Pcr-Screening for Viral Infections during Allogeneic Stem Cell Transplantation: Clinical Benefit and Economic Consideration.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2240-2240
Author(s):  
Susanne Matthes-Martin ◽  
Thomas Lion ◽  
Anita Lawitschka ◽  
Brigitta Keck ◽  
Susanne Karlhuber ◽  
...  
Keyword(s):  
T Cell ◽  
Viral Infection ◽  
Clinical Benefit ◽  
Viral Infections ◽  
Clinical Symptoms ◽  
Viral Disease ◽  
Pcr Screening ◽  
Significant Difference ◽  
Ebv Viremia ◽  
Viral Screening

Abstract Viral infections remain a major cause for transplant related mortality. The introduction of PCR-based assays permits rapid, specific and highly sensitive detection of various viral infections prior to clinical symptoms and thus facilitates preemtive treatment strategies. However a broad routine screening by PCR during the early post-transplant period is cost-intensive. Clinical benefit of broad vs restriced viral screening by PCR was evaluated in total of 98 consecutive pediatric SCT-patients(pts). The first 56 consecutive pts underwent broad viral screening including CMV, ADV, EBV, HSV, VZV, HHV6, HHV7, HHV8, PVB19, RSV, BKV, Enterovirus, Influenza A and B, and Parainfluenza 1–3. PCR-screening was performed twice weekly until day +28 and once weekly until day +100 in peripheral blood (PB), stool, urine and mouth wash. A total of 15675 samples were analyzed. HSV-IgG positive pts. received prophylactic acyclovir. All pts. received preemptive treatment for CMV viremia (gancyclovir) and ADV viremia (cidofovir). Pts with EBV-viremia exceeding 103 copies per ml PB received gancyclovir. In pts. undergoing the broad screening 50/56 pts were positive for at least one virus. The overall incidence of viremia was 61%. HHV6 was detectable in 66% (39% in PB), HHV7 in 16% (11% in PB), CMV in 36% (all in PB, in 23% additionally positive in other sites), EBV in 39% (35% in PB), ADV in 27% (5% in PB), BKV in 13% (all in urine) and PVB19 in one pts. Although the first detection of a viral infection occured before day +120 in all children, PCR positivity persisted throughout the first year post-transplant in many cases. There was no significant difference in the incidence of overall viral infection, viremia or multiple viremia between pts. with T-cell depleted grafts and those with unmanipulated grafts. However T-cell depletion was associated with significantly more lethal viral infections (32% vs 6%, p=0,0127). There was no significant difference in the incidence of viral infections, viremia and lethal viral disease between pts receiving myeloablative conditioning and those receiving reduced intensity conditioning. Isolated HHV6 or HHV7 viremia was not associated with any clinical symptoms and there was no difference concerning the incidence of CMV viremia, lethal viral disease or TRM between pts with and without HHV6 viremia. Of the 20 pts with CMV viremia, 6 pts had lethal CMV disease. 10% of the patients with EBV viremia were symptomatic, the disease being lethal in one case. The three pts who developed ADV viremia had previously been ADV positive in stool. All three pts died from disseminated ADV disease despite treatment with cidofovir. All pts with BKV positive urine had hemorrhagic cystitis. On the basis of these results, the viral screening for the subsequent 42 pts PCR screening was restricted to ADV, CMV and EBV in PB, ADV in stool and BKV in urine once weekly until day +28 and every two weeks thereafter, reducing the cost of the viral screening to 13%. For the patients undergoing restricted screening there was no difference concerning the incidence of CMV, EBV, ADV viremia and the incidence of lethal viral disease (18% vs 14%). We conclude that broad and cost intensive PCR screening for viral infections is of no clinical benefit.

scholarly journals Viral infection prevents diabetes by inducing regulatory T cells through NKT cell–plasmacytoid dendritic cell interplay

