RESUMO
Profound immune dysregulation and impaired response to the SARS-CoV-2 vaccine put patients with chronic lymphocytic leukemia (CLL) at risk of severe COVID-19. We compared humoral memory and T-cell responses after booster dose vaccination or breakthrough infection. (Green) Quantitative determination of anti-Spike specific antibodies. Booster doses increased seroconversion rate and antibody titers in all patient categories, ultimately generating humoral responses similar to those observed in the postinfection cohort. In detail, humoral response with overscale median antibody titers arose in >80% of patients in watch and wait, off-therapy in remission, or under treatment with venetoclax single-agent. Anti-CD20 antibodies and active treatment with BTK inhibitors (BTKi) represent limiting factors of humoral response, still memory mounted in ~40% of cases following booster doses or infection. (Blue) Evaluation of SARS-CoV-2-specific T-cell responses. Number of T-cell functional activation markers documented in each patient. The vast majority of patients, including those seronegative, developed T-cell responses, qualitatively similar between treatment groups or between vaccination alone and infection cases. These data highlight the efficacy of booster doses in eliciting T-cell immunity independently of treatment status and support the use of additional vaccination boosters to stimulate humoral immunity in patients on active CLL-directed treatments.
Assuntos
COVID-19 , Leucemia Linfocítica Crônica de Células B , Humanos , SARS-CoV-2 , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Vacinas contra COVID-19 , Anticorpos , Subunidade alfa de Receptor de Interleucina-2 , Imunidade Celular , Anticorpos Antivirais , VacinaçãoRESUMO
BACKGROUND: Oral mucositis is a frequently seen complication in the first weeks after hematopoietic stem cell transplantation recipients which can severely affects patients quality of life. In this study, a labelled and label-free proteomics approach were used to identify differences between the salivary proteomes of autologous hematopoietic stem cell transplantation (ASCT) recipients developing ulcerative oral mucositis (ULC-OM; WHO score ≥ 2) or not (NON-OM). METHODS: In the TMT-labelled analysis we pooled saliva samples from 5 ULC-OM patients at each of 5 timepoints: baseline, 1, 2, 3 weeks and 3 months after ASCT and compared these with pooled samples from 5 NON-OM patients. For the label-free analysis we analyzed saliva samples from 9 ULC-OM and 10 NON-OM patients at 6 different timepoints (including 12 months after ASCT) with Data-Independent Acquisition (DIA). As spectral library, all samples were grouped (ULC-OM vs NON-OM) and analyzed with Data Dependent Analysis (DDA). PCA plots and a volcano plot were generated in RStudio and differently regulated proteins were analyzed using GO analysis with g:Profiler. RESULTS: A different clustering of ULC-OM pools was found at baseline, weeks 2 and 3 after ASCT with TMT-labelled analysis. Using label-free analysis, week 1-3 samples clustered distinctly from the other timepoints. Unique and up-regulated proteins in the NON-OM group (DDA analysis) were involved in immune system-related processes, while those proteins in the ULC-OM group were intracellular proteins indicating cell lysis. CONCLUSIONS: The salivary proteome in ASCT recipients has a tissue protective or tissue-damage signature, that corresponded with the absence or presence of ulcerative oral mucositis, respectively. TRIAL REGISTRATION: The study is registered in the national trial register (NTR5760; automatically added to the International Clinical Trial Registry Platform).
Assuntos
Transplante de Células-Tronco Hematopoéticas , Mieloma Múltiplo , Estomatite Aftosa , Estomatite , Humanos , Melfalan , Proteoma , Mieloma Múltiplo/complicações , Proteômica , Qualidade de Vida , Estomatite/complicações , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Estomatite Aftosa/complicaçõesRESUMO
Innate lymphoid cells (ILC) are important barrier tissue immune regulators. They play a pivotal role in early non-specific protection against infiltrating pathogens, regulation of epithelial integrity, suppression of pro-inflammatory immune responses and shaping the intestinal microbiota. GATA2 haploinsufficiency causes an immune disorder that is characterized by bone marrow failure and (near) absence of monocytes, dendritic cells, B cells and natural killer (NK) cells. T cells develop normally, albeit at lower numbers. Here, we describe the absence of ILCs and their progenitors in blood and bone marrow of two patients with GATA2 haploinsufficiency and show that all subsets of ILCs appear after allogeneic hematopoietic stem cell transplantation, irrespective of the preparative conditioning regimen. Our data indicate that GATA2 is involved in the development of hematopoietic precursor cells (HPC) towards the ILC lineage.
