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1.
Medicine (Baltimore) ; 98(41): e17348, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31593084

RESUMO

Immune checkpoint inhibitors (ICIs) like cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA4) and programmed death cell protein 1 (anti-PD1) have revolutionized cancer treatment. As ICI use becomes widespread, more immune-related adverse events (irAE's) are being reported. Our aim was to investigate the frequency and nature of new irAE's as well as report the frequency of flare-ups of pre-existing autoimmune conditions occurring after ICI therapy.We performed a retrospective chart review of all patients treated for cancer with anti-PD1 or anti-CTLA4 or combination therapy at our tertiary care center from January 2014 to April 2016. Demographic data, cancer type and stage, irAE's (new immune disorders and disease flares of pre-existing autoimmune disorders on ICI therapy), and drug treatment information were extracted.We identified 220 patients treated with ICI therapy during the study period out of which 27% (60/220) developed irAE's. 11% in anti-CTLA4 group and 16% among anti-PD1 treated patients developed irAE's. IrAE's resulted in discontinuation of cancer therapy in 28% of those who developed irAE's. 21.4% had a flare of their autoimmune disease but only 1 required discontinuation of immunotherapy.IrAE's are an important emerging clinical disease entity for specialists to be aware of. Our study shows that ICI's can be safely used in patients with pre-existing autoimmune conditions with close monitoring. However, there is still a large unmet need to have a better understanding of how to systematically evaluate and manage patients with irAE's as well as for identifying the predictors of irAE's.


Assuntos
Antineoplásicos Imunológicos/efeitos adversos , Doenças do Sistema Imunitário/induzido quimicamente , Imunoterapia/efeitos adversos , Melanoma/tratamento farmacológico , Neoplasias/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Doenças Autoimunes/induzido quimicamente , Doenças Autoimunes/imunologia , Antígeno CTLA-4/antagonistas & inibidores , Feminino , Humanos , Doenças do Sistema Imunitário/imunologia , Masculino , Melanoma/imunologia , Pessoa de Meia-Idade , Neoplasias/imunologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Estudos Retrospectivos
3.
Toxicol Lett ; 304: 30-38, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30605750

RESUMO

Clinical study showed that smoking during pregnancy deceased the thymus size in newborns. However, the long-term effect remains unclear. This study was aimed to observe the effects of prenatal nicotine exposure (PNE) on the development of thymus and the T-lymphocyte subpopulation in mice offspring from the neonatal to adulthood. Both the thymus weight and cytometry data indicated that PNE caused persistent thymic hypoplasia in male offspring from neonatal to adult period and transient changes in female offspring from neonatal to prepuberal period. Flow cytometry analysis disclosed a permanent decreased proportion and number of mature CD4 single-positive (SP) T cells in thymus of both sex. In addition, the PNE male offspring showed a more serious thymus atrophy in the ovalbumin (OVA)-sensitized model. Moreover, increased autophagic vacuole and elevated mRNA expression of Beclin 1 were noted in PNE fetal thymus. In conclusion, PNE offspring showed thymus atrophy and CD 4 SP T cell reduction at different life stages. Mechanically, PNE induced excessive autophagy in fetal thymocytes might be involved in these changes. All the results provided evidence for elucidating the PNE-induced programmed immune diseases.


Assuntos
Linfócitos T CD4-Positivos/efeitos dos fármacos , Doenças do Sistema Imunitário/induzido quimicamente , Nicotina/toxicidade , Agonistas Nicotínicos/toxicidade , Efeitos Tardios da Exposição Pré-Natal , Timócitos/efeitos dos fármacos , Timo/efeitos dos fármacos , Fatores Etários , Animais , Animais Recém-Nascidos , Autofagia/efeitos dos fármacos , Proteína Beclina-1/genética , Proteína Beclina-1/metabolismo , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/patologia , Feminino , Doenças do Sistema Imunitário/imunologia , Doenças do Sistema Imunitário/metabolismo , Doenças do Sistema Imunitário/patologia , Masculino , Exposição Materna , Camundongos Endogâmicos BALB C , Ovalbumina/imunologia , Fenótipo , Gravidez , Timócitos/imunologia , Timócitos/metabolismo , Timócitos/patologia , Timo/imunologia , Timo/metabolismo , Timo/patologia
5.
J Toxicol Sci ; 43(1): 33-44, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29415950