2011 ◽  
Vol 208 (4) ◽  
pp. 729-745 ◽  
Author(s):  
Julien Diana ◽  
Vedran Brezar ◽  
Lucie Beaudoin ◽  
Marc Dalod ◽  
Andrew Mellor ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Dendritic Cell ◽  
Regulatory T Cells ◽  
Viral Infection ◽  
Pancreatic Islets ◽  
Viral Infections ◽  
Plasmacytoid Dendritic Cell ◽  
Inkt Cells ◽  
Pancreatic Lymph Nodes

Type 1 diabetes (T1D) is an autoimmune disease resulting from T cell–mediated destruction of insulin-producing β cells, and viral infections can prevent the onset of disease. Invariant natural killer T cells (iNKT cells) exert a regulatory role in T1D by inhibiting autoimmune T cell responses. As iNKT cell–plasmacytoid dendritic cell (pDC) cooperation controls viral replication in the pancreatic islets, we investigated whether this cellular cross talk could interfere with T1D development during viral infection. Using both virus-induced and spontaneous mouse models of T1D, we show that upon viral infection, iNKT cells induce TGF-β–producing pDCs in the pancreatic lymph nodes (LNs). These tolerogenic pDCs convert naive anti-islet T cells into Foxp3+ CD4+ regulatory T cells (T reg cells) in pancreatic LNs. T reg cells are then recruited into the pancreatic islets where they produce TGF-β, which dampens the activity of viral- and islet-specific CD8+ T cells, thereby preventing T1D development in both T1D models. These findings reveal a crucial cooperation between iNKT cells, pDCs, and T reg cells for prevention of T1D by viral infection.

scholarly journals A Combination of Anti-PD-L1 Treatment and Therapeutic Vaccination Facilitates Improved Retroviral Clearance via Reactivation of Highly Exhausted T Cells

mBio ◽  
2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Torben Knuschke ◽  
Sebastian Kollenda ◽  
Christina Wenzek ◽  
Gennadiy Zelinskyy ◽  
Philine Steinbach ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Combination Therapy ◽  
Viral Infection ◽  
Viral Infections ◽  
T Cell Immunity ◽  
Chronic Viral Infection ◽  
Therapeutic Vaccination ◽  
Chronic Viral Infections ◽  
Cell Immunity

ABSTRACT PD-1-targeted therapies have shown modest antiviral effects in preclinical models of chronic viral infection. Thus, novel therapy protocols are necessary to enhance T cell immunity and viral control to overcome T cell dysfunction and immunosuppression. Here, we demonstrate that nanoparticle-based therapeutic vaccination improved PD-1-targeted therapy during chronic infection with Friend retrovirus (FV). Prevention of inhibitory signals by blocking PD-L1 in combination with therapeutic vaccination with nanoparticles containing the microbial compound CpG and a CD8+ T cell Gag epitope peptide synergistically enhanced functional virus-specific CD8+ T cell responses and improved viral clearance. We characterized the CD8+ T cell populations that were affected by this combination therapy, demonstrating that new effector cells were generated and that exhausted CD8+ T cells were reactivated at the same time. While CD8+ T cells with high PD-1 (PD-1hi) expression turned into a large population of granzyme B-expressing CD8+ T cells after combination therapy, CXCR5-expressing follicular cytotoxic CD8+ T cells also expanded to a high degree. Thus, our study describes a very efficient approach to enhance virus control and may help us to understand the mechanisms of combination immunotherapy reactivating CD8+ T cell immunity. A better understanding of CD8+ T cell immunity during combination therapy will be important for developing efficient checkpoint therapies against chronic viral infections and cancer. IMPORTANCE Despite significant efforts, vaccines are not yet available for every infectious pathogen, and the search for a protective approach to prevent the establishment of chronic infections, i.e., with HIV, continues. Immune checkpoint therapies targeting inhibitory receptors, such as PD-1, have shown impressive results against solid tumors. However, immune checkpoint therapies have not yet been licensed to treat chronic viral infections, since a blockade of inhibitory receptors alone provides only limited benefit, as demonstrated in preclinical models of chronic viral infection. Thus, there is a high interest in the development of potent combination immunotherapies. Here, we tested whether the combination of a PD-L1 blockade and therapeutic vaccination with functionalized nanoparticles is a potent therapy during chronic Friend retrovirus infection. We demonstrate that the combination therapy induced a synergistic reinvigoration of the exhausted virus-specific CD8+ T cell immunity. Taken together, our results provide further information on how to improve PD-1-targeted therapies during chronic viral infection and cancer.

