RESUMO
PURPOSE: Glial fibrillary acidic protein astrocytopathy (GFAP-A) pathogenesis remains uncertain, with potential viral involvement. More clinical cases are needed to deepen our understanding of this disease, along with the exploration of more effective treatment options to provide clinicians with additional choices. METHODS: We report a severe case of GFAP-A secondary to EBV infection, characterized predominantly by central respiratory failure. Additionally, we conducted a literature review summarizing the characteristics of GFAP-IgG-positive patients associated with EBV infection. RESULTS: Among the 13 patients identified, fever (92.3%) and headache (84.6%) were the most common initial symptoms, while urinary dysfunction was universally present in all patients. Over half of the patients with altered consciousness required endotracheal intubation (7/11, 63.6%), with only one individual experiencing complete resolution without any residual sequela. Only two patients (16.7%) displayed the classic feature of periventricular enhancement on neuroimaging, whereas T2-FLAIR hyperintensities were more prevalent. All patients tested positive for GFAP-IgG in CSF, and 91.7% (11/12) had detectable serum GFAP-IgG antibodies. Three patients (23.1%) achieved full recovery solely through antiviral therapy. In patients receiving various immunotherapies, 60% (6/10) still had residual sequelae. CONCLUSION: EBV infection may contribute to the pathogenesis of GFAP-A. GFAP antibody testing is recommended for diagnostic evaluation in cases of central nervous system viral infections presenting with respiratory insufficiency. For severe GFAP-A patients, Protein A immunoadsorption (Protein A IA).
Assuntos
Infecções por Vírus Epstein-Barr , Proteína Glial Fibrilar Ácida , Imunoglobulinas Intravenosas , Humanos , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/terapia , Imunoglobulinas Intravenosas/uso terapêutico , Masculino , Hipoventilação/terapia , Feminino , Herpesvirus Humano 4 , AdultoRESUMO
Adoptive immunotherapy with Epstein-Barr virus (EBV)-specific T cells is an effective treatment for relapsed or refractory EBV-induced post-transplant lymphoproliferative disorders (PTLD) with overall survival rates of up to 69%. EBV-specific T cells have been conventionally made by repeated stimulation with EBV-transformed lymphoblastoid cell lines (LCL), which act as antigen-presenting cells. However, this process is expensive, takes many months, and has practical risks associated with live virus. We have developed a peptide-based, virus-free, serum-free closed system to manufacture a bank of virus-specific T cells (VST) for clinical use. We compared these with standard LCL-derived VST using comprehensive characterization and potency assays to determine differences that might influence clinical benefits. Multi-parameter flow cytometry revealed that peptide-derived VST had an expanded central memory population and less exhaustion marker expression than LCL-derived VST. A quantitative HLA-matched allogeneic cytotoxicity assay demonstrated similar specific killing of EBV-infected targets, though peptide-derived EBV T cells had a significantly higher expression of antiviral cytokines and degranulation markers after antigen recall. High-throughput T cell receptor-beta (TCRß) sequencing demonstrated oligoclonal repertoires, with more matches to known EBV-binding complementary determining region 3 (CDR3) sequences in peptide-derived EBV T cells. Peptide-derived products showed broader and enhanced specificities to EBV nuclear antigens (EBNAs) in both CD8 and CD4 compartments, which may improve the targeting of highly expressed latency antigens in PTLD. Importantly, peptide-based isolation and expansion allows rapid manufacture and significantly increased product yield over conventional LCL-based approaches.