RESUMO

Crotonaldehyde is a ubiquitous air pollutant in the environment. It is reported to be harmful to the biosystems in vivo and in vitro. The exposure to crotonaldehyde irritates the mucous membranes and induces edema, hyperemia, cell necrosis, inflammation, and acute respiratory distress syndrome in the lungs. However, the effects of crotonaldehyde on the immune system have not been reported. In the present study, 6-8 weeks old male Wistar rats were exposed to crotonaldehyde by intratracheal instillation at doses of 4, 8, and 16 µL/kg body weight (b.w.). The general damage in the animals was investigated; the cell counting and the biochemical analysis in the peripheral blood were tested. Furthermore, we investigated the functions of alveolar macrophages (AMs), the alterations of the T-lymphocyte subsets, and the cell composition in the bronchoalveolar lavage fluid (BALF). We found that the activities of the animals were changed after exposure to crotonaldehyde, the cellular ratios and the biochemical components in the peripheral blood were altered, the ratio of mononuclear phagocytes decreased, and the ratios of lymphocytes and granulocytes elevated significantly in BALF. Meanwhile, crotonaldehyde altered the ratio of the T-lymphocyte subsets, and the phagocytic rates and indices of AMs increased obviously. In conclusion, crotonaldehyde induces dysfunction of immune system in male Wistar rats.


Assuntos
Poluentes Atmosféricos/efeitos adversos , Aldeídos/efeitos adversos , Doenças do Sistema Imunitário/induzido quimicamente , Doenças do Sistema Imunitário/imunologia , Doença Aguda , Animais , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Humanos , Macrófagos Alveolares/imunologia , Masculino , Fagócitos/imunologia , Ratos Wistar , Subpopulações de Linfócitos T/imunologia
6.
Yakugaku Zasshi ; 138(1): 123-134, 2018.
Artigo em Japonês | MEDLINE | ID: mdl-29311458

RESUMO

OTC combination cold remedies are widely used in Japan. In the present study, we aimed to evaluate the adverse event profiles of OTC combination cold remedy based on the components using the Japanese Adverse Drug Event Report (JADER) database. The JADER database contained 430587 reports between April 2004 and November 2016. 1084 adverse events associated with the use of OTC combination cold remedy were reported. Reporting odds ratio (ROR) was used to detect safety signals. The ROR values for "skin and subcutaneous tissue disorders", "hepatobiliary disorders", and "immune system disorders" stratified by system organ class of the Medical Dictionary for Regulatory Activities (MedDRA) were 9.82 (8.71-11.06), 2.63 (2.25-3.07), and 3.13 (2.63-3.74), respectively. OTC combination cold remedy containing acetaminophen exhibited a significantly higher reporting ratio for "hepatobiliary disorders" than OTC combination cold remedy without acetaminophen. We demonstrated the potential risk of OTC combination cold remedy in a real-life setting. Our results suggested that the monitoring of individuals using OTC combination cold remedy is important.


Assuntos
Acetaminofen/efeitos adversos , Sistemas de Notificação de Reações Adversas a Medicamentos , Mineração de Dados , Bases de Dados Factuais , Uso de Medicamentos/estatística & dados numéricos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Medicamentos sem Prescrição/efeitos adversos , Acetaminofen/administração & dosagem , Sistemas de Notificação de Reações Adversas a Medicamentos/estatística & dados numéricos , Doenças Biliares/induzido quimicamente , Doenças Biliares/epidemiologia , Doença Hepática Induzida por Substâncias e Drogas/epidemiologia , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Combinação de Medicamentos , Doenças do Sistema Imunitário/induzido quimicamente , Doenças do Sistema Imunitário/epidemiologia , Japão/epidemiologia , Medicamentos sem Prescrição/administração & dosagem , Razão de Chances , Risco , Dermatopatias/induzido quimicamente , Dermatopatias/epidemiologia , Fatores de Tempo
7.
Endocrinology ; 159(1): 32-45, 2018 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-29145569