scholarly journals Th1 and Th2 Cytokine mRNA Profiles in Childhood Nephrotic Syndrome

1999 ◽  
Vol 10 (3) ◽  
pp. 529-537
Author(s):  
HUI-KIM YAP ◽  
WAI CHEUNG ◽  
BELINDA MURUGASU ◽  
SZE-KEEN SIM ◽  
CHING-CHING SEAH ◽  
...  
Keyword(s):  
Nephrotic Syndrome ◽  
T Cell ◽  
Mrna Expression ◽  
T Cell Activation ◽  
Viral Infections ◽  
Interleukin 2 ◽  
Interferon Γ ◽  
Paired Data ◽  
Cytokine Mrna ◽  
Significant Difference

Abstract. Idiopathic nephrotic syndrome of childhood is thought to be associated with T lymphocyte dysfunction often triggered by viral infections, with the production of circulating factor(s) resulting in proteinuria. In view of the conflicting evidence of T cell activation and Th1 or Th2 pattern of cytokine synthesis in this disease, this study examined the mRNA expression of interleukin-2 (IL-2), interferon-γ, IL-4, and IL-13 from CD4+ and CD8+ T cells in steroid-responsive nephrotic patients in relapse and remission. Fifty-five children with steroid-responsive nephrotic syndrome were included in this study, together with 34 normal controls and 24 patient controls with viral infections. RNA was isolated from purified CD4+ or CD8+ cells from peripheral blood and subjected to reverse transcription-PCR. Cytokine mRNA expression was measured semiquantitatively, and a cytokine index was derived from densitometric readings, with cyclophilin as the housekeeping gene. Both cross-sectional and paired data showed an increased CD4+ and CD8+ IL-13 mRNA expression in patients with nephrotic relapse as compared to remission, normal, and patient controls (P <0.008). This was also associated with increased cytoplasmic IL-13 expression in phorbol myristate acetate/ionomycin-activated CD3+ cells (6.66 ± 3.39%) from patients with nephrotic relapse compared to remission (2.59 ± 1.35%) (P < 0.0001). However, there was no significant difference in CD4+ or CD8+ IL-2, interferon-γ and IL-4 mRNA expression. IL-13 is an important T cell cytokine with anti-inflammatory and immunomodulatory functions on B cells and monocytes. It is conceivable that IL-13 may act on monocytes to produce vascular permeability factor(s) involved in the pathogenesis of proteinuria in patients with relapse nephrotic syndrome.

Molecular and immune predictors of response and toxicity to combined CTLA-4 and PD-1 blockade in metastatic melanoma (MM) patients (pts).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 9579-9579 ◽  
Author(s):  
Wei-Shen Chen ◽  
Miles Cameron Andrews ◽  
Christine Spencer ◽  
Hussein Abdul-Hassan Tawbi ◽  
Alexander Lazar ◽  
...  
Keyword(s):  
T Cell ◽  
Clinical Benefit ◽  
Combined Treatment ◽  
Mutational Load ◽  
Cell Repertoire ◽  
Significant Difference ◽  
Grade 3 ◽  
Immune Related Genes ◽  
T Cell Clonality ◽  
Cell Clonality