Assuntos
Infecções por Vírus Epstein-Barr , Herpesvirus Humano 4 , Imunoterapia Adotiva , Peptídeos , Humanos , Herpesvirus Humano 4/imunologia , Imunoterapia Adotiva/métodos , Peptídeos/imunologia , Infecções por Vírus Epstein-Barr/imunologia , Infecções por Vírus Epstein-Barr/terapia , Linhagem Celular Transformada , Ativação Linfocitária/imunologia , Linfócitos T/imunologiaRESUMO
Invariant natural killer T (iNKT) cells are a conserved population of innate T lymphocytes that are uniquely suitable as off-the-shelf cellular immunotherapies due to their lack of alloreactivity. Two major subpopulations of human iNKT cells have been delineated, a CD4- subset that has a TH1/cytolytic profile, and a CD4+ subset that appears polyfunctional and can produce both regulatory and immunostimulatory cytokines. Whether these two subsets differ in anti-tumour effects is not known. Using live cell imaging, we found that CD4- iNKT cells limited growth of CD1d+ Epstein-Barr virus (EBV)-infected B-lymphoblastoid spheroids in vitro, whereas CD4+ iNKT cells showed little or no direct anti-tumour activity. However, the effects of the two subsets were reversed when we tested them as adoptive immunotherapies in vivo using a xenograft model of EBV-driven human B cell lymphoma. We found that EBV-infected B cells down-regulated CD1d in vivo, and administering CD4- iNKT cells had no discernable impact on tumour mass. In contrast, xenotransplanted mice bearing lymphomas showed rapid reduction in tumour mass after administering CD4+ iNKT cells. Immunotherapeutic CD4+ iNKT cells trafficked to both spleen and tumour and were associated with subsequently enhanced responses of xenotransplanted human T cells against EBV. CD4+ iNKT cells also had adjuvant-like effects on monocyte-derived DCs and promoted antigen-dependent responses of human T cells in vitro. These results show that allogeneic CD4+ iNKT cellular immunotherapy leads to marked anti-tumour activity through indirect pathways that do not require tumour cell CD1d expression and that are associated with enhanced activity of antigen-specific T cells.
Assuntos
Antígenos CD1d , Infecções por Vírus Epstein-Barr , Herpesvirus Humano 4 , Imunoterapia Adotiva , Linfoma de Células B , Células T Matadoras Naturais , Antígenos CD1d/metabolismo , Antígenos CD1d/imunologia , Humanos , Animais , Células T Matadoras Naturais/imunologia , Imunoterapia Adotiva/métodos , Herpesvirus Humano 4/imunologia , Linfoma de Células B/imunologia , Linfoma de Células B/terapia , Camundongos , Infecções por Vírus Epstein-Barr/imunologia , Infecções por Vírus Epstein-Barr/terapia , Ensaios Antitumorais Modelo de Xenoenxerto , Linhagem Celular Tumoral , Camundongos SCID , Camundongos Endogâmicos NODRESUMO
Multiple sclerosis (MS), an intricate neurological disorder, continues to challenge our understanding of the pivotal interplay between the immune system and the central nervous system (CNS). This condition arises from the immune system's misdirected attack on nerve fiber protection, known as myelin sheath, alongside nerve fibers themselves. This enigmatic condition, characterized by demyelination and varied clinical manifestations, prompts exploration into its multifaceted etiology and potential therapeutic avenues. Research has revealed a potential connection between Epstein Barr virus (EBV), specifically Epstein Barr Nuclear Antigen 1 (EBNA-1), and MS. The immune response to EBNA-1 antigen triggers the production of anti-EBNA-1 molecules, including IgG that identify a similar amino acid sequence to EBNA-1 in myelin, inadvertently targeting myelin sheath and contributing to MS progression. Currently, no treatment exists for EBNA-1-induced MS apart from symptom management. Addressing this, a novel potential therapeutic avenue utilizing small interference RNAs (siRNA) has been designed. By targeting the conserved EBNA-1 gene sequences in EBV types 1 and 2, five potential siRNAs were identified in our analysis. Thorough evaluations encompassing off-target binding, thermodynamics and secondary structure elucidation, efficacy prediction, siRNA-mRNA sequence binding affinity exploration, melting temperature, and docking of siRNAs with human argonaute protein 2 (AGO2) were conducted to elucidate the siRNAs efficiency. These designed siRNA molecules harnessed promising silencing activity in the EBNA-1 gene encoding the EBNA-1 antigen protein and thus have the potential to mitigate the severity of this dangerous virus.
Assuntos
Infecções por Vírus Epstein-Barr , Antígenos Nucleares do Vírus Epstein-Barr , Herpesvirus Humano 4 , Esclerose Múltipla , RNA Interferente Pequeno , Esclerose Múltipla/terapia , Esclerose Múltipla/genética , Humanos , Herpesvirus Humano 4/genética , Antígenos Nucleares do Vírus Epstein-Barr/genética , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/uso terapêutico , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/terapiaRESUMO
Posttransplant lymphoproliferative disease (PTLD) is a major therapeutic challenge that has been difficult to study using human cells because of a lack of suitable models for mechanistic characterization. Here, we show that ex vivo-differentiated B cells isolated from a subset of healthy donors can elicit pathologies similar to PTLD when transferred into immunodeficient mice. The primary driver of PTLD-like pathologies were IgM-producing plasmablasts with Epstein-Barr virus (EBV) genomes that expressed genes commonly associated with EBV latency. We show that a small subset of EBV+ peripheral blood-derived B cells expressing self-reactive, nonmutated B cell receptors (BCRs) expand rapidly in culture in the absence of BCR stimulation. Furthermore, we found that in vitro and in vivo expansion of EBV+ plasmablasts required BCR signaling. Last, treatment of immunodeficient mice with the BCR pathway inhibitor, ibrutinib, delays onset of PTLD-like pathologies in vivo. These data have implications for the diagnosis and care of transplant recipients who are at risk of developing PTLD.
