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1.
Blood ; 141(7): 743-755, 2023 02 16.
Artículo en Inglés | MEDLINE | ID: mdl-36332176

RESUMEN

The development of a second malignancy after the diagnosis of childhood acute lymphoblastic leukemia (ALL) is a rare event. Certain second malignancies have been linked with specific elements of leukemia therapy, yet the etiology of most second neoplasms remains obscure and their optimal management strategies are unclear. This is a first comprehensive report of non-Hodgkin lymphomas (NHLs) following pediatric ALL therapy, excluding stem-cell transplantation. We analyzed data of patients who developed NHL following ALL diagnosis and were enrolled in 12 collaborative pediatric ALL trials between 1980-2018. Eighty-five patients developed NHL, with mature B-cell lymphoproliferations as the dominant subtype (56 of 85 cases). Forty-six of these 56 cases (82%) occurred during or within 6 months of maintenance therapy. The majority exhibited histopathological characteristics associated with immunodeficiency (65%), predominantly evidence of Epstein-Barr virus-driven lymphoproliferation. We investigated 66 cases of post-ALL immunodeficiency-associated lymphoid neoplasms, 52 from our study and 14 additional cases from a literature search. With a median follow-up of 4.9 years, the 5-year overall survival for the 66 patients with immunodeficiency-associated lymphoid neoplasms was 67.4% (95% confidence interval [CI], 56-81). Five-year cumulative risks of lymphoid neoplasm- and leukemia-related mortality were 20% (95% CI, 10.2-30) and 12.4% (95% CI, 2.7-22), respectively. Concurrent hemophagocytic lymphohistiocytosis was associated with increased mortality (hazard ratio, 7.32; 95% CI, 1.62-32.98; P = .01). A large proportion of post-ALL lymphoid neoplasms are associated with an immunodeficient state, likely precipitated by ALL maintenance therapy. Awareness of this underrecognized entity and pertinent diagnostic tests are crucial for early diagnosis and optimal therapy.


Asunto(s)
Infecciones por Virus de Epstein-Barr , Linfoma no Hodgkin , Linfoma , Neoplasias Primarias Secundarias , Leucemia-Linfoma Linfoblástico de Células Precursoras , Niño , Humanos , Herpesvirus Humano 4 , Infecciones por Virus de Epstein-Barr/complicaciones , Infecciones por Virus de Epstein-Barr/diagnóstico , Linfoma/complicaciones , Linfoma no Hodgkin/patología , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicaciones
2.
Proc Natl Acad Sci U S A ; 119(15): e2119893119, 2022 04 12.
Artículo en Inglés | MEDLINE | ID: mdl-35385354

RESUMEN

The emergence of SARS-CoV-2 triggering the COVID-19 pandemic ranks as arguably the greatest medical emergency of the last century. COVID-19 has highlighted health disparities both within and between countries and will leave a lasting impact on global society. Nonetheless, substantial investment in life sciences over recent decades has facilitated a rapid scientific response with innovations in viral characterization, testing, and sequencing. Perhaps most remarkably, this permitted the development of highly effective vaccines, which are being distributed globally at unprecedented speed. In contrast, drug treatments for the established disease have delivered limited benefits so far. Innovative and rapid approaches in the design and execution of large-scale clinical trials and repurposing of existing drugs have saved many lives; however, many more remain at risk. In this review we describe challenges and unmet needs, discuss existing therapeutics, and address future opportunities. Consideration is given to factors that have hindered drug development in order to support planning for the next pandemic challenge and to allow rapid and cost-effective development of new therapeutics with equitable delivery.


Asunto(s)
Tratamiento Farmacológico de COVID-19 , Pandemias , Vacunas contra la COVID-19 , Desarrollo de Medicamentos , Humanos , Pandemias/prevención & control , SARS-CoV-2
3.
Br J Haematol ; 205(4): 1489-1496, 2024 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-39072718

RESUMEN

The Kids ITP Tools (KIT) is a health-related quality of life (HRQoL) questionnaire that evaluates quality of life in children with immune thrombocytopenia (ITP). There are three formats: Child Self-Report, Parent Proxy-Report and Parent Impact-Report. This study aimed to develop a domain structure by grouping-related questions from the questionnaire into domains that independently reflect various aspects of HRQoL. The study was conducted in two phases. Phase 1 involved an online survey distributed to experts to identify conceptual domains for the KIT. Phase 2 utilized a statistical approach to analyse responses from patients with ITP and their families. A revised KIT 2.0 was ultimately developed to aid in treatment decision-making and monitoring of ITP.


