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2.
Leuk Lymphoma ; : 1-12, 2020 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-32264729

RESUMO

Pharmacokinetic (PK) conflicts can arise between supportive care medications (SCM) and chemotherapy in children with hematologic malignancy (HM). In this retrospective study, medical records for children (28 days-18 years) diagnosed with HM and receiving an SCM antimicrobial were collected from a hospital network between 1 May 2000 and 31 December 2014. PK drug-gene associations were obtained from a curated pharmacogenomics database. Among 730 patients (median age of 7.5 (IQR 3.7-13.9) years), primarily diagnosed with lymphoid leukemia (52%), lymphoma (28%), or acute myeloid leukemia (16%), chemotherapy was administered in 2846 hospitalizations. SCM accounted for 90.5% (n = 448) of distinct drugs with 93% (n = 679) of children, receiving ≥5 different SCM/hospitalization. Same-day SCM/chemotherapeutic PK gene overlap occurred in 48.3% of hospitalizations and was associated with age (p = 0.026), number of SCM, HM subtype, surgery, and hematopoietic stem cell transplant (p < 0.0001). A high and variable SCM burden among children with HM receiving chemotherapy poses a risk for unanticipated PK conflicts.

3.
Front Pharmacol ; 10: 1191, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31680968

RESUMO

Neonatal sepsis causes significant mortality and morbidity worldwide. Diagnosis is usually confirmed via blood culture results. Blood culture sepsis confirmation can take days and suffer from contamination and false negatives. Empiric therapy with antibiotics is common. This study aims to retrospectively describe and compare treatments of blood culture-confirmed and unconfirmed, but suspected, sepsis within the University of Utah Hospital system. Electronic health records were obtained from 1,248 neonates from January 1, 2006, to December 31, 2017. Sepsis was categorized into early-onset (≤3 days of birth, EOS) and late-onset (>3 and ≤28 days of birth, LOS) and categorized as culture-confirmed sepsis if a pathogen was cultured from the blood and unconfirmed if all blood cultures were negative with no potentially contaminated blood cultures. Of 1,010 neonates in the EOS cohort, 23 (2.3%) were culture-confirmed, most with Escherichia coli (42%). Treatment for unconfirmed EOS lasted an average of 6.1 days with primarily gentamicin and ampicillin while confirmed patients were treated for an average of 12.3 days with increased administration of cefotaxime. Of 311 neonates in the LOS cohort, 62 (20%) were culture-confirmed, most culturing coagulase