9579 Background: Combined treatment with ipilimumab and nivolumab (Ipi/Nivo) achieves clinical responses in > 50% of mm pts. However, responses are not universal and toxicity may be limiting, thus biomarkers of response and toxicity are needed to optimize and personalize this therapy. Methods: Tumor biopsies were collected before (n = 29) and on treatment (n = 7) from mm pts (n = 40) treated with Ipi/Nivo. Whole exome sequencing (WES), gene expression profiling, TCR sequencing, and immunohistochemistry (IHC) were performed to define molecular and immune features of the tumors. Radiographic responses in patients were assessed via RECIST 1.1criteria, and patients were classified as responders (R) deriving clinical benefit (with SD, PR, CR) and non-responders (NR) not deriving clinical benefit (PD). Toxicity was also scored, with patients dichotomized into low toxicity ( < grade 2) versus high toxicity ( > grade 3) re: immune-related (IR) toxicities. Results: In this cohort, the response rate was 80%, with 53% of patients experiencing > grade 3 toxicity. There was no significant difference in baseline mutational load in responders (R) vs non-responders (NR) to Ipi/Nivo, but NR had a higher burden of copy number alterations (CNA; p = 0.013), with frequent alterations detected in PTEN, JAK2, and B2M. There were no significant differences in baseline CD8+ T cell density, expression of immune-related genes, or T cell clonality for R vs NR pts. Ipi/Nivo treatment increased intratumoral T cell clonality, but this did not correlate with response. A more diverse peripheral T cell repertoire at baseline was detected in pts who developed IR toxicity (p < 0.05). Conclusions: This data suggests that responses to Ipi/Nivo in mm may occur in the absence of high mutational load or brisk immune infiltrate at baseline. Putative mechanisms of resistance to Ipi/Nivo include high burden of CNA and alterations in PTEN, JAK2, and B2M. Together these studies identify candidate biomarkers of resistance and toxicity for Ipi/Nivo, though they need to be tested in larger cohorts and across cancer types.

INCLUSION-BEARING CELLS IN THE URINE IN CERTAIN VIRAL INFECTIONS

PEDIATRICS ◽  
1959 ◽  
Vol 24 (1) ◽  
pp. 7-12
Author(s):  
Robert P. Bolande
Keyword(s):  
Urinary Tract ◽  
Viral Infection ◽  
Viral Infections ◽  
Viral Disease ◽  
Cytopathic Effects ◽  
Large Numbers

An inclusion-bearing cell is described which appears in the urine of patients with measles, german measles, chickenpox, mumps and herpangina. The presence of the inclusion-bearing cells in large numbers in the urine is very characteristic of measles, but not pathognomonic of that illness or viral disease in general. The possibility that the inclusions represent the cytopathic effects of viral infection on cells derived from the blood or urinary tract stroma is discussed.

scholarly journals Selenium, Selenoproteins and Viral Infection

Nutrients ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 2101 ◽  
Author(s):  
Olivia Guillin ◽  
Caroline Vindry ◽  
Théophile Ohlmann ◽  
Laurent Chavatte
Keyword(s):  
Oxidative Stress ◽  
Viral Replication ◽  
Viral Infection ◽  
Antioxidant Defense ◽  
Viral Infections ◽  
Clinical Symptoms ◽  
Biological Activities ◽  
Redox Homeostasis ◽  
Selenium Deficiency ◽  
Antioxidant Defense System

Reactive oxygen species (ROS) are frequently produced during viral infections. Generation of these ROS can be both beneficial and detrimental for many cellular functions. When overwhelming the antioxidant defense system, the excess of ROS induces oxidative stress. Viral infections lead to diseases characterized by a broad spectrum of clinical symptoms, with oxidative stress being one of their hallmarks. In many cases, ROS can, in turn, enhance viral replication leading to an amplification loop. Another important parameter for viral replication and pathogenicity is the nutritional status of the host. Viral infection simultaneously increases the demand for micronutrients and causes their loss, which leads to a deficiency that can be compensated by micronutrient supplementation. Among the nutrients implicated in viral infection, selenium (Se) has an important role in antioxidant defense, redox signaling and redox homeostasis. Most of biological activities of selenium is performed through its incorporation as a rare amino acid selenocysteine in the essential family of selenoproteins. Selenium deficiency, which is the main regulator of selenoprotein expression, has been associated with the pathogenicity of several viruses. In addition, several selenoprotein members, including glutathione peroxidases (GPX), thioredoxin reductases (TXNRD) seemed important in different models of viral replication. Finally, the formal identification of viral selenoproteins in the genome of molluscum contagiosum and fowlpox viruses demonstrated the importance of selenoproteins in viral cycle.