Asunto(s)
Púrpura Trombocitopénica Idiopática , Calidad de Vida , Humanos , Niño , Púrpura Trombocitopénica Idiopática/terapia , Masculino , Femenino , Encuestas y Cuestionarios , Adolescente , Preescolar , Padres/psicología
4.
Haemophilia ; 30(2): 306-319, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38239180

RESUMEN

AIM: For people with haemophilia A (PwHA), bleeding in the joints leads to joint damage and haemophilia-related arthropathy, impacting range of motion and life expectancy. Existing guidelines for managing haemophilia A support healthcare professionals (HCPs) and PwHA in their efforts to preserve joint health. However, such guidance should be reviewed, considering emerging evidence and consensus as presented in this manuscript. METHODS: Fifteen HCPs experienced in the management of PwHA in the UK participated in a three-round Delphi panel. Consensus was defined at ≥70% of panellists agreeing or disagreeing for Likert-scale questions, and ≥70% selecting the same option for multiple- or single-choice questions. Questions not reaching consensus were revised for the next round. RESULTS: 26.8% (11/41), 44.8% (13/29) and 93.3% (14/15) of statements reached consensus in Rounds 1, 2 and 3, respectively. HCPs agreed that prophylaxis should be offered to patients with a baseline factor VIII (FVIII) level of ≤5 IU/dL and that, where there is no treatment burden, the aim of prophylaxis should be to achieve a trough FVIII level ≥15 IU/dL and maintain a longer period with FVIII levels of ≥20-30 IU/dL to provide better bleed protection. The aspirational goal for PwHA is to prevent all joint bleeds, which may be achieved by maintaining normalised (50-150 IU/dL) FVIII levels. CONCLUSION: The panel of experts were largely aligned on approaches to preserving joint health in PwHA, and this consensus may help guide HCPs.


Asunto(s)
Hemofilia A , Humanos , Hemofilia A/tratamiento farmacológico , Factor VIII/uso terapéutico , Consenso , Hemartrosis/prevención & control , Hemorragia/prevención & control , Reino Unido
5.
Immunity ; 42(6): 1130-42, 2015 Jun 16.
Artículo en Inglés | MEDLINE | ID: mdl-26070484

RESUMEN

Tissue-infiltrating Ly6C(hi) monocytes play diverse roles in immunity, ranging from pathogen killing to immune regulation. How and where this diversity of function is imposed remains poorly understood. Here we show that during acute gastrointestinal infection, priming of monocytes for regulatory function preceded systemic inflammation and was initiated prior to bone marrow egress. Notably, natural killer (NK) cell-derived IFN-γ promoted a regulatory program in monocyte progenitors during development. Early bone marrow NK cell activation was controlled by systemic interleukin-12 (IL-12) produced by Batf3-dependent dendritic cells (DCs) in the mucosal-associated lymphoid tissue (MALT). This work challenges the paradigm that monocyte function is dominantly imposed by local signals after tissue recruitment, and instead proposes a sequential model of differentiation in which monocytes are pre-emptively educated during development in the bone marrow to promote their tissue-specific function.


Asunto(s)
Células de la Médula Ósea/inmunología , Células Dendríticas/inmunología , Mucosa Intestinal/inmunología , Células Asesinas Naturales/inmunología , Leucocitos Mononucleares/inmunología , Toxoplasma/inmunología , Toxoplasmosis/inmunología , Animales , Antígenos Ly/metabolismo , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/genética , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/metabolismo , Células de la Médula Ósea/parasitología , Diferenciación Celular , Células Cultivadas , Interferón gamma/metabolismo , Interleucina-12/genética , Interleucina-12/metabolismo , Mucosa Intestinal/parasitología , Células Asesinas Naturales/parasitología , Leucocitos Mononucleares/parasitología , Activación de Linfocitos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Modelos Inmunológicos , Especificidad de Órganos/inmunología , Proteínas Represoras/genética , Proteínas Represoras/metabolismo
6.
Eur Respir J ; 61(5)2023 05.
Artículo en Inglés | MEDLINE | ID: mdl-36922030