Assuntos
Deficiência de GATA2 , Transplante de Células-Tronco Hematopoéticas , Imunidade Inata , Humanos , Fator de Transcrição GATA2/genética , Células Matadoras Naturais , Condicionamento Pré-Transplante , LinfócitosRESUMO
Allogeneic stem cell transplantation can cause chronic graft versus host disease (cGVHD). A number of patients manifest cGVHD in and around the mouth. It can present itself as clinically as mucosal lesions and/or salivary gland dysfunction and/or sclerotic changes. Cheeks and tongue are most commonly affected, but the palate, gingiva and lips can also be impacted. Oral cGVHD is associated with mucosal sensitivity, pain, (severe) oral dryness, altered taste, restricted mouth opening and difficulty swallowing, all of which may contribute to a significant decrease of the patient's quality of life. Patients also run an increased risk of developing squamous cell carcinoma of the oral mucosa. The diagnosis of cGVHD is almost always based on the patient's medical history and clinical picture. Treatment of symptoms is based on the patient's problem(s). Dental professionals can provide patients with supportive preventive care aimed at reducing symptoms and preventing further deterioration of oral health.
Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Doenças da Boca , Doença Crônica , Doença Enxerto-Hospedeiro/tratamento farmacológico , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/patologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Doenças da Boca/diagnóstico , Doenças da Boca/etiologia , Doenças da Boca/terapia , Mucosa Bucal/patologia , Qualidade de VidaRESUMO
The aim of this multicentre, longitudinal study was to determine salivary changes in relation to oral mucositis (OM) in multiple myeloma patients following high-dose melphalan and autologous hematopoietic stem cell transplantation (ASCT). Unstimulated and stimulated whole-mouth saliva samples (UWS and SWS) were collected before ASCT, 1×/wk during the hospitalisation phase, and 3 and 12 months post-ASCT. During the hospitalisation period OM was scored 3×/wk (WHO system). Flow rate, pH, total protein concentration (Nanodrop), albumin, lactoferrin, neutrophil defensin-1 (HNP1), total IgA and S100A8/A9 (ELISA) were determined. Mixed models were used to evaluate differences between ulcerative (u)OM (≥2 WHO, n = 20) and non-uOM (n = 31) groups. Until 18 days after ASCT, flow rate, pH, total IgA and HNP1 levels decreased in UWS and/or SWS, while log lactoferrin levels were significantly increased (UWS: p = 0.016 95% CI [0.36, 3.58], SWS: p < 0.001 95% CI [1.14, 3.29]). Twelve months post-ASCT, salivary protein levels were similar to baseline except for log total IgA, which was higher (UWS: p < 0.001 95% CI [0.49, 1.29], SWS: p < 0.001 95% CI [0.72, 1.45]). No differences between uOM and non-uOM groups were observed. Changes in salivary proteins indicated an inflammatory reaction in salivary glands coinciding with mucosal and systemic reactions in response to high-dose melphalan.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Mieloma Múltiplo , Estomatite , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Estudos Longitudinais , Melfalan , Estomatite/etiologia , Transplante AutólogoRESUMO
Targeted cancer therapy with monoclonal antibodies has proven successful for different cancer types but is limited by the availability of suitable antibody targets. CD43s, a unique sialylated form of CD43 expressed by hematologic malignancies, is a recently identified target and antibodies interacting with CD43s may have therapeutic potential against acute myeloid leukemia (AML) and myelodysplastic syndrome. CD43s is recognized by the human antibody AT1413, that was derived from a high-risk AML patient who successfully cleared leukemia after allogeneic stem cell transplantation. Here we observed that AT1413 binds also to certain non-hematopoietic tumor cells, particularly melanoma and breast cancer. AT1413 immune precipitated CD43s from melanoma cells confirming that it recognizes the same target on melanoma as on AML. AT1413 induced antibody-dependent cellular cytotoxicity against short-term cultured patient-derived melanoma samples. However, AT1413 was unable to affect the growth of melanoma cells in vivo. To increase the efficacy of AT1413 as a therapeutic antibody, we generated two different formats of bispecific T-cell engaging antibodies (TCEs): one binding bivalently (bTCE) and the other monovalently (knob-in-hole; KiH) to both CD43s and CD3ε. In vitro, these TCEs redirected T-cell cytotoxicity against melanoma cells with differences in potencies. To investigate their effects in vivo, we grafted mice that harbor a human immune system with the melanoma cell line A375. Treatment with both AT1413 bTCE and AT1413 KiH significantly reduced tumor outgrowth in these mice. These data indicate a broad therapeutic potential of AT1413 that includes AML and CD43s-expressing solid tumors that originate from CD43-negative tissues.