scholarly journals IL-10 blockade facilitates DNA vaccine-induced T cell responses and enhances clearance of persistent virus infection

2008 ◽  
Vol 205 (3) ◽  
pp. 533-541 ◽  
Author(s):  
David G. Brooks ◽  
Andrew M. Lee ◽  
Heidi Elsaesser ◽  
Dorian B. McGavern ◽  
Michael B.A. Oldstone
Keyword(s):  
T Cell ◽  
Viral Infection ◽  
Dna Vaccine ◽  
Viral Infections ◽  
T Cell Responses ◽  
Lymphocytic Choriomeningitis ◽  
T Cell Immunity ◽  
Therapeutic Vaccination ◽  
Cell Responses ◽  
Cell Immunity

Therapeutic vaccination is a potentially powerful strategy to establish immune control and eradicate persistent viral infections. Large and multifunctional antiviral T cell responses are associated with control of viral persistence; however, for reasons that were mostly unclear, current therapeutic vaccination approaches to restore T cell immunity and control viral infection have been ineffective. Herein, we confirmed that neutralization of the immunosuppressive factor interleukin (IL)-10 stimulated T cell responses and improved control of established persistent lymphocytic choriomeningitis virus (LCMV) infection. Importantly, blockade of IL-10 also allowed an otherwise ineffective therapeutic DNA vaccine to further stimulate antiviral immunity, thereby increasing T cell responses and enhancing clearance of persistent LCMV replication. We therefore propose that a reason that current therapeutic vaccination strategies fail to resurrect/sustain T cell responses is because they do not alleviate the immunosuppressive environment. Consequently, blocking key suppressive factors could render ineffective vaccines more efficient at improving T cell immunity, and thereby allow immune-mediated control of persistent viral infection.

scholarly journals Respiratory Viral Infections in Infants: Causes, Clinical Symptoms, Virology, and Immunology

2010 ◽  
Vol 23 (1) ◽  
pp. 74-98 ◽  
Author(s):  
John S. Tregoning ◽  
Jürgen Schwarze
Keyword(s):  
Immune Response ◽  
Immune System ◽  
Viral Infection ◽  
Viral Infections ◽  
Clinical Symptoms ◽  
Later Life ◽  
Treatment Needs ◽  
Syncytial Virus ◽  
Degree Of Similarity

SUMMARY In global terms, respiratory viral infection is a major cause of morbidity and mortality. Infancy, in particular, is a time of increased disease susceptibility and severity. Early-life viral infection causes acute illness and can be associated with the development of wheezing and asthma in later life. The most commonly detected viruses are respiratory syncytial virus (RSV), rhinovirus (RV), and influenza virus. In this review we explore the complete picture from epidemiology and virology to clinical impact and immunology. Three striking aspects emerge. The first is the degree of similarity: although the infecting viruses are all different, the clinical outcome, viral evasion strategies, immune response, and long-term sequelae share many common features. The second is the interplay between the infant immune system and viral infection: the immaturity of the infant immune system alters the outcome of viral infection, but at the same time, viral infection shapes the development of the infant immune system and its future responses. Finally, both the virus and the immune response contribute to damage to the lungs and subsequent disease, and therefore, any prevention or treatment needs to address both of these factors.

scholarly journals Viral persistence redirects CD4 T cell differentiation toward T follicular helper cells