RESUMEN

BACKGROUND: COVID-19 is associated with a dysregulated immune response but it is unclear how immune dysfunction contributes to the chronic morbidity persisting in many COVID-19 patients during convalescence (long COVID). METHODS: We assessed phenotypical and functional changes of monocytes in COVID-19 patients during hospitalisation and up to 9 months of convalescence following COVID-19, respiratory syncytial virus or influenza A. Patients with progressive fibrosing interstitial lung disease were included as a positive control for severe, ongoing lung injury. RESULTS: Monocyte alterations in acute COVID-19 patients included aberrant expression of leukocyte migration molecules, continuing into convalescence (n=142) and corresponding with specific symptoms of long COVID. Long COVID patients with unresolved lung injury, indicated by sustained shortness of breath and abnormal chest radiology, were defined by high monocyte expression of C-X-C motif chemokine receptor 6 (CXCR6) (p<0.0001) and adhesion molecule P-selectin glycoprotein ligand 1 (p<0.01), alongside preferential migration of monocytes towards the CXCR6 ligand C-X-C motif chemokine ligand 16 (CXCL16) (p<0.05), which is abundantly expressed in the lung. Monocyte CXCR6 and lung CXCL16 were heightened in patients with progressive fibrosing interstitial lung disease (p<0.001), confirming a role for the CXCR6-CXCL16 axis in ongoing lung injury. Conversely, monocytes from long COVID patients with ongoing fatigue exhibited a sustained reduction of the prostaglandin-generating enzyme cyclooxygenase 2 (p<0.01) and CXCR2 expression (p<0.05). These monocyte changes were not present in respiratory syncytial virus or influenza A convalescence. CONCLUSIONS: Our data define unique monocyte signatures that define subgroups of long COVID patients, indicating a key role for monocyte migration in COVID-19 pathophysiology. Targeting these pathways may provide novel therapeutic opportunities in COVID-19 patients with persistent morbidity.


Asunto(s)
COVID-19 , Gripe Humana , Lesión Pulmonar , Humanos , Monocitos/metabolismo , Quimiocinas CXC/metabolismo , Receptores Virales/metabolismo , Receptores CXCR6 , Receptores de Quimiocina/metabolismo , Síndrome Post Agudo de COVID-19 , Ligandos , Convalecencia , Receptores Depuradores/metabolismo , Quimiocina CXCL16 , Gravedad del Paciente
7.
Nat Immunol ; 12(3): 247-54, 2011 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-21278738

RESUMEN

Interleukin 2 (IL-2), a cytokine linked to human autoimmune disease, limits IL-17 production. Here we found that deletion of the gene encoding the transcription factor STAT3 in T cells abrogated IL-17 production and attenuated autoimmunity associated with IL-2 deficiency. Whereas STAT3 induced IL-17 and the transcription factor RORγt and inhibited the transcription factor Foxp3, IL-2 inhibited IL-17 independently of Foxp3 and RORγt. STAT3 and STAT5 bound to multiple common sites across the locus encoding IL-17. The induction of STAT5 binding by IL-2 was associated with less binding of STAT3 at these sites and the inhibition of associated active epigenetic marks. 'Titration' of the relative activation of STAT3 and STAT5 modulated the specification of cells to the IL-17-producing helper T cell (T(H)17 cell) subset. Thus, the balance rather than the absolute magnitude of these signals determined the propensity of cells to make a key inflammatory cytokine.


Asunto(s)
Regulación de la Expresión Génica , Interleucina-17/genética , Interleucina-17/inmunología , Factor de Transcripción STAT3/inmunología , Factor de Transcripción STAT5/inmunología , Linfocitos T/inmunología , Animales , Diferenciación Celular , Citometría de Flujo , Sitios Genéticos , Humanos , Immunoblotting , Interleucina-2/genética , Interleucina-2/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa
8.
Blood ; 137(13): 1731-1740, 2021 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-33150355