RESUMO

The incidence of metabolic disorders like type 2 diabetes and obesity continues to increase. In addition to the well-known contributors to these disorders, such as food intake and sedentary lifestyle, recent research in the exposure science discipline provides evidence that exposure to endocrine-disrupting chemicals like bisphenol A and phthalates via multiple routes (e.g., food, drink, skin contact) also contribute to the increased risk of metabolic disorders. Endocrine-disrupting chemicals (EDCs) can disrupt any aspect of hormone action. It is becoming increasingly clear that EDCs not only affect endocrine function but also adversely affect immune system function. In this review, we focus on human, animal, and in vitro studies that demonstrate EDC exposure induces dysfunction of the immune system, which, in turn, has detrimental effects on metabolic health. These findings highlight how the immune system is emerging as a novel player by which EDCs may mediate their effects on metabolic health. We also discuss studies highlighting mechanisms by which EDCs affect the immune system. Finally, we consider that a better understanding of the immunomodulatory roles of EDCs will provide clues to enhance metabolic function and contribute toward the long-term goal of reducing the burden of environmentally induced diabetes and obesity.


Assuntos
Disruptores Endócrinos/toxicidade , Exposição Ambiental/efeitos adversos , Doença Ambiental/induzido quimicamente , Saúde Global , Transição Epidemiológica , Doenças do Sistema Imunitário/induzido quimicamente , Sistema Imunitário/efeitos dos fármacos , Animais , Doença Ambiental/epidemiologia , Doença Ambiental/imunologia , Doença Ambiental/metabolismo , Humanos , Sistema Imunitário/imunologia , Sistema Imunitário/metabolismo , Doenças do Sistema Imunitário/epidemiologia , Doenças do Sistema Imunitário/imunologia , Doenças do Sistema Imunitário/metabolismo , Prevalência
8.
Ann Oncol ; 28(10): 2377-2385, 2017 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-28945858

RESUMO

Background: Immune checkpoint inhibitor (ICI) monoclonal antibodies (mAbs) targeting cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed cell death protein 1 (PD-1) or its ligand (PD-L1) produce unique toxicity profiles. The objective of this review was to identify patterns and incidence of immune-related adverse events (irAE) based on tumour type and ICI class. Methods: Medline, EMBASE and COCHRANE databases were searched to identify prospective monotherapy trials of ICIs from 2003 to November 2015. Paired reviewers selected studies for inclusion and extracted data. Odds ratio (OR), χ2 tests and multivariable regression models were used to analyse for effect size and associations. Results: We identified 48 trials (6938 patients), including 26 CTLA-4, 17 PD-1, 2 PD-L1 trials, and 3 studies tested both CTLA-4 and PD-1. Grade 3/4 irAE were more common with CTLA-4 mAbs compared with PD-1 (31% versus 10%). All grades colitis (OR 8.7, 95% CI 5.8-12.9), hypophysitis (OR 6.5, 95% CI 3.0-14.3) and rash (OR 2.0, 95% CI 1.8-2.3) were more frequent with CTLA-4 mAbs; whereas pneumonitis (OR 6.4, 95% CI 3.2-12.7), hypothyroidism (OR 4.3, 95% CI 2.9-6.3), arthralgia (OR 3.5, 95% CI 2.6-4.8) and vitiligo (OR 3.5, 95% CI 2.3-5.3) were more common with PD-1 mAbs. Comparison of irAE from the three most studied tumour types in PD-1 mAbs trials [melanoma (n = 2048), non-small-cell lung cancer (n = 1030) and renal cell carcinoma (n = 573)] showed melanoma patients had a higher frequency of gastrointestinal and skin irAE and lower frequency of pneumonitis. Discussion: CTLA-4 and PD-1 mAbs have distinct irAE profiles. Different immune microenvironments may drive histology-specific irAE patterns. Other tumour-dependent irAE profiles may be identified as data emerge from ICI trials.


