Viral Infections in Transplant Recipients

Razonable, Raymund R.; Eid, Albert J.

doi:10.1007/978-3-319-19674-9_47

Cited by 20 publications

(20 citation statements)

References 130 publications

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“…Immunosuppressive therapy to deplete T cells, redirect T-cell trafficking, or terminate T-cell response pathways after solid organ (SOT) and hematopoietic stem cell transplantation (HSCT) is mainly used to prevent graft rejection or severe graft-vs.-host disease (GvHD) (1–3). Immunocompromised patients are highly susceptible to viral infection and reactivation by endogenous herpes viruses such as cytomegalovirus (CMV) and Epstein-Barr virus (EBV), which are associated with high morbidity and mortality (4, 5). Current treatment strategies involve administering effective antiviral drug therapies, reducing the degree of immunosuppression, or changing the individual immunosuppressive drug regimen in order to restore virus-specific T cell-mediated immune responses (4, 6–10).…”

Section: Introductionmentioning

confidence: 99%

Selective Effects of mTOR Inhibitor Sirolimus on Naïve and CMV-Specific T Cells Extending Its Applicable Range Beyond Immunosuppression

et al. 2018

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Cytomegalovirus (CMV) infection/reactivation remains among the most important complications of immunosuppression after transplantation. However, recent clinical observations indicate that mammalian target of rapamycin (mTOR) inhibition with sirolimus may improve the outcome of CMV complications. Underlying mechanisms of this observation, particularly the effect of sirolimus on naïve- and CMV-specific cytotoxic CD8+ T-cell (CMV-CTL) functionality is still undiscovered. Here, the influence of sirolimus on naïve and memory CMV-CTLs was determined by CD3/CD28 crosslinking and alloreactivity assays. After stimulating CMV-CTL with HLA-A*02:01-restricted CMVpp65-peptide loaded artificial antigen-presenting cells (aAPCs), we measured the effect of sirolimus on T-cell proliferation, phenotype, and functionality. Sirolimus significantly improved CMV-specific effector memory T-cell function and negatively influenced naïve T cells. This unique mechanism of action was further characterized by increased secretion of interferon-gamma (IFN-γ), granzyme B (GzB) and enhanced target-cell-dependent cytotoxic capacity of activated CMV-CTLs. Next-generation-sequencing (NGS) was applied to monitor T-cell receptor (TCR)-repertoire dynamics and to verify, that the increased functionality was not related to sirolimus-resistant CTL-clones. Instead, modulation of environmental cues during CMV-CTL development via IL-2 receptor (IL-2R)-driven signal transducer and activator of transcription-5 (STAT-5) signaling under mTOR inhibition allowed fine-tuning of T-cell programming for enhanced antiviral response with stable TCR-repertoire dynamics. We show for the first time that sirolimus acts selectively on human naïve and memory T cells and improves CMV-specific T-cell function via modulation of the environmental milieu. The data emphasize the importance to extend immune monitoring including cytokine levels and T-cell functionality which will help to identify patients who may benefit from individually tailored immunosuppression.

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Section: Introductionmentioning

confidence: 99%

Selective Effects of mTOR Inhibitor Sirolimus on Naïve and CMV-Specific T Cells Extending Its Applicable Range Beyond Immunosuppression

et al. 2018

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“…The clinical symptoms of BKV-HC vary to a great extent in Allo-SCT recipients from asymptomatic hematuria to massive hemorrhage leading to urinary obstruction and renal failure [2,9,10]. Previous studies demonstrated that BKV-HC is associated with not only increased morbidity and but also increased mortality in Allo-SCT patients [6,7,11,12], and studies have also defined potential risk factors for the development of BKV-HC [4,5,13,14,15], most of which have not been observed consistently in several reports.…”

Section: Introductionmentioning

confidence: 99%

BK Virus-Hemorrhagic Cystitis Following Allogeneic Stem Cell Transplantation: Clinical Characteristics and Utility of Leflunomide Treatment