Assuntos
Infecções por Vírus Epstein-Barr , Transtornos Linfoproliferativos , Humanos , Animais , Camundongos , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/terapia , Herpesvirus Humano 4 , Transtornos Linfoproliferativos/terapia , Transdução de Sinais , Linfócitos BAssuntos
Proteínas de Transporte de Cátions , Infecções por Vírus Epstein-Barr , Doença de Hodgkin , Imunoterapia , Linfócitos T , Gêmeos Monozigóticos , Humanos , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/terapia , Herpesvirus Humano 4 , Doença de Hodgkin/terapia , Proteínas de Transporte de Cátions/deficiência , Proteínas de Transporte de Cátions/genéticaRESUMO
OBJECTIVE: Monitoring the disease status of Epstein-Barr virus (EBV)-related hemophagocytic lymphohistiocytosis (HLH) patients is crucial. This study aimed to investigate the different strategies and outcomes of patients with EBV-HLH and re-elevated EBV-DNA. METHOD: A retrospective analysis was conducted on 20 patients diagnosed with EBV-HLH. Clinical features, laboratory tests, treatments, plasma EBV-DNA levels, and outcomes were assessed. Three cases were highlighted for detailed analysis. RESULTS: Nine of the 20 patients had a re-elevation of EBV-DNA during treatment, and 55.5 % (5/9) experienced relapses. Patients with persistently positive plasma EBV-DNA (n = 4) and those with re-elevated EBV-DNA after conversion (n = 9) showed a significantly higher relapse rate compared to those with persistently negative EBV-HLH (n = 7) (p < 0.05). Among the highlighted cases, Case 1 exhibited plasma EBV-DNA re-elevation after four weeks of treatment without relapse, maintaining stability with the original treatment regimen, and eventually, his plasma EBV-DNA turned negative. In Case 2, plasma EBV-DNA was elevated again with a recurrence of HLH after L-DEP. Consequently, she underwent allogeneic hematopoietic stem cell transplantation and eventually achieved complete remission (CR) with negative plasma EBV-DNA. Case 3 experienced plasma EBV-DNA re-elevation after L-DEP but remained in CR, discontinuing chemotherapy without relapse. CONCLUSION: The re-elevation of plasma EBV-DNA during EBV-HLH treatment poses challenges in determining disease status and treatment strategies. Optimal management decisions require a combination of the level of elevated EBV-DNA, the intensity of hyperinflammation, and the patient's immune function.
Assuntos
DNA Viral , Infecções por Vírus Epstein-Barr , Herpesvirus Humano 4 , Linfo-Histiocitose Hemofagocítica , Recidiva , Humanos , Linfo-Histiocitose Hemofagocítica/terapia , Linfo-Histiocitose Hemofagocítica/sangue , Linfo-Histiocitose Hemofagocítica/virologia , Estudos Retrospectivos , Masculino , Infecções por Vírus Epstein-Barr/sangue , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/terapia , Feminino , DNA Viral/sangue , Pré-Escolar , Criança , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/isolamento & purificação , Lactente , Adolescente , Resultado do Tratamento , Relevância ClínicaRESUMO
BACKGROUND/AIM: Adoptive cell therapy using antigen-specific T cells is a promising treatment modality for cancer patients. Various methods to isolate specific T cells and identify corresponding T cell receptor (TCR) sequences are known. This study aimed to identify antigen-specific TCR from T cells isolated using carboxyfluorescein succinimidyl ester (CFSE), which marks proliferating activated T cells. MATERIALS AND METHODS: CFSE stained healthy donor peripheral blood mononuclear cells (PBMCs) were treated with cytomegalovirus (CMV) or Epstein-Barr virus (EBV) peptides for seven days. Then, proliferating T cells with decreased CFSE staining were isolated and single cell VDJ sequencing was performed on isolated T cells to identify antigen-specific TCRs. RESULTS: As antigen-specific TCR candidates, ten TCR clones were selected for the CMV antigen and five for the EBV antigen. The reactivity of ten CMV TCR-transduced T cells and one EBV TCR-transduced T cell toward T2 cells pulsed with CMV or EBV peptide was confirmed via NFAT-luciferase, IFN-γ ELISA, and cytotoxicity assays. CONCLUSION: Identification of antigen-specific TCRs with CFSE staining is a valid method for the development of effective immunotherapy. The identified CMV- or EBV-specific TCRs can be used for adoptive cell therapy to treat cancer.