Assuntos
Anticorpos Monoclonais/efeitos adversos , Antineoplásicos Imunológicos/efeitos adversos , Antígeno CTLA-4/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/imunologia , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/imunologia , Antígeno CTLA-4/imunologia , Ensaios Clínicos como Assunto/métodos , Humanos , Doenças do Sistema Imunitário/induzido quimicamente , Doenças do Sistema Imunitário/imunologia , Neoplasias/imunologia , Receptor de Morte Celular Programada 1/imunologia , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos
9.
Immunopharmacol Immunotoxicol ; 39(6): 305-317, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28828896

RESUMO

Trichloroethylene (TCE) is one of the most common ground water contaminants in USA. Even though recent regulation mandates restricted utilization of TCE, its use is not completely prohibited, especially in industrial and manufacturing processes. The risk of TCE on human health is an ongoing field of study and its implications on certain diseases such as cancer has been recognized and well-documented. However, the link between TCE and immune disorders is still an under-studied area. Studies on the risk of TCE on the immune system is usually focused on certain immune class disorders, but consensus on the impact of TCE on the immune system has not been established. This review presents representative work that investigates the effect of TCE on immune disorders and highlights future opportunities. We attempt to provide a broader perspective of the risks of TCE on the immune system and human health.


Assuntos
Doenças do Sistema Imunitário/induzido quimicamente , Sistema Imunitário/efeitos dos fármacos , Tricloroetileno/efeitos adversos , Animais , Humanos , Risco
10.
Am J Respir Crit Care Med ; 196(10): 1325-1336, 2017 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-28657793

RESUMO

RATIONALE: Dysregulated neutrophil functions with age and sepsis are described. Statins are associated with improved infection survival in some observational studies, but trials in critically ill patients have not shown benefit. Statins also alter neutrophil responses in vitro. OBJECTIVES: To assess neutrophil migratory accuracy with age during respiratory infections and determine if and how a statin intervention could alter these blunted responses. METHODS: The migratory accuracy of blood neutrophils from young (aged <35 yr) and old (aged >60 yr) patients in health and during a lower respiratory tract infection, community-acquired pneumonia, and pneumonia associated with sepsis was assessed with and without simvastatin. In vitro results were confirmed in a double-blind randomized clinical trial in healthy elders. Cell adhesion markers were assessed. MEASUREMENTS AND MAIN RESULTS: In vitro neutrophil migratory accuracy in the elderly deteriorated as the severity of the infectious pulmonary insult increased, without recovery at 6 weeks. Simvastatin rescued neutrophil migration with age and during mild to moderate infection, at high dose in older adults, but not during more severe sepsis. Confirming in vitro results, high-dose (80-mg) simvastatin improved neutrophil migratory accuracy without impeding other neutrophil functions in a double-blind randomized clinical trial in healthy elders. Simvastatin modified surface adhesion molecule expression and activity, facilitating accurate migration in the elderly. CONCLUSIONS: Infections in older adults are associated with prolonged, impaired neutrophil migration, potentially contributing to poor outcomes. Statins improve neutrophil migration in vivo in health and in vitro in milder infective events, but not in severe sepsis, supporting their potential utility as an early intervention during pulmonary infections. Clinical trial registered with www.clinicaltrialsregister.eu (2011-002082-38).