Assuntos
Anticorpos Biespecíficos/farmacologia , Anticorpos Monoclonais/farmacologia , Antineoplásicos Imunológicos/farmacologia , Complexo CD3/imunologia , Leucossialina/imunologia , Melanoma/terapia , Ácido N-Acetilneuramínico/química , Linfócitos T/imunologia , Animais , Apoptose , Proliferação de Células , Citotoxicidade Imunológica , Feminino , Humanos , Técnicas In Vitro , Melanoma/imunologia , Melanoma/patologia , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
For many high-risk haematologic malignancies, such as acute myeloid leukaemia, the success of therapy relies mainly on invoking a curative antitumour immune response. This can be achieved by inducing a graft-versus-leukaemia response following allogeneic haematopoietic cell transplantation. While the contribution of T cells and natural killer cells to graft-versus-leukaemia responses is established, the contribution of B cells and antibodies is relatively unexplored. This article reviews what is known about the contribution of B cells and tumour-specific antibody responses to a successful graft-versus-leukaemia response leading to eradication of the tumour.
RESUMO
FMT has gained enormous momentum in the treatment of acute inflammatory and infectious diseases. Despite an encouraging safety profile, FMT has been met with caution in the oncological setting due to perceived infectious risks in immunocompromised patients. Theoretical risks aside, the application of FMT in oncology may stand to benefit patients, via modulation of treatment efficacy and the mitigation of treatment complications. Here, we summarize most recent safety data of FMT in immunocompromised cohorts, including people with cancer, highlighting that FMT may actually provide protection against bacterial translocation via introduction of a diverse microbiome and restoration of epithelial defenses. We also discuss the emerging translational applications of FMT within supportive oncology, including the prevention and treatment of graft vs. host disease and sepsis, treatment of immunotherapy-induced colitis and restoration of the gut microbiome in survivors of childhood cancer.
Assuntos
Colite/etiologia , Colite/terapia , Transplante de Microbiota Fecal , Microbioma Gastrointestinal , Hospedeiro Imunocomprometido , Neoplasias/complicações , Cuidados Paliativos , Animais , Infecções por Clostridium/etiologia , Infecções por Clostridium/terapia , Transplante de Microbiota Fecal/efeitos adversos , Transplante de Microbiota Fecal/métodos , Humanos , Cuidados Paliativos/métodosAssuntos
Vírus GB C , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Hepatite E , Aloenxertos , Feminino , Doença Enxerto-Hospedeiro/epidemiologia , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/patologia , Hepatite E/epidemiologia , Hepatite E/etiologia , Hepatite E/patologia , Humanos , Masculino , Estudos RetrospectivosRESUMO
CAR T-cells are autologous T-cells transduced with a chimeric antigen receptor (CAR). The CAR contains an antigen recognition part (originating from an antibody), a T-cell receptor transmembrane and cytoplasmic signalling part, and one or more co-stimulatory domains. While CAR T-cells can be directed against any tumour target, most experience thus far has been obtained with targeting of the B-cell antigen CD19 that is expressed by B-cell acute lymphocytic leukaemia, chronic lymphocytic leukaemia and other B-cell lymphomas. The first clinical results are promising, although there are profound differences in response between patients with different haematological malignancies. Treatment-related side effects have been observed that require specific management. This review will explain the mechanism of action, summarise the experience to date and point out future directions for this hopeful new addition to the therapeutic armamentarium in the treatment of lymphoproliferative B-cell malignancies.