Assuntos
Infecções por Citomegalovirus , Infecções por Vírus Epstein-Barr , Fluoresceínas , Neoplasias , Succinimidas , Humanos , Linfócitos T , Infecções por Vírus Epstein-Barr/terapia , Herpesvirus Humano 4 , Leucócitos Mononucleares , Citomegalovirus , Receptores de Antígenos de Linfócitos TRESUMO
Post-transplant lymphoproliferative disorders (PTLD) is a devastating complication of kidney transplantation with an insidious presentation and potential to disseminate aggressively. This review delineates the risk factors, prognostic indexes, screening, current management algorithm and promising treatment strategies for PTLD. Kidneys from both extended criteria donors (ECD) and living donors (LD) are being increasingly used to expand the donor pool. This review also delineates whether PTLD outcomes vary based on these donor sources. While Epstein-Barr virus (EBV) is a well-known risk factor for PTLD development, the use of T-cell depleting induction agents has been increasingly implicated in aggressive, monomorphic forms of PTLD. Research regarding maintenance therapy is sparse. The international prognostic index seems to be the most validate prognostic tool. Screening for PTLD is controversial, as annual PET-CT is most sensitive but costly, while targeted monitoring of EBV-seronegative patients was more economically feasible, is recommended by the American Society of Transplantation, but is limited to a subset of the population. Other screening strategies such as using Immunoglobulin/T-cell receptor require further validation. A risk-stratified approach is taken in the treatment of PTLD. The first step is the reduction of immunosuppressants, after which rituximab and chemotherapy may be introduced if unsuccessful. Some novel treatments have also shown potential benefit in studies: brentuximab vedotin, chimeric antigen receptor T-cell therapy and EBV-specific cytotoxic T lymphocytes. Analysis of LD v DD recipients show no significant difference in incidence and mortality of PTLD but did reveal a shortened time to development of PTLD from transplant. Analysis of SCD vs ECD recipients show a higher incidence of PTLD in the ECD group, which might be attributed to longer time on dialysis for these patients, age, and the pro-inflammatory nature of these organs. However, incidence of PTLD overall is still extremely low. Efforts should be focused on optimising recipients instead. Minimising the use of T-cell depleting therapy while encouraging research on the effect of new immunosuppressants on PTLD, screening for EBV status are essential, while enabling shared decision-making during counselling when choosing kidney donor types and individualised risk tailoring are strongly advocated.
Assuntos
Infecções por Vírus Epstein-Barr , Transplante de Rim , Transtornos Linfoproliferativos , Humanos , Transplante de Rim/efeitos adversos , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/diagnóstico , Infecções por Vírus Epstein-Barr/terapia , Herpesvirus Humano 4 , Prognóstico , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/efeitos adversos , Fatores de Risco , Transtornos Linfoproliferativos/diagnóstico , Transtornos Linfoproliferativos/etiologia , Transtornos Linfoproliferativos/terapia , Doadores de Tecidos , Imunossupressores/efeitos adversosRESUMO
Nasopharyngeal carcinoma (NPC) is one of the most common tumors in South China and Southeast Asia and is thought to be associated with Epstein-Barr virus (EBV) infection. Downregulation of latent membrane protein 1 (LMP1) encoded by EBV can reduce the expression of NF-κB and PI3K, induce apoptosis, and inhibit the growth of EBV-related NPC. For targeted cleavage of the Lmp1 oncogene via the CRISPR/Cas9 gene editing system, a post cross-linked ROS-responsive poly(ß-amino ester) (PBAE) polymeric vector was developed for the delivery of CRISPR/Cas9 plasmids both in vitro and in vivo. After composition optimization, the resultant polymer-plasmid polyplex nanoparticles (NPs) showed a diameter of â¼230 nm and a zeta potential of 22.3 mV with good stability. Compared with the non-cross-linked system, the cross-linked NPs exhibited efficient and quick cell uptake, higher transfection efficiency in EBV-positive C666-1 cells (53.5% vs. 40.6%), more efficient gene editing ability against the Mucin2 model gene (Muc2) (17.9% vs. 15.4%) and Lmp1 (8.5% vs. 5.6%), and lower intracellular reactive oxygen species (ROS) levels. The NPs achieved good tumor penetration and tumor growth inhibition in the C666-1 xenograft tumor model via Lmp1 cleavage, indicating their potential for gene therapy of EBV-related NPC.