RESUMEN

The cornerstone of life-saving therapy in immune-mediated thrombotic thrombocytopenic purpura (iTTP) has been plasma exchange (PEX) combined with immunomodulatory strategies. Caplacizumab, a novel anti-von Willebrand factor nanobody trialed in 2 multicenter randomized controlled trials (RCTs) leading to European Union and US Food and Drug Administration approval, has been available in the United Kingdom (UK) through a patient access scheme. Data were collected retrospectively from 2018 to 2020 for 85 patients (4 children) receiving caplacizumab from 22 UK hospitals. Patient characteristics and outcomes in the real-world clinical setting were compared with caplacizumab trial end points and historical outcomes in the precaplacizumab era. Eighty-four of 85 patients received steroid and rituximab alongside PEX; 26% required intubation. Median time to platelet count normalization (3 days), duration of PEX (7 days), and hospital stay (12 days) were comparable with RCT data. Median duration of PEX and time from PEX initiation to platelet count normalization were favorable compared with historical outcomes (P < .05). Thrombotic thrombocytopenic purpura (TTP) recurred in 5 of 85 patients; all had persistent ADAMTS13 activity < 5 IU/dL. Of 31 adverse events in 26 patients, 17 of 31 (55%) were bleeding episodes, and 5 of 31 (16%) were thrombotic events (2 unrelated to caplacizumab); mortality was 6% (5/85), with no deaths attributed to caplacizumab. In 4 of 5 deaths, caplacizumab was introduced >48 hours after PEX initiation (3-21 days). This real-world evidence represents the first and largest series of TTP patients, including pediatric patients, receiving caplacizumab outside of clinical trials. Representative of true clinical practice, the findings provide valuable information for clinicians treating TTP globally.


Asunto(s)
Fibrinolíticos/uso terapéutico , Púrpura Trombocitopénica Trombótica/tratamiento farmacológico , Anticuerpos de Dominio Único/uso terapéutico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Manejo de la Enfermedad , Femenino , Fibrinolíticos/efectos adversos , Humanos , Masculino , Persona de Mediana Edad , Púrpura Trombocitopénica Trombótica/epidemiología , Anticuerpos de Dominio Único/efectos adversos , Resultado del Tratamiento , Reino Unido/epidemiología , Adulto Joven , Factor de von Willebrand/antagonistas & inhibidores
9.
Haematologica ; 108(10): 2783-2793, 2023 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-37051753

RESUMEN

Current immune thrombocytopenia (ITP) guidelines target children and adults, leading to oversimplification. Adolescents and young adults (AYAS) comprise a separate group with distinct health and psychosocial issues. This study aimed to describe the clinical presentation and therapeutic strategies of ITP among AYAS. We analyzed data from two large ITP registries (PARC-ITP; CARMEN-France) and included newly diagnosed ITP patients (aged 12-25 years) with an initial platelet counts of <100×109/L. Patients with secondary ITP or non-immune thrombocytopenia (n=57) and pregnant women (n=10) were excluded. Of the 656 cases of AYAS with primary ITP registered from 2004 up to 2021, 12-month follow-up data were available for 72%. The initial median platelet count was 12×109/L. In 109 patients (17%), the diagnosis was incidental, without documented bleeding. Apart from gynecological bleeding, the clinical and therapeutical characteristics of females and males were similar. Platelet-enhancing drugs were reported in 66%, 45%, and 30% of patients at diagnosis, 1-6 months, and 6-12 months after diagnosis, respectively. Corticosteroids were the preferred treatment at all time points. At 12 months, 50% of all patients developed chronic ITP. In the subgroup of patients with initial severe thrombocytopenia (<20×109/L), those receiving frontline treatment had a higher remission rate at 1 year than those who followed an initial watch-and-wait strategy (53% and 32%; P<0.05). Our analysis indicates that the remission rate at 1 year may be associated with the initial treatment strategy. This hypothesis must be confirmed in prospective studies.


Asunto(s)
Púrpura Trombocitopénica Idiopática , Trombocitopenia , Masculino , Niño , Humanos , Femenino , Adolescente , Adulto Joven , Embarazo , Púrpura Trombocitopénica Idiopática/terapia , Púrpura Trombocitopénica Idiopática/tratamiento farmacológico , Estudios Prospectivos , Recuento de Plaquetas , Hemorragia/diagnóstico
10.
Immunology ; 167(4): 558-575, 2022 12.
Artículo en Inglés | MEDLINE | ID: mdl-35881080