Assuntos
Infecções Comunitárias Adquiridas/tratamento farmacológico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Doenças do Sistema Imunitário/induzido quimicamente , Doenças do Sistema Imunitário/tratamento farmacológico , Transtornos Leucocíticos/induzido quimicamente , Transtornos Leucocíticos/tratamento farmacológico , Infecções Respiratórias/tratamento farmacológico , Sepse/tratamento farmacológico , Sinvastatina/uso terapêutico , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
11.
Eur J Cancer ; 82: 34-44, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28646772

RESUMO

AIM: The growing use of immune checkpoint inhibitors (ICIs) is associated with the occurrence of immune-related adverse events (irAEs). Few data are published on systemic, immunohaematological and rheumatic irAEs. In a pharmacovigilance database analysis, we screened for these irAEs and calculated their prevalence. PATIENTS AND METHODS: Participants were recruited via Registre des Effets Indésirables Sévères des Anticorps Monoclonaux Immunomodulateurs en Cancérologie (REISAMIC)1 a French registry of grade ≥2 irAEs occurring in ICI-treated patients. The pathologies of interest were systemic autoimmune and inflammatory diseases, rheumatic diseases and immune cytopenia. RESULTS: Out of 908 patients treated with anti-Programmed cell Death 1 (PD1)/anti-Programmed cell Death-Ligand 1 (PD-L1) agents (together with an anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4) agent in 40 cases) between December 2012 and December 2016 at a single centre, 21 patients experienced systemic irAEs. The types and the prevalence of irAEs were as follows: immune thrombocytopenia (0.2%), Sjögren syndrome (0.3%), rheumatoid arthritis (0.2%), polymyalgia rheumatica (0.2%), psoriatic arthritis (0.2%), seronegative polyarthritis (0.7%) and sarcoidosis (0.2%). Patients with Sjögren syndrome or seronegative polyarthritis were more likely to have received combination therapy with ipilimumab (2.5% for both). We described these 21 cases, together with nine additional cases from five other centres. Most irAE were moderately severe (grade 2, 63%). The median time to onset was 57°days (interquartile range (IQR) 24-117). The ICI was withdrawn in 12 cases, 25 patients (83%) received corticosteroids, and five patients (17%) received immunosuppressant/immunomodulatory agents. The irAEs resolved fully or partially in 28 cases (93%). CONCLUSION: Although systemic, immunohaematological and rheumatic diseases are rarely associated with ICI use, the prevalence is higher when two ICIs are combined. Corticosteroids are often effective and may enable the continued administration of ICIs. Studies designed to identify at-risk patients are warranted.


Assuntos
Antineoplásicos/efeitos adversos , Doenças do Sistema Imunitário/induzido quimicamente , Doenças do Sistema Imunitário/epidemiologia , Fatores Imunológicos/efeitos adversos , Imunossupressores/efeitos adversos , Imunoterapia/efeitos adversos , Neoplasias/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígeno B7-H1/antagonistas & inibidores , França/epidemiologia , Humanos , Imunoterapia/métodos , Pessoa de Meia-Idade , Prevalência , Receptor de Morte Celular Programada 1/antagonistas & inibidores
12.
Artigo em Alemão | MEDLINE | ID: mdl-28466130

RESUMO

The main task of the immune system is to protect the body against invading pathogens. To be able to do so, immune cells must be able to recognize and combat exogenous challenges and at the same time tolerate body-borne structures. A complex regulatory network controls the sensitive balance between defense and tolerance. Perturbation of this network ultimately leads to the development of chronic inflammation, such as allergies, autoimmune reactions, and infections, because the immune system is no longer able to efficiently eliminate invading pathogens. Environmental pollutants can cause such perturbations by affecting the function of immune cells in such a way that they would react hypersensitively against allergens and the body's own structures, respectively, or that they would be no longer able to adequately combat pathogens. This indirect effect is also known as adjuvant effect. For pesticides, heavy metals, wood preservatives, or volatile organic compounds such adjuvant effects are well known. Examples of the mechanism by which environmental toxins contribute to chronic inflammatory diseases are manifold and will be discussed along asthma and allergies.While the immune system of healthy adults is typically well able to distinguish between foreign and endogenous substances even under adverse environmental conditions, that of children would react much more sensible upon comparable environmental challenges. To prevent priming for diseases by environmental cues during that highly sensitive period of early childhood children are to be particularly protected.