Assuntos
Carcinoma , Infecções por Vírus Epstein-Barr , Neoplasias Nasofaríngeas , Polímeros , Humanos , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/terapia , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Infecções por Vírus Epstein-Barr/genética , Infecções por Vírus Epstein-Barr/terapia , Infecções por Vírus Epstein-Barr/metabolismo , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/terapia , Terapia GenéticaRESUMO
Epstein-Barr virus (EBV) infection can engender severe B cell lymphoproliferative diseases1,2. The primary infection is often asymptomatic or causes infectious mononucleosis (IM), a self-limiting lymphoproliferative disorder3. Selective vulnerability to EBV has been reported in association with inherited mutations impairing T cell immunity to EBV4. Here we report biallelic loss-of-function variants in IL27RA that underlie an acute and severe primary EBV infection with a nevertheless favourable outcome requiring a minimal treatment. One mutant allele (rs201107107) was enriched in the Finnish population (minor allele frequency = 0.0068) and carried a high risk of severe infectious mononucleosis when homozygous. IL27RA encodes the IL-27 receptor alpha subunit5,6. In the absence of IL-27RA, phosphorylation of STAT1 and STAT3 by IL-27 is abolished in T cells. In in vitro studies, IL-27 exerts a synergistic effect on T-cell-receptor-dependent T cell proliferation7 that is deficient in cells from the patients, leading to impaired expansion of potent anti-EBV effector cytotoxic CD8+ T cells. IL-27 is produced by EBV-infected B lymphocytes and an IL-27RA-IL-27 autocrine loop is required for the maintenance of EBV-transformed B cells. This potentially explains the eventual favourable outcome of the EBV-induced viral disease in patients with IL-27RA deficiency. Furthermore, we identified neutralizing anti-IL-27 autoantibodies in most individuals who developed sporadic infectious mononucleosis and chronic EBV infection. These results demonstrate the critical role of IL-27RA-IL-27 in immunity to EBV, but also the hijacking of this defence by EBV to promote the expansion of infected transformed B cells.
Assuntos
Infecções por Vírus Epstein-Barr , Interleucina-27 , Receptores de Interleucina , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Adulto Jovem , Alelos , Linfócitos B/patologia , Linfócitos B/virologia , Linfócitos T CD8-Positivos/patologia , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/genética , Infecções por Vírus Epstein-Barr/terapia , Finlândia , Frequência do Gene , Herpesvirus Humano 4 , Homozigoto , Mononucleose Infecciosa/complicações , Mononucleose Infecciosa/genética , Mononucleose Infecciosa/terapia , Interleucina-27/imunologia , Interleucina-27/metabolismo , Mutação com Perda de Função , Receptores de Interleucina/deficiência , Receptores de Interleucina/genética , Receptores de Interleucina/metabolismo , Resultado do TratamentoRESUMO
PURPOSE OF REVIEW: Epidemiological evidence implicates Epstein-Barr virus (EBV) as the cause of multiple sclerosis (MS). However, its biological role in the pathogenesis of MS is uncertain. The article provides an overview of the role of EBV in the pathogenesis of MS and makes a case for targeting EBV as a treatment strategy for MS. RECENT FINDINGS: EBV potentially triggers autoimmunity via molecular mimicry or immune dysregulation. Another hypothesis, supported by immunological and virological data, indicates that active EBV infection via latent-lytic infection cycling within the central nervous system or periphery drives MS disease activity. This supports testing small molecule anti-EBV agents targeting both latent and lytic infection, central nervous system-penetrant B-cell therapies and EBV-targeted immunotherapies in MS. Immunotherapies may include EBV-specific cytotoxic or chimeric antigen receptors T-cells, therapeutic EBV vaccines and immune reconstitution therapies to boost endogenous EBV-targeted cytotoxic T-cell responses. SUMMARY: EBV is the probable cause of MS and is likely to be driving MS disease activity via latent-lytic infection cycling. There is evidence that all licensed MS disease-modifying therapies target EBV, and there is a compelling case for testing other anti-EBV strategies as potential treatments for MS.