Assuntos
Transtornos Linfoproliferativos/terapia , Receptores de Antígenos de Linfócitos T/uso terapêutico , Linfócitos B , Ensaios Clínicos como Assunto , Humanos , Receptores de Antígenos de Linfócitos T/administração & dosagem , Receptores de Antígenos de Linfócitos T/imunologia , Linfócitos TAssuntos
Doença Enxerto-Hospedeiro/tratamento farmacológico , Leucemia Mieloide Aguda/patologia , Rituximab/efeitos adversos , Adulto , Linfócitos B/imunologia , Linfócitos B/fisiologia , Evolução Fatal , Doença Enxerto-Hospedeiro/etiologia , Efeito Enxerto vs Leucemia/efeitos dos fármacos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Leucemia Mieloide Aguda/complicações , Leucemia Mieloide Aguda/terapia , Masculino , Recidiva , Transplante HomólogoRESUMO
Current methods to determine cellular cytotoxicity in vitro are hampered by background signals that are caused by auto-fluorescent target and effector cells and by non-specific cell death. We combined and adjusted existing cell viability assays to develop a method that allows for highly reproducible, accurate, single cell analysis by high throughput FACS, in which non-specific cell death is corrected for. In this assay the number of living, calcein AM labeled cells that are green fluorescent are quantified by adding a fixed number of unlabeled calibration beads to the analysis. Using this modified FACS calcein AM retention method, we found EC50 values to be highly reproducible and considerably lower compared to EC50 values obtained by conventional assays, displaying the high sensitivity of this assay.
Assuntos
Citotoxicidade Imunológica , Citometria de Fluxo/métodos , Fluoresceínas/química , Células Matadoras Naturais/imunologia , Bioensaio , Linhagem Celular Tumoral , Sobrevivência Celular , Corantes Fluorescentes/química , Humanos , Rituximab/química , Trastuzumab/química , Células Tumorais CultivadasRESUMO
Hematopoietic stem cell transplantation (HSCT) is widely used as a potentially curative treatment for patients with various hematological malignancies, bone marrow failure syndromes, and congenital immune deficiencies. The prevalence of oral complications in both autologous and allogeneic HSCT recipients remains high, despite advances in transplant medicine and in supportive care. Frequently encountered oral complications include mucositis, infections, oral dryness, taste changes, and graft versus host disease in allogeneic HSCT. Oral complications are associated with substantial morbidity and in some cases with increased mortality and may significantly affect quality of life, even many years after HSCT. Inflammatory processes are key in the pathobiology of most oral complications in HSCT recipients. This review article will discuss frequently encountered oral complications associated with HSCT focusing on the inflammatory pathways and inflammatory mediators involved in their pathogenesis.
Assuntos
Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Administração Oral , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/metabolismo , Humanos , Inflamação/etiologia , Inflamação/metabolismo , Mucosite/etiologia , Mucosite/metabolismoAssuntos
Pão/microbiologia , Leucemia Mieloide Aguda/microbiologia , Exposição Ocupacional/efeitos adversos , Saccharomyces cerevisiae/isolamento & purificação , Feminino , Microbiologia de Alimentos , Fungemia/microbiologia , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Pessoa de Meia-IdadeAssuntos
Anemia Aplástica/virologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Parvovirus B19 Humano , Idoso , Anemia Aplástica/diagnóstico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Ciclofosfamida/administração & dosagem , Doxorrubicina/administração & dosagem , Humanos , Masculino , Infecções por Parvoviridae , Prednisona/administração & dosagem , Vincristina/administração & dosagemAssuntos
Infecções por Citomegalovirus/diagnóstico , Hemorragia Gastrointestinal/virologia , Mieloma Múltiplo/complicações , Idoso , Anticorpos Antivirais/sangue , Colo/virologia , Citomegalovirus/imunologia , Citomegalovirus/isolamento & purificação , Infecções por Citomegalovirus/complicações , Hemorragia Gastrointestinal/complicações , Hemorragia Gastrointestinal/diagnóstico , Humanos , Imunoglobulina G/sangue , Corpos de Inclusão Viral/virologia , Mucosa Intestinal/virologia , Masculino , Mieloma Múltiplo/imunologiaRESUMO
A 91-year-old woman was admitted to a nursing home because of functional deterioration: poor vision and hearing, and diminished mobility. She had been widowed for 30 years, had no children and a very small social network. She described herself as 'tired of life', and alluded to the assisted suicide of the former senator Brongersma, where this term was the trigger to the administration of assistance. The Supreme Court however ruled afterwards that a physician has no capacity in 'questions of life and death', but only in requests for help with a medically classifiable underlying disorder. The patient was not assisted in dying and her condition deteriorated further. Some time later she fell and contracted a clinical hip fracture. She refused to be brought to hospital and was given fentanyl plasters. A week later she died. The question on how to respond to the very elderly who seek help because they wish to die, is being discussed in the Netherlands. The term 'tired of life' appears to be rather confusing, as it has no medical connotation. It is recommended that elderly persons who ask for help in dying because they are 'tired of life', based on physical handicaps, are evaluated carefully to determine the severity of the handicaps and the hopelessness and unbearableness of the suffering. This could lead to the patient receiving assistance in dying.