Assuntos
Adjuvantes Imunológicos/toxicidade , Exposição Ambiental/efeitos adversos , Poluentes Ambientais/efeitos adversos , Doenças do Sistema Imunitário/induzido quimicamente , Doenças do Sistema Imunitário/imunologia , Imunidade Inata/imunologia , Medicina Baseada em Evidências , Humanos , Imunidade Inata/efeitos dos fármacos , Modelos Imunológicos
13.
J Immunother Cancer ; 5: 19, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28344807

RESUMO

BACKGROUND: CTLA-4 (Cytotoxic T-lymphocyte-associated protein 4) was the first immune checkpoint receptor clinically targeted for use in cancer treatment. It is expressed exclusively on T-cells where its primary role is to regulate the amplitude of the early stages of T-cell activation.1 Ipilimumab, a CTLA-4 blocking antibody, has been widely used for the treatment of patients with high risk and metastatic melanoma. Given its mechanism of action and consequent immune activation, the side effect profile of this drug greatly differs from that of standard cytotoxic chemotherapy. Adverse events are from the most part immune-mediated, ranging from the more common, such as rash and fatigue, to the less common, such as immune endocrinopathy and colitis. CASE PRESENTATION: We describe a case of immune-mediated thrombotic thrombocytopenic purpura (TTP) in a 68 year-old woman with high risk, stage III melanoma occurring after 3 cycles of adjuvant treatment with ipilimumab as part of a clinical trial. CONCLUSION: The range of immune-mediated adverse events during treatment with ipilimumab is wide and varied and clinicians should have a high degree of suspicion when managing these patients.


Assuntos
Antígeno CTLA-4/antagonistas & inibidores , Ipilimumab/efeitos adversos , Melanoma/tratamento farmacológico , Púrpura Trombocitopênica Trombótica/patologia , Idoso , Antígeno CTLA-4/imunologia , Antígeno CTLA-4/uso terapêutico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/imunologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Feminino , Humanos , Doenças do Sistema Imunitário/induzido quimicamente , Doenças do Sistema Imunitário/patologia , Ipilimumab/administração & dosagem , Melanoma/complicações , Melanoma/imunologia , Melanoma/patologia , Púrpura Trombocitopênica Trombótica/induzido quimicamente , Púrpura Trombocitopênica Trombótica/diagnóstico , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T Citotóxicos/efeitos dos fármacos
15.
J Pediatr Hematol Oncol ; 39(1): 1-5, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27820131

RESUMO

BACKGROUND: Children with leukemia suffer immune dysfunction from their malignancy and chemotherapy. The immune system components most affected, the degree to which immune suppression occurs, and the duration of immunodeficiency are incompletely characterized. This study measures immunologic parameters following completion of therapy. METHODS: This is a prospective, single institution cohort study. Eligible children with acute myelogenous or acute lymphoblastic leukemia diagnosed between 1 and 21 years of age were enrolled at therapy completion. Immune parameters were assessed at the end of therapy and 6 months later: complete blood counts, immunoglobulin levels, quantitative lymphocyte subsets, mitogen-induced lymphocyte proliferation, natural killer cell function, and vaccine titers. RESULTS: Twenty patients were evaluated; 13 (65%) were female, 15 had acute lymphoblastic leukemia (75%). Mean age at diagnosis was 7.9 years. At end of therapy, all patients had some degree of immune dysfunction. At 6 months posttherapy, persistent abnormalities included: leukopenia (25%), neutropenia (15%), lymphopenia (5%), hypogammaglobulinemia (25%), one or more subtherapeutic vaccine titers (100%), abnormal lymphocyte subset levels (20%), decreased (15%), or absent (10%) natural killer cell function and abnormal lymphocyte proliferative responses (25%). CONCLUSIONS: All patients had multiple abnormalities at end of therapy, and all patients had some degree of persistent immune dysfunction at 6 months after completion of therapy. Clinical implications of these laboratory abnormalities are currently unknown; longer term evaluations are ongoing. We demonstrate that survivors of childhood cancer have lasting quantitative and functional immunologic defects and may remain at risk for infectious complications after completion of therapy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Doenças do Sistema Imunitário/etiologia , Leucemia Mieloide Aguda/imunologia , Subpopulações de Linfócitos/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Sobreviventes , Imunidade Adaptativa , Adolescente , Agamaglobulinemia/induzido quimicamente , Agamaglobulinemia/etiologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Criança , Pré-Escolar , Testes Imunológicos de Citotoxicidade , Feminino , Humanos , Doenças do Sistema Imunitário/induzido quimicamente , Lactente , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/patologia , Leucemia Mieloide Aguda/tratamento farmacológico , Leucopenia/induzido quimicamente , Leucopenia/etiologia , Ativação Linfocitária , Contagem de Linfócitos , Subpopulações de Linfócitos/patologia , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Estudos Prospectivos , Vacinação
18.
Crit Rev Toxicol ; 46(4): 279-331, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26761418