Assuntos
Infecções por Vírus Epstein-Barr , Herpesvirus Humano 4 , Esclerose Múltipla , Humanos , Esclerose Múltipla/imunologia , Esclerose Múltipla/terapia , Infecções por Vírus Epstein-Barr/imunologia , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/terapia , Herpesvirus Humano 4/imunologia , Imunoterapia/métodosRESUMO
Epstein-Barr Virus (EBV) is a ubiquitous herpes type virus that is associated with post-transplant lymphoproliferative disorder (PTLD). Usual management includes reduction or cessation of immunosuppression and in some cases chemotherapy including rituximab. However, limited therapies are available if PTLD is refractory to rituximab. Several clinical trials have investigated the use of EBV-directed T cells in rituximab-refractory patients; however, data regarding response is scarce and inconclusive. Herein, we describe a patient with EBV-PTLD refractory to rituximab after orthotopic heart transplantation (OHT) requiring EBV-directed T-cell therapy. This article aims to highlight the unique and aggressive clinical presentation and progression of PTLD with utilization of EBV-directed T-cell therapy for management and associated pitfalls.
Assuntos
Infecções por Vírus Epstein-Barr , Transplante de Coração , Transplante de Células-Tronco Hematopoéticas , Transtornos Linfoproliferativos , Humanos , Pré-Escolar , Herpesvirus Humano 4 , Rituximab/uso terapêutico , Infecções por Vírus Epstein-Barr/terapia , Infecções por Vírus Epstein-Barr/tratamento farmacológico , Transtornos Linfoproliferativos/diagnóstico , Transtornos Linfoproliferativos/etiologia , Transtornos Linfoproliferativos/terapia , Terapia Baseada em Transplante de Células e TecidosRESUMO
Epstein-Barr virus (EBV)-associated lymphoproliferative diseases (EBV-LPDs) are common complications that occur after solid organ transplantation or allogeneic hematopoietic stem-cell transplantation (HSCT). However, their occurrence and treatment post-chimeric antigen receptor-modified T (CAR-T) cell therapy has not been reported. Two patients had been diagnosed with EBV-positive aggressive B-cell lymphoma and experienced relapses after multiple lines of treatment. After receiving CAR-T cell therapy in tandem with autologous HSCT, the patients achieved complete remission. However, with a median time of 38.5 months after CAR-T cell therapy, B-cell-derived EBV-LPDs were diagnosed, and they were relieved through the administration of immune checkpoint inhibitor or B-cell-depleting agents. Collectively, our report suggests that EBV-LPDs may represent a long-term adverse event after CAR-T cell therapy, especially in patients who previously had EBV-positive disorders, and they can be resolved by immune normalization strategy or B-cell depleting therapy.
Assuntos
Infecções por Vírus Epstein-Barr , Transplante de Células-Tronco Hematopoéticas , Imunoterapia Adotiva , Transtornos Linfoproliferativos , Humanos , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/terapia , Imunoterapia Adotiva/efeitos adversos , Transtornos Linfoproliferativos/etiologia , Transtornos Linfoproliferativos/terapia , Transtornos Linfoproliferativos/virologia , Masculino , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Feminino , Herpesvirus Humano 4/imunologia , Adulto , Pessoa de Meia-Idade , Linfoma de Células B/terapia , Linfoma de Células B/imunologia , Linfoma de Células B/virologia , Receptores de Antígenos Quiméricos/uso terapêutico , Receptores de Antígenos Quiméricos/imunologia , Inibidores de Checkpoint Imunológico/efeitos adversos , Inibidores de Checkpoint Imunológico/uso terapêuticoRESUMO
Familial hemophagocytic lymphohistiocytosis (FHL) is an inherited, often fatal immune deficiency characterized by severe systemic hyperinflammation. Although allogeneic bone marrow transplantation can be curative, more effective therapies are urgently needed. FHL is caused by inactivating mutations in proteins that regulate cellular immunity. Here, we used an adeno-associated virus-based CRISPR-Cas9 system with an inhibitor of nonhomologous end joining to repair such mutations in potentially long-lived T cells ex vivo. Repaired CD8 memory T cells efficiently cured lethal hyperinflammation in a mouse model of Epstein-Barr virus-triggered FHL2, a subtype caused by perforin-1 (Prf1) deficiency. Furthermore, repair of PRF1 and Munc13-4 (UNC13D)-whose deficiency causes the FHL subtype FHL3-in mutant memory T cells from two critically ill patients with FHL restored T cell cytotoxicity. These results provide a starting point for the treatment of genetic T cell immune dysregulation syndromes with repaired autologous T cells.