RESUMEN

Post-stroke infection is a common complication of stroke that is associated with poor outcome. We previously reported that stroke induces an ablation of multiple sub-populations of B cells and reduces levels of immunoglobulin M (IgM) antibody, which coincides with the development of spontaneous bacterial pneumonia. The loss of IgM after stroke could be an important determinant of infection susceptibility and highlights this pathway as a target for intervention. We treated mice with a replacement dose of IgM-enriched intravenous immunoglobulin (IgM-IVIg) prior to and 24 h after middle cerebral artery occlusion (MCAO) and allowed them to recover for 2- or 5-day post-surgery. Treatment with IgM-IVIg enhanced bacterial clearance from the lung after MCAO and improved lung pathology but did not impact brain infarct volume. IgM-IVIg treatment induced immunomodulatory effects systemically, including rescue of splenic plasma B cell numbers and endogenous mouse IgM and IgA circulating immunoglobulin concentrations that were reduced by MCAO. Treatment attenuated MCAO-induced elevation of selected pro-inflammatory cytokines in the lung. IgM-IVIg treatment did not increase the number of lung mononuclear phagocytes or directly modulate macrophage phagocytic capacity but enhanced phagocytosis of Staphylococcus aureus bioparticles in vitro. Low-dose IgM-IVIg contributes to increased clearance of spontaneous lung bacteria after MCAO likely via increasing availability of antibody in the lung to enhance opsonophagocytic activity. Immunomodulatory effects of IgM-IVIg treatment may also contribute to reduced levels of damage in the lung after MCAO. IgM-IVIg shows promise as an antibacterial and immunomodulatory agent to use in the treatment of post-stroke infection.


Asunto(s)
Infecciones Bacterianas , Accidente Cerebrovascular , Ratones , Animales , Inmunoglobulinas Intravenosas/uso terapéutico , Factores Inmunológicos , Inmunoglobulina M , Accidente Cerebrovascular/complicaciones , Accidente Cerebrovascular/terapia , Bacterias , Pulmón
11.
Immunity ; 39(3): 599-610, 2013 Sep 19.
Artículo en Inglés | MEDLINE | ID: mdl-24012416

RESUMEN

It is thought that monocytes rapidly differentiate to macrophages or dendritic cells (DCs) upon leaving blood. Here we have shown that Ly-6C⁺ monocytes constitutively trafficked into skin, lung, and lymph nodes (LNs). Entry was unaffected in gnotobiotic mice. Monocytes in resting lung and LN had similar gene expression profiles to blood monocytes but elevated transcripts of a limited number of genes including cyclo-oxygenase-2 (COX-2) and major histocompatibility complex class II (MHCII), induced by monocyte interaction with endothelium. Parabiosis, bromodoxyuridine (BrdU) pulse-chase analysis, and intranasal instillation of tracers indicated that instead of contributing to resident macrophages in the lung, recruited endogenous monocytes acquired antigen for carriage to draining LNs, a function redundant with DCs though differentiation to DCs did not occur. Thus, monocytes can enter steady-state nonlymphoid organs and recirculate to LNs without differentiation to macrophages or DCs, revising a long-held view that monocytes become tissue-resident macrophages by default.


Asunto(s)
Diferenciación Celular , Células Dendríticas/metabolismo , Ganglios Linfáticos/citología , Macrófagos/metabolismo , Monocitos/inmunología , Monocitos/metabolismo , Animales , Antígenos Ly/metabolismo , Movimiento Celular , Ciclooxigenasa 2/genética , Células Dendríticas/citología , Células Dendríticas/inmunología , Endotelio/metabolismo , Antígenos de Histocompatibilidad Clase II/genética , Antígenos de Histocompatibilidad Clase II/inmunología , Pulmón/citología , Ganglios Linfáticos/inmunología , Macrófagos/citología , Macrófagos/inmunología , Ratones , Ratones Endogámicos C57BL , Piel/citología
12.
Cerebrovasc Dis ; 51(4): 461-472, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-34983048

RESUMEN

INTRODUCTION: Stroke is characterized by deleterious oxidative stress. Selenoprotein enzymes are essential endogenous antioxidants, and detailed insight into their role after stroke could define new therapeutic treatments. This systematic review aimed to elucidate how blood selenoprotein concentration and activity change in the acute phase of stroke. METHODS: We searched PubMed, EMBASE, and Medline databases for studies measuring serial blood selenoprotein concentration or activity in acute stroke patients or in stroke patients compared to non-stroke controls. Meta-analyses of studies stratified by the type of stroke, blood compartment, and type of selenoprotein measurement were conducted. RESULTS: Eighteen studies and data from 941 stroke patients and 708 non-stroke controls were included in this review. Glutathione peroxidase (GPx) was the only identified selenoprotein, and its activity was most frequently measured. Results from 12 studies and 693 patients showed that compared to non-stroke controls in acute ischaemic stroke patients, the GPx activity increased in haemolysate (standardized mean difference [SMD]: 0.27, 95% CI: 0.07-0.47) but decreased in plasma (mean difference [MD]: -1.08 U/L, 95% CI: -1.94 to -0.22) and serum (SMD: -0.54, 95% CI: -0.91 to -0.17). From 4 identified studies in 106 acute haemorrhagic stroke patients, the GPx activity decreased in haemolysate (SMD: -0.40, 95% CI: -0.68 to -0.13) and remained unchanged in plasma (MD: -0.10 U/L, 95% CI: -0.81 to 0.61) and serum (MD: -5.00 U/mL, 95% CI: -36.17 to 26.17) compared to non-stroke controls. Results from studies assessing the GPx activity in the haemolysate compartment were inconsistent and characterized by high heterogeneity. CONCLUSIONS: Our results suggest a reduction of the blood GPx activity in acute ischaemic stroke patients, a lack of evidence regarding a role for GPx in haemorrhagic stroke patients, and insufficient evidence for other selenoproteins.


