesting that the presence of nonreplicating virus in the allograft may still be sufficient to induce adaptive immunity. Consistent with this, Wilson et al (34) showed that GCV-treated mice developed antibodies after MCMV infection which protected against subsequent lethal dose MCMV challenge, indicating that GCV itself does not necessarily abrogate the adaptive immune response. The contribution of this CMV-associated lymphoid response to activation of alloimmunity may be of further interest, as viral infections have been proposed to contribute to heterologous immunity in transplantation (35–37).…”

Section: Discussionmentioning

confidence: 76%

Ganciclovir Transiently Attenuates Murine Cytomegalovirus-Associated Renal Allograft Inflammation

Shimamura

Saunders²,

Rha³

et al. 2011

Transplantation

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Background. Prophylactic ganciclovir (GCV) is used in high-risk renal transplant patients to prevent acute cytomegalovirus (CMV) disease, but its impact on inflammation within the allograft itself remains undefined. Methods. To study the effect of GCV prophylaxis on allograft inflammation, murine CMV (MCMV)-infected allo-grafts were analyzed in a murine donor positive/recipient negative allogeneic renal transplantation model by flow cytometry and immunofluorescent staining. Results. By flow cytometry, CD45+ leukocyte infiltrates were more abundant in MCMV-infected allografts at 14 days posttransplant compared with uninfected grafts (P<0.01) and decreased in the presence of GCV (P<0.05). CD11c+ dendritic cells, Gr-1+ myeloid cells, CD204+ macrophages, and CD49b+ natural killer cells were reduced in GCV-treated allografts compared with MCMV-infected grafts without GCV treatment (P<0.05). However, GCV failed to reduce these cell types to levels found in MCMV-uninfected allografts. By day 7 after cessation of GCV prophylaxis, dendritic cells, macrophages, and natural killer cells increased in number and became statistically indistinguishable from numbers of cells found in MCMV-infected allografts without GCV. GCV treatment did not affect the numbers of CD4+, CD8+, or CD19+/B220+ lymphocytes infiltrating the allografts. Infiltrates were confirmed histologically by immunofluorescent staining for CD3+ and CD11b+ cells. Conclusions. In this model, MCMV-infected allografts developed significantly greater innate and adaptive leukocytic infiltrates compared with uninfected grafts. GCV attenuated the MCMV-associated innate leukocyte infiltrates in infected allo-grafts but not the lymphocytic infiltrates. The attenuated innate response was limited to the period of GCV prophylaxis.

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“…In the murine CMV model, the combination of CMV hyperimmune globulin plus ganciclovir is far more effective prophylactically and therapeutically than either modality alone (20, 21). In landmark studies in human transplant recipients, a hyperimmune globulin preparation significantly reduced the incidence of symptomatic disease in renal transplant recipients at risk for primary infection, although prophylactic benefits were modulated by the type of immunosuppressive therapy administered (22–25).…”

Section: Impact Of Cmv‐igmentioning

confidence: 99%

Cytomegalovirus in solid organ transplantation

Rubin

2001

Transplant Infectious Dis

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Despite substantial advances made in controlling the effects of cytomegalovirus (CMV) infection, it remains the single most important pathogen in solid organ transplantation (SOT). Because CMV shares some characteristics with other human herpesviruses, it is also an important model system for understanding the actions of herpesviruses 6 and 7, Epstein-Barr virus (EBV) and, potentially, hepatitis C and B. As the lessons learned from HIV influenced our thinking about other viral infections (e.g. importance of viral load), so too what is learned about CMV will be applied to other herpesviruses. The pervasive nature of CMV and the common problems posed by this virus prompted the convening of a panel of experts in the field of SOT to discuss issues associated with CMV in transplant recipients. This supplement reflects the presentations and discussions at this symposium, including the clinical implications of CMV drug resistance, economic impact of CMV on transplant programs, the rationale for CMV hyperimmune globulin (CMW-IGIV, CytoGam) in SOT, antibody inhibition of CMV, hypogammaglobulinemia, role of CMV in allograft vasculopathy, and the clinical use of CytoGam therapy in a variety of SOT patients. A number of questions during the general discussion prompted the addition of other material to this Supplement, including the development of CMV-IGIV for clinical use in SOT recipients and resource utilization associated with CMV-related hospital readmissions.

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9-(1-3-Dihydroxy-2-propoxymethyl)guanine prevents death but not immunity in murine cytomegalovirus-infected normal and immunosuppressed BALB/c mice

Cited by 22 publications

References 14 publications

Combined antibody and ganciclovir treatment of murine cytomegalovirus-infected normal and immunosuppressed BALB/c mice

Combined antibody and ganciclovir treatment of murine cytomegalovirus-infected normal and immunosuppressed BALB/c mice

Ganciclovir Transiently Attenuates Murine Cytomegalovirus-Associated Renal Allograft Inflammation

Cytomegalovirus in solid organ transplantation

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