Assuntos
Infecções por Vírus Epstein-Barr , Linfo-Histiocitose Hemofagocítica , Animais , Camundongos , Humanos , Linfo-Histiocitose Hemofagocítica/genética , Linfo-Histiocitose Hemofagocítica/terapia , Sistemas CRISPR-Cas , Infecções por Vírus Epstein-Barr/genética , Infecções por Vírus Epstein-Barr/terapia , Células T de Memória , Herpesvirus Humano 4 , Proteínas de Membrana/genéticaRESUMO
Systemic Epstein-Barr virus-positive T-cell lymphoma of childhood (S-EBV-TCL) is a rare disease for which there is no standard of care. S-EBV-TCL is often associated with hemophagocytic lymphohistiocytosis and is generally thought of on the spectrum of EBV-related disease. For the few reported cases of cure in the literature, hematopoietic stem cell transplant has been required because it is the only treatment that has induced complete remission in patients suffering from EBV-associated T-cell or natural killer cell lymphoproliferative diseases, except hemophagocytic lymphohistiocytosis. Here, we present the case of one patient who was successfully cured with a modified regimen of dose-adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin), followed by hematopoietic stem cell transplant using a reduced-intensity conditioning regimen.
Assuntos
Infecções por Vírus Epstein-Barr , Transplante de Células-Tronco Hematopoéticas , Linfo-Histiocitose Hemofagocítica , Linfoma de Células T Periférico , Linfoma de Células T , Humanos , Linfo-Histiocitose Hemofagocítica/patologia , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/terapia , Infecções por Vírus Epstein-Barr/patologia , Herpesvirus Humano 4 , Linfócitos T/patologia , Linfoma de Células T/complicações , Transplante de Células-Tronco Hematopoéticas/efeitos adversosRESUMO
La enfermedad de Castleman (ECM) es un desorden linfoproliferativo y con un pronóstico desfavorable, que se lo ha asociado a la infección por el virus herpes humano tipo 8 (HHV-8). El mecanismo supuesto de ac-ción del HHV-8 sería la secreción de interleuquinas (IL) virales, homólo-gas a IL humanas tales como IL-6 e IL-10. La coinfección por HHV-8 y vi-rus Epstein Barr (EBV) es bien conocida en pacientes con infección por el virus de la inmunodeficiencia humana tipo 1 (HIV-1). Estos gamma-herpesvirus se asocian a trastornos linfoproliferativos que son favore-cidos por la inmunosupresión. Puede presentarse en el contexto de un buen estado inmunológico y su tratamiento se basa en el uso de quimioterapia. La reactivación del EBV latente es favorecida por la infección por HIV-1 y el uso de drogas inmunosupresoras, determinando un potencial riesgo para el desarrollo de nuevos desór-denes linfoproliferativos. Se presenta el caso de un paciente con enferme-dad de Castleman asociado a la infección por HIV-1 y HHV-8, que presentó como complicación post-qui-mioterapia reactivación de infección EBV. Se realizó una revisión del concepto de ECM y la relación pato-génica entre los virus HIV-1, HHV-8 y EBV
Castleman's disease (CD) is a lymphoproliferative disorder with an unfavorable prognosis, which has been associated with human herpes virus 8 (HHV-8) infection. The presumed mechanism of action of HHV-8 would be the secretion of viral interleukin (IL), homologous to human IL such as IL-6 and IL-10. The co-HHV8 infection and Epstein Barr virus (EBV) is well known in patients infected with the HIV type 1 (HIV-1). These gamma-herpesvirus were associated with lymphoproliferative disorders that are favored by immunosuppression. It can occur in the context of a patient's good immune system and its treatment is based on the use of chemotherapy. Reactivation of latent EBV is favored by HIV-1 and the use of immunosuppressive drugs, determining a potential risk for the development of new lymphoproliferative disorders.We report here a patient with Castleman's disease associated with HIV-1 and HHV-8, who presented, as a complication of the chemotherapy, the reactivation of EBV infection. A review of the concept of CD and the pathogenic relationship between HIV-1, HHV-8 and EBV virus was performed
Assuntos
Humanos , Masculino , Pessoa de Meia-Idade , Infecções por HIV/terapia , Hiperplasia do Linfonodo Gigante/terapia , Herpesvirus Humano 8 , Infecções por Vírus Epstein-Barr/terapiaRESUMO
A infecção pelo vírus Epstein-Barr tem alta prevalência, ao passo que 90% da população mundial adulta já teve contato com ele. A primo-infecção geralmente ocorre na infância, apresentando- -se de forma subclínica. Com o avançar da idade, a incidência de infecção sintomática aumenta progressivamente, atingindo o pico entre 15 e 24 anos de idade. Em geral, trata-se de uma doença benigna, na qual a manifestação clínica mais comum é a mononucleose infecciosa. No entanto, a infecção pode acometer qualquer órgão ou sistema, e podem estar presentes tosse, dor abdominal, náuseas, vômitos, hepatoesplenomegalia, icterícia, entre outros. As complicações são raras e podem acometer o fígado, os rins, o sistema nervoso central, o coração, os pulmões e os genitais. Relatamos o caso de paciente adolescente previamente hígido com infecção por vírus Epstein-Barr e evolução para icterícia, pericardite e lesões importantes em orofaringe e genitais. O diagnóstico de infecção pelo Epstein-Barr foi feito por sorologia, e houve boa evolução do caso.