RESUMO

Whether perfluorooctanoate (PFOA) and perfluorooctanesulfonate (PFOS), two widely used and biopersistent synthetic chemicals, are immunotoxic in humans is unclear. Accordingly, this article systematically and critically reviews the epidemiologic evidence on the association between exposure to PFOA and PFOS and various immune-related health conditions in humans. Twenty-four epidemiologic studies have reported associations of PFOA and/or PFOS with immune-related health conditions, including ten studies of immune biomarker levels or gene expression patterns, ten studies of atopic or allergic disorders, five studies of infectious diseases, four studies of vaccine responses, and five studies of chronic inflammatory or autoimmune conditions (with several studies evaluating multiple endpoints). Asthma, the most commonly studied condition, was evaluated in seven studies. With few, often methodologically limited studies of any particular health condition, generally inconsistent results, and an inability to exclude confounding, bias, or chance as an explanation for observed associations, the available epidemiologic evidence is insufficient to reach a conclusion about a causal relationship between exposure to PFOA and PFOS and any immune-related health condition in humans. When interpreting such studies, an immunodeficiency should not be presumed to exist when there is no evidence of a clinical abnormality. Large, prospective studies with repeated exposure assessment in independent populations are needed to confirm some suggestive associations with certain endpoints.


Assuntos
Ácidos Alcanossulfônicos/envenenamento , Caprilatos/envenenamento , Exposição Ambiental/estatística & dados numéricos , Fluorcarbonetos/envenenamento , Doenças do Sistema Imunitário/epidemiologia , Ácidos Alcanossulfônicos/toxicidade , Animais , Asma/induzido quimicamente , Asma/epidemiologia , Caprilatos/toxicidade , Fluorcarbonetos/toxicidade , Humanos , Sistema Imunitário/efeitos dos fármacos , Doenças do Sistema Imunitário/induzido quimicamente , Imunotoxinas/envenenamento , Imunotoxinas/toxicidade
19.
Afr J Tradit Complement Altern Med ; 13(5): 153-159, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-28487906