Assuntos
Qualidade de Vida , Suicídio Assistido , Idoso , Idoso de 80 Anos ou mais , Atitude Frente a Morte , Tomada de Decisões , Feminino , Humanos , Países BaixosRESUMO
T cell differentiation in the thymus is characterized by a hierarchical order of rearrangement steps in the T cell receptor (TCR) genes, resulting in the joining of V, D, and J gene segments. During each of the rearrangement steps, DNA fragments between rearranging V, D, and J gene segments are deleted as circular excision products, the so-called TRECs (T cell receptor excision circles). TRECs are assumed to have a high over-time stability, but they can not multiply and consequently are diluted during T cell proliferation. It was recently suggested that quantitative detection of TRECs would allow for direct measurement of thymic output. The deltaRec-psiJalpha TREC appears to be the best marker, because the majority of thymocyte expansion occurs before this TREC is formed. However, apart from thymic output several other factors determine the TREC content of a T cell population, such as cell division and cell death. Likewise, the number of TRECs depends not only on thymic output, but also on the longevity of naive T cells. This warrants caution with regard to the interpretation of TREC data as measured in healthy and diseased individuals. deltaRec-psiJalpha TREC detection is a new and elegant tool for identification of recent thymic emigrants in the periphery, but further research is required for making quantitative estimations of thymic output with the use of TREC analysis.
Assuntos
Rearranjo Gênico , Receptores de Antígenos de Linfócitos T/metabolismo , Timo/citologia , Timo/metabolismo , Animais , Fármacos Anti-HIV/uso terapêutico , Biomarcadores , Diferenciação Celular , Divisão Celular , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , HIV-1/metabolismo , Humanos , Modelos Biológicos , Receptores de Antígenos de Linfócitos T/genética , Linfócitos T/citologia , Fatores de TempoRESUMO
Multiple sclerosis is believed to result from a CD4+ T-cell response against myelin antigens. Peptidoglycan, a major component of the Gram-positive bacterial cell wall, is a functional lipopolysaccharide analogue with potent proinflammatory properties and is conceivably a mediator of sterile inflammation. Here we demonstrate that peptidoglycan is present within antigen-presenting cells in the brain of multiple sclerosis patients. These cells have macrophage and dendritic cell characteristics, and are immunocompetent as evidenced by co-expression of inflammatory cytokines and co-stimulatory molecules. In addition, intrathecal plasma cells specific for peptidoglycan are present in multiple sclerosis brain tissue, and antibodies binding peptidoglycan are present in CSF during active disease. Peptidoglycan may thus contribute to T- and B-cell activity during brain inflammation without a requirement for local bacterial replication.
Assuntos
Sistema Nervoso Central/imunologia , Esclerose Múltipla/imunologia , Peptidoglicano/análise , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais , Antígenos de Bactérias/análise , Autopsia , Linfócitos B/imunologia , Progressão da Doença , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Imuno-Histoquímica , Inflamação , Masculino , Pessoa de Meia-Idade , Linfócitos T/imunologiaRESUMO
OBJECTIVES: Peptidoglycan (PG), a component of Gram-positive bacteria, may be involved in rheumatoid arthritis (RA) because of its ability to induce production of proinflammatory cytokines, to induce arthritis in rodents, and its presence in antigen-presenting cells in RA joints. METHODS: In the present study, physiologically relevant PG was able to induce T-cell proliferation in peripheral blood and synovial fluid samples of RA patients, but the magnitude of the response did not differ from that of cells from healthy subjects. In addition, production of cytokines associated with RA (interleukins (IL)-1beta, IL-6, IL-8, IL-10, IL-12 and tumour necrosis factor alpha) and of the matrix metalloproteinase, gelatinase B (MMP-9), was induced in blood and synovial fluid cultures of RA patients. CONCLUSION: The fact that PG, which can be found in synovial tissues of RA patients is able to induce the production of inflammatory mediators supports the hypothesis that PG plays a role in the pathogenesis of RA by influencing the inflammatory microenvironment of the joint.