Asunto(s)
Isquemia Encefálica , Accidente Cerebrovascular Hemorrágico , Accidente Cerebrovascular Isquémico , Selenoproteínas , Antioxidantes , Isquemia Encefálica/diagnóstico , Isquemia Encefálica/patología , Glutatión Peroxidasa , Accidente Cerebrovascular Hemorrágico/diagnóstico , Accidente Cerebrovascular Hemorrágico/patología , Humanos , Accidente Cerebrovascular Isquémico/diagnóstico , Accidente Cerebrovascular Isquémico/patología , Selenio , Selenoproteínas/metabolismo
14.
Ann Hematol ; 100(9): 2143-2154, 2021 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-34308495

RESUMEN

Immune thrombocytopenia (ITP) is a disease of heterogenous origin characterized by low platelet counts and an increased bleeding tendency. Three disease phases have been described: newly diagnosed (≤ 3 months after diagnosis), persistent (> 3-12 months after diagnosis), and chronic (> 12 months after diagnosis). The majority of children with ITP have short-lived disease and will not need treatment. For children with newly diagnosed ITP, who have increased bleeding symptoms, short courses of steroids are recommended. In children who do not respond to first-line treatment or who become steroid dependent, thrombopoietin receptor agonists (TPO-RAs) are recommended because of their efficacy and safety profiles. In this narrative review, we evaluate the available evidence on the use of the TPO-RA romiplostim to treat children with newly diagnosed or persistent ITP and identify data from five clinical trials, five real-world studies, and a case report. While the data are more limited for children with newly diagnosed ITP than for persistent ITP, the collective body of evidence suggests that romiplostim is efficacious in increasing platelet counts in children with newly diagnosed or persistent ITP and may result in long-lasting treatment-free responses in some patients. Furthermore, romiplostim was found to be well tolerated in the identified studies. Collectively, the data suggest that earlier treatment with romiplostim may help children to avoid the side effects associated with corticosteroid use and reduce the need for subsequent treatment.


Asunto(s)
Púrpura Trombocitopénica Idiopática/tratamiento farmacológico , Receptores Fc/uso terapéutico , Receptores de Trombopoyetina/agonistas , Proteínas Recombinantes de Fusión/uso terapéutico , Trombopoyetina/uso terapéutico , Niño , Ensayos Clínicos como Asunto , Manejo de la Enfermedad , Hemorragia/diagnóstico , Hemorragia/tratamiento farmacológico , Humanos , Púrpura Trombocitopénica Idiopática/diagnóstico
15.
Immunity ; 37(4): 622-33, 2012 Oct 19.
Artículo en Inglés | MEDLINE | ID: mdl-23041065

RESUMEN

T helper (Th) cells are critical for defenses against infection and recognize peptides bound to class II major histocompatibility complex (MHC II) molecules. Although transcription factors have been identified that direct Th cells into specific effector fates, whether a "master" regulator controls the developmental program common to all Th cells remains unclear. Here, we showed that the two transcription factors Thpok and LRF share this function. Although disruption of both factors did not prevent the generation of MHC II-specific T cells, these cells failed to express Th cell genes or undergo Th cell differentiation in vivo. In contrast, T cells lacking Thpok, which only displayed LRF-dependent functions, contributed to multiple effector responses, both in vitro and in vivo, with the notable exception of Th2 cell responses that control extracellular parasites. These findings identify the Thpok-LRF pair as a core node of Th cell differentiation and function.