2011 ◽  
Vol 208 (5) ◽  
pp. 987-999 ◽  
Author(s):  
Laura M. Fahey ◽  
Elizabeth B. Wilson ◽  
Heidi Elsaesser ◽  
Chris D. Fistonich ◽  
Dorian B. McGavern ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Viral Infection ◽  
Cd4 T Cells ◽  
Viral Infections ◽  
Viral Persistence ◽  
Cd4 T Cell ◽  
T Follicular Helper Cells ◽  
Helper Cells ◽  
Follicular Helper

CD4 T cell responses are crucial to prevent and control viral infection; however, virus-specific CD4 T cell activity is considered to be rapidly lost during many persistent viral infections. This is largely caused by the fact that during viral persistence CD4 T cells do not produce the classical Th1 cytokines associated with control of acute viral infections. Considering that CD4 T cell help is critical for both CD8 T cell and B cell functions, it is unclear how CD4 T cells can lose responsiveness but continue to sustain long-term control of persistent viral replication. We now demonstrate that CD4 T cell function is not extinguished as a result of viral persistence. Instead, viral persistence and prolonged T cell receptor stimulation progressively redirects CD4 T cell development away from the Th1 response induced during an acute infection toward T follicular helper cells. Importantly, this sustained CD4 T cell functionality is critical to maintain immunity and ultimately aid in the control of persistent viral infection.

Effect of Melan-Α/Μart-1-peptide vaccination plus IMP321 on antitumor immunity and clinical benefit in patients receiving autologous PBMCs after lymphodepletion.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e20011-e20011
Author(s):  
Emanuela Romano ◽  
Helene Bichat ◽  
Athina Stravodimou ◽  
Pedro Romero ◽  
Speiser E Daniel ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Clinical Benefit ◽  
Fold Increase ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
Great Promise ◽  
Control Group ◽  
Significant Difference

e20011 Background: Immunotherapy offers great promise for cancer treatmet. Strong evidence supports adoptive cell transfer (ACT) and immunemodulation for regression of advanced melanoma. Few studies assessed the potential synergy between these two strategies. Methods: Twelve patients with metastatic melanoma received multiple Melan-A/Mart-1-peptide vaccinations with (n=6) or without (n=6) IMP321 (LAG-3Ig fusion protein) as an adjuvant in combination with lymphodepleting chemotherapy and ACT. All patients were selected on the basis of ex vivo detectable Melan-A-specific CD8 T cell responses and were immunized at day (D) 0, 8, 15, 22, 28, 52, and 74 post-reinfusion. Results: One-week after reinfusion of bulk autologous PBMCs, a significant expansion of Melan-A-specific CD8 T cells was measured in >83% (n=5) and <17% (n=1) of patients from the IMP321 and control groups, respectively (p=0.02). Compared to the control group, the mean fold increase of Melan-A-specific CD8 T cells was respectively >2-, >4-, and >6-fold higher in the IMP321 group at D15, D30, and D60 (p=0.02). A long-lasting Melan-A-specific CD8 T-cell response was significantly associated with IMP321 (p<0.001). A higher proportion of Melan-A-specific CD8 TEMRA (i.e., CD45RA+CCR7-CD127-) cells was observed in the IMP321 group at the peak of the response (p <0.002), whereas no significant difference was observed in the expression of co-inhibitory receptors (i.e., PD-1, 2B4, TIM3, CD160). IMP321 was associated with a significantly (p<0.04) reduced expansion of regulatory T cells (TREGS); we observed a negative correlation between the fold increase of Melan-A-specific CD8 T cells and the relative expansion of TREGS. Clinical benefit (assessed as CR, PR, and SD) was observed in none of the control patients vs 67% (4/6) of patients from the IMP321 group, (p=0.02). Conclusions: Vaccination with IMP321 as an adjuvant in combination with lymphodepleting chemotherapy and ACT provided clinical benefit and this was associated with a more robust and durable cellular antitumor immune response, supporting further development of IMP321 for future immunotherapeutic strategies. Clinical trial information: NCT00324623.

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