Park¹,

Lim²,

Yi³

et al. 2016

Tjh

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Objective:BK virus-hemorrhagic cystitis (BKV-HC) is a potential cause of morbidity and mortality in patients having undergone allogeneic stem cell transplantation (Allo-SCT). We analyzed the clinical features of BKV-HC following Allo-SCT and reported the utility of leflunomide therapy for BKV-HC.Materials and Methods:From January 2005 to June 2014, among the 69 patients that underwent Allo-SCT in our institution, the patients who experienced BKV-HC were investigated retrospectively.Results:HC was observed in 30 patients (43.5%), and among them, 18 of the cases (26.1%) were identified as BKV-HC. The median age of the patients (12 males and 6 females) was 45 years (minimum-maximum: 13-63). Patients received Allo-SCT for acute myeloid leukemia (n=11), aplastic anemia (n=4), myelodysplastic syndrome (n=2), and non-Hodgkin lymphoma (n=1). The donor types were human leukocyte antigen (HLA)-matched sibling donor for six patients, HLA-matched unrelated donor for nine, and haploidentical familial donor for two. The median onset and duration of BKV-HC was on day 21 after transplantation (minimum-maximum: 7-97) and 22 days (minimum-maximum: 6-107). Eleven patients (62.1%) had grade I-II HC and seven patients (38.9%) had grade III-IV (high-grade) HC. Among the seven patients who had high-grade HC, one had complete response, one had partial response, and five had no response. Among the five nonresponders, one died of BKV-HC associated complications. The remaining four patients were treated with leflunomide, achieving complete response (n=2) and partial response (n=2). The median duration from the start of leflunomide therapy to response was 13 days (minimum-maximum: 8-17 days). All patients tolerated the leflunomide treatment well, with three patients having mild gastrointestinal symptoms, including anorexia and abdominal bloating.Conclusion:BKV-HC was commonly observed in patients with HC following Allo-SCT. In high-grade BKV-HC patients who do not respond to supportive care, leflunomide may be a feasible option without significant toxicity.

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“…In immunocompromised patients, such as solid-organ transplant or hematopoietic stem cell transplant recipients, human ADV infections leaf to high morbidity and mortality. 2 In fact, human ADV is reportedly the most increased virus in transplant recipients, especially in pediatric units. 3 No effective therapy or definitely approved drug has yet been developed for ADV associated diseases.…”

Section: Introductionmentioning

confidence: 99%

In vitro anti-adenoviral activities of ethanol extract, fractions, and main phenolic compounds of pomegranate (Punica granatumL.) peel

Karimi

Moradi

Rabiei

et al. 2020

Antivir Chem Chemother

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Background Adenovirus causes a number of diseases in human, and can cause serious infection in severely immunosuppressed individuals. Despite the seriousness of adenovirus infection, there is no definitely approved anti-adenoviral therapy. Many studies have shown that compounds derived from medicinal plants have antiviral activity. Therefore, this study evaluated in vitro anti-adenoviral activity of ethanol extract, fractions, and main phenolic compounds of pomegranate peel. Methods The ethanol extract of pomegranate peel was prepared with maceration method and fractionated by consecutive liquid/liquid partition. The cytotoxic and anti-adenovirus activities of the extract, fractions, and main phenolic compounds (ellagic acid, punicalagin and gallic acid) were evaluated on Hep-2 cell line using MTT assay. Inhibitory effect on adsorption and post-adsorption phases of the virus replication cycle was also evaluated. Results Pomegranate peel extract had a desirable effect against adenovirus with IC50 of 5.77 µg/mL and selectivity index of 49.9. Among the fractions and compounds, the n-butanol fraction and gallic acid had the highest anti-adenoviral activity with IC50 of 2.16 µg/mL and 4.67 µM and selectivity indices of 122.5 and 10.5, respectively. The crude extract, n-butanol fraction and gallic acid inhibited the virus replication in post-adsorption phase ( p < 0.01). Conclusion Pomegranate peel extract, especially its n-butanol fraction, could serve as a new promising anti-adenovirus agent due to high inhibitory effect against adenovirus replication. The effect of the n-butanol fraction may be related to the synergistic effect or other compounds of this fraction. Further understanding of the bioassay guided isolation of natural compounds of this fraction seems essential.

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Viral Infections in Transplant Recipients

Cited by 20 publications

References 130 publications

Selective Effects of mTOR Inhibitor Sirolimus on Naïve and CMV-Specific T Cells Extending Its Applicable Range Beyond Immunosuppression

Selective Effects of mTOR Inhibitor Sirolimus on Naïve and CMV-Specific T Cells Extending Its Applicable Range Beyond Immunosuppression

BK Virus-Hemorrhagic Cystitis Following Allogeneic Stem Cell Transplantation: Clinical Characteristics and Utility of Leflunomide Treatment

In vitro anti-adenoviral activities of ethanol extract, fractions, and main phenolic compounds of pomegranate (Punica granatumL.) peel

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