Asunto(s)
Diferenciación Celular , Proteínas de Unión al ADN/inmunología , Linfocitos T Colaboradores-Inductores/inmunología , Factores de Transcripción/inmunología , Animales , Células Cultivadas , Regulación de la Expresión Génica , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Linfocitos T Colaboradores-Inductores/citología , Factores de Transcripción/deficiencia
16.
Immunity ; 37(3): 511-23, 2012 Sep 21.
Artículo en Inglés | MEDLINE | ID: mdl-22981537

RESUMEN

Interferon-γ (IFN-γ) promotes a population of T-bet(+) CXCR3(+) regulatory T (Treg) cells that limit T helper 1 (Th1) cell-mediated pathology. Our studies demonstrate that interleukin-27 (IL-27) also promoted expression of T-bet and CXCR3 in Treg cells. During infection with Toxoplasma gondii, a similar population emerged that limited T cell responses and was dependent on IFN-γ in the periphery but on IL-27 at mucosal sites. Transfer of Treg cells ameliorated the infection-induced pathology observed in Il27(-/-) mice, and this was dependent on their ability to produce IL-10. Microarray analysis revealed that Treg cells exposed to either IFN-γ or IL-27 have distinct transcriptional profiles. Thus, IFN-γ and IL-27 have different roles in Treg cell biology and IL-27 is a key cytokine that promotes the development of Treg cells specialized to control Th1 cell-mediated immunity at local sites of inflammation.


Asunto(s)
Interferón gamma/farmacología , Interleucina-17/farmacología , Salmonelosis Animal/inmunología , Linfocitos T Reguladores/efectos de los fármacos , Toxoplasmosis Animal/inmunología , Animales , Diferenciación Celular/efectos de los fármacos , Diferenciación Celular/inmunología , Células Cultivadas , Femenino , Citometría de Flujo , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/inmunología , Factores de Transcripción Forkhead/metabolismo , Perfilación de la Expresión Génica , Interferón gamma/genética , Interferón gamma/inmunología , Interleucina-17/genética , Interleucina-17/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos CBA , Ratones Noqueados , Ratones Transgénicos , Análisis de Secuencia por Matrices de Oligonucleótidos , Receptores CXCR3/genética , Receptores CXCR3/inmunología , Receptores CXCR3/metabolismo , Factor de Transcripción STAT1/genética , Factor de Transcripción STAT1/inmunología , Factor de Transcripción STAT1/metabolismo , Salmonelosis Animal/microbiología , Salmonelosis Animal/patología , Salmonella typhimurium/inmunología , Proteínas de Dominio T Box/genética , Proteínas de Dominio T Box/inmunología , Proteínas de Dominio T Box/metabolismo , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Toxoplasma/inmunología , Toxoplasmosis Animal/parasitología , Toxoplasmosis Animal/patología
17.
Acta Haematol ; 144(4): 418-426, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33789275

RESUMEN

BACKGROUND: Recent evidence suggests that in patients with immune thrombocytopenia (ITP) with a stable response on thrombopoietin receptor agonists, treatment may be tapered and/or discontinued. OBJECTIVES: The objective of this study was to provide a guide for tapering and discontinuation of TPO-RA therapy in patients with ITP, based on hematologist survey results, existing evidence, and expert consensus. PATIENTS/METHODS: UK hematologists completed a survey to characterize self-reported practice patterns related to TPO-RA tapering and discontinuation in patients with ITP. Using a modified Delphi panel approach, ITP experts developed consensus statements regarding the use of TPO-RA tapering and discontinuation. RESULTS: Survey respondents estimated that 30-34% of their patients were suitable for tapering or discontinuation and that 29-35% of these patients required treatment re-initiation after an average treatment-free interval of 86-106 days. No clear predictors of patient suitability or response to tapering or discontinuation were identified. The ITP expert consensus was that approximately 30% of patients are eligible for tapering and discontinuation, which may be considered after 6-12 months for patients demonstrating an adequate treatment response (platelet count >50,000/µL at ≥75% of assessments in the preceding 6 months). Treatment re-initiation may be considered if the platelet count decreases or if the patient becomes symptomatic. Individual differences need to be taken into account when considering TPO-RA tapering or discontinuation. CONCLUSIONS: Tapering and discontinuation of TPO-RA therapy may be considered for certain patients with ITP. Further study is needed to better predict patients likely to achieve sustained off-treatment responses after tapering and discontinuation.