Epstein-Barr virus infection has a high prevalence, since 90% of the adult population worldwide have already had contact with the virus. The primary infection usually occurs in childhood, being subclinically presented. With aging. the incidence of a symptomatic infection progressively increases, reaching the peak between 15 and 24 years of age. In general, it is a benign disease,in which the most common clinical manifestation is Infectious Mononucleosis; however, the infection can occur in any organ or system, and cough, abdominal pain, nausea, vomiting, hepatosplenomegaly, jaundice, and other symptoms may be present. Complications are rare and can affect the liver, kidneys, central nervous system, heart, lungs and genitals. We report the case of a previously healthy adolescent patient with Epstein-Barr Virus infection and progression to jaundice, pericarditis, and important lesions in the oropharynx and genitals. The diagnosis of Epstein-Barr infection was made through serology, and the patient had good evolution.
Assuntos
Humanos , Masculino , Adolescente , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/diagnóstico , Infecções por Vírus Epstein-Barr/terapia , Herpesvirus Humano 4 , Genitália Masculina/lesões , Mononucleose Infecciosa , Icterícia , Orofaringe/lesões , PericarditeRESUMO
Epstein-Barr virus (EBV)-related post-transplant lymphoproliferative disease (PTLD) is one of the most serious complications associated with solid organ and hematopoietic stem cell transplantation. PTLD is most frequently seen with primary EBV infection post-transplant, a common scenario for pediatric solid organ recipients. Risk factors for infection or reactivation of EBV following solid organ transplant are stronger immunosuppressive therapy regimens, and being seronegative for receptor. For hematopoietic stem cell transplantation, the risk factors relate to the type of transplant, human leukocyte antigen disparity, the use of stronger immunosuppressants, T-cell depletion, and severe graft-versus-host disease. Mortality is high, and most frequent in patients who develop PTLD in the first six months post-transplant. The primary goal of this article is to provide an overview of the clinical manifestations, diagnosis, accepted therapies, and management of EBV infection in transplant recipients, and to suggest that the adoption of monitoring protocols could contribute to a reduction in related complications.
Assuntos
Humanos , Infecções por Vírus Epstein-Barr , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transtornos Linfoproliferativos/virologia , Transplante de Órgãos/efeitos adversos , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/prevenção & controle , Infecções por Vírus Epstein-Barr/terapia , Terapia de Imunossupressão/métodos , Imunossupressores/uso terapêutico , Fatores de RiscoRESUMO
Se describe un paciente masculino de 10 años de edad con historia de mialgia, debilidad progresiva en miembros inferiores, fiebre y vómitos. Se postuló el diagnóstico clínico de Síndrome de Guillain-Barré el cual fue subsecuentemente demostrado con el resultado de líquido cefalorraquídeo (LCR) y electromiografía. A su admisión se describió una faringoamigdalitis exudativa y una sinusitis etmoidal, y posteriormente durante el curso de su enfermedad desarrolló una parálisis facial derecha. No habia historia de enfermedad diarreica aguada o enfermedad respiratoria previa al inicio de sus síntomas neurológicos. Los frotis y cultivos de heces fueron negativos por Campylobacter jejuni, al igual que la inmunofluorescencia para virus respiratorios y serología por CMV. Se documentó mediante una IgM positiva en suero la infección aguda por el virus Epstein-Barr. El paciente fue tratado exitosamente con un curso de cinco días de gammaglobulina endovenosa y un mes después, en la consulta externa, se documenta la ausencia de secuelas neurológicas