RESUMO

BACKGROUND: The use of cyclophosphamide in cancer therapy is usually associated with challenging immunosuppression which exposes patients to increased risk of anemia and necessitating preventive measures during therapy. This study was carried out to investigate the efficacy of the hydro-ethanolic extract of the root of Z. zanthoxyloides in preventing and/or improving cyclophosphamide induced myelosuppression and oxidative stress in rats. MATERIALS AND METHODS: Animals were divided into 6 groups of 6 rats each and were pretreated oral doses of 75, 150 and 225 mg/kg of the extract for 7 days and then co-administered with 2.5 mg/kg cyclophosphamide for 28 days. RESULTS: The LD50 of the extract was found to be 1682.3 mg/kg. Phytochemical analysis of the plant extract showed the presence of tannins, saponins, alkaloids and flavonoids, glycosides, terpenoids and phenols. In the anti-oxidant enzyme assay, CAT was significantly (p < 0.05) increased for animals treated with 150 mg/kg+CP compared to 75 mg/kg+CP and 225 mg/kg+CP. GPx was significantly (p < 0.01) increased in rats treated with 75 mg/kg+CP compared to 150 mg/kg+CP and control. SOD was significantly (p < 0.01) increased in rats treated with 75 mg/kg+CP compared to the control. WBC was significantly (p < 0.05) reduced for 225 mg/kg, 225 mg/kg+CP (p < 0.001), 150 mg/kg+CP (p < 0.001), 75 mg/kg+CP (p < 0.001) and CP administered rats (p < 0.001) respectively compared to the control. LDL and CHOL were significantly reduced (p < 0.05) for rats treated with 75 mg/kg+CP, 225 mg/kg+CP and 225 mg/kg. CONCLUSION: Findings from this study demonstrates that the hydro-ethanolic root extract of Z. zanthoxyloides could be beneficial in hyperlipidemia and in cases of malignancies with abnormal cholesterol metabolism an effect which may be mediated via combating oxidative stress. List of Abbreviations: EDTA: Ethylenediamine-tetra acetate; MDA: Malondialdehyde; PCV: Packed cell volume; RBC: Red blood cell; HGB: Hemoglobin; WBC: White blood cell; ALT: Alanine transaminase; AST: Aspartate transaminase; CHOL: Cholesterol; LDL: Low density lipoprotein; HDL: High density lipoprotein; GSH: Reduced glutathione; SOD: Superoxide dismutase; CAT: Catalase; CP: Cyclophosphamide.


Assuntos
Antioxidantes/farmacologia , Etanol/farmacologia , Doenças do Sistema Imunitário/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Zanthoxylum/química , Animais , Antineoplásicos Alquilantes/efeitos adversos , Ciclofosfamida/efeitos adversos , Modelos Animais de Doenças , Feminino , Doenças do Sistema Imunitário/sangue , Doenças do Sistema Imunitário/induzido quimicamente , Imunossupressão/efeitos adversos , Masculino , Fitoterapia/métodos , Extratos Vegetais/química , Raízes de Plantas/química , Ratos , Superóxido Dismutase/metabolismo
20.
Urologe A ; 54(10): 1376-84, 2015 Oct.
Artigo em Alemão | MEDLINE | ID: mdl-26459580

RESUMO

BACKGROUND: Current immunosuppressive protocols effectively prevent acute rejection of renal allografts. Extensive drug toxicity and the deleterious effects of long-term immunosuppression are associated with significant morbidity and mortality. OBJECTIVES: The purpose of this article is to provide an overview over modern immunosuppressants and their unwanted side effects and to discuss strategies for improved long-term transplant survival. METHODS: Review of the current topic-related literature and discussion of our own experience. RESULTS: The use of antibody induction together with an initial combination therapy of calcineurin inhibitors, mycophenolate and steroids is recommended and results in excellent early outcomes. Detrimental effects include an increased incidence of infections, malignomas, and cardiovascular diseases. Long-term transplant survival is impaired by extensive drug toxicity and the frequent development of donor specific antibodies. Reduction of overall cumulative exposure to immunosuppressants or the reduction of specific toxic drugs such as calcineurin inhibitors and steroids may improve long-term results. Alternative immunosuppressants like mTOR inhibitors and belatacept appear to be effective and safe but their long-term effects on patient and allograft survival needs to be established in clinical trials. CONCLUSIONS: Current immunosuppressants provide effective protection from renal allograft rejection. However, their use is complicated by serious side effects. In the future, development of novel immunosuppressants and optimization of minimization strategies may help to improve long-term success after kidney transplantation.


Assuntos
Rejeição de Enxerto/etiologia , Rejeição de Enxerto/prevenção & controle , Doenças do Sistema Imunitário/induzido quimicamente , Imunossupressores/administração & dosagem , Imunossupressores/efeitos adversos , Transplante de Rim/efeitos adversos , Doenças Cardiovasculares/induzido quimicamente , Doenças Cardiovasculares/prevenção & controle , Medicina Baseada em Evidências , Humanos , Doenças do Sistema Imunitário/prevenção & controle , Neoplasias/induzido quimicamente , Neoplasias/prevenção & controle , Fatores de Risco
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