Asunto(s)
Púrpura Trombocitopénica Idiopática/tratamiento farmacológico , Receptores de Trombopoyetina/agonistas , Benzoatos/uso terapéutico , Humanos , Hidrazinas/uso terapéutico , Cumplimiento de la Medicación , Médicos/psicología , Recuento de Plaquetas , Pirazoles/uso terapéutico , Receptores Fc/uso terapéutico , Proteínas Recombinantes de Fusión/uso terapéutico , Recurrencia , Inducción de Remisión , Retratamiento , Autoinforme , Encuestas y Cuestionarios , Trombopoyetina/uso terapéutico
18.
Proc Natl Acad Sci U S A ; 115(42): 10738-10743, 2018 10 16.
Artículo en Inglés | MEDLINE | ID: mdl-30279177

RESUMEN

γδ T cells are enriched at barrier sites such as the gut, skin, and lung, where their roles in maintaining barrier integrity are well established. However, how these cells contribute to homeostasis at the gingiva, a key oral barrier and site of the common chronic inflammatory disease periodontitis, has not been explored. Here we demonstrate that the gingiva is policed by γδ T cells with a T cell receptor (TCR) repertoire that diversifies during development. Gingival γδ T cells accumulated rapidly after birth in response to barrier damage, and strikingly, their absence resulted in enhanced pathology in murine models of the oral inflammatory disease periodontitis. Alterations in bacterial communities could not account for the increased disease severity seen in γδ T cell-deficient mice. Instead, gingival γδ T cells produced the wound healing associated cytokine amphiregulin, administration of which rescued the elevated oral pathology of tcrδ-/- mice. Collectively, our results identify γδ T cells as critical constituents of the immuno-surveillance network that safeguard gingival tissue homeostasis.


Asunto(s)
Anfirregulina/metabolismo , Homeostasis , Boca/inmunología , Periodontitis/inmunología , Receptores de Antígenos de Linfocitos T gamma-delta/fisiología , Subgrupos de Linfocitos T/inmunología , Animales , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Boca/metabolismo , Periodontitis/metabolismo , Periodontitis/patología , Subgrupos de Linfocitos T/metabolismo
19.
Br J Haematol ; 189(6): 1038-1043, 2020 06.
Artículo en Inglés | MEDLINE | ID: mdl-32374026

RESUMEN

This document aims to provide practical guidance for the assessment and management of patients with thrombocytopenia, with a particular focus on immune thrombocytopenia (ITP), during the COVID-19 pandemic. The intention is to support clinicians and, although recommendations have been provided, it is not a formal guideline. Nor is there sufficient evidence base to conclude that alternative approaches to treatment are incorrect. Instead, it is a consensus written by clinicians with an interest in ITP or coagulation disorders and reviewed by members of the UK ITP forum.


Asunto(s)
Betacoronavirus , Infecciones por Coronavirus , Pandemias , Neumonía Viral , Púrpura Trombocitopénica Idiopática , Adulto , COVID-19 , Infecciones por Coronavirus/epidemiología , Infecciones por Coronavirus/etiología , Infecciones por Coronavirus/terapia , Femenino , Humanos , Masculino , Neumonía Viral/epidemiología , Neumonía Viral/etiología , Neumonía Viral/terapia , Guías de Práctica Clínica como Asunto , Púrpura Trombocitopénica Idiopática/congénito , Púrpura Trombocitopénica Idiopática/epidemiología , Púrpura Trombocitopénica Idiopática/terapia , SARS-CoV-2
20.
Immunity ; 35(1): 13-22, 2011 Jul 22.
Artículo en Inglés | MEDLINE | ID: mdl-21777796

RESUMEN

Vitamin A elicits a broad array of immune responses through its metabolite, retinoic acid (RA). Recent evidence indicates that loss of RA leads to impaired immunity, whereas excess RA can potentially promote inflammatory disorders. In this review, we discuss recent advances showcasing the crucial contributions of RA to both immunological tolerance and the elicitation of adaptive immune responses. Further, we provide a comprehensive overview of the cell types and factors that control the production of RA and discuss how host perturbations may affect the ability of this metabolite to control tolerance and immunity or to instigate pathology.


Asunto(s)
Inmunidad Adaptativa , Tolerancia Inmunológica , Infecciones/inmunología , Linfocitos T Reguladores/inmunología , Tretinoina/inmunología , Animales , Movimiento Celular , Humanos , Inmunidad Mucosa , Inmunoglobulina A/inmunología , Transducción de Señal/inmunología , Vitamina A/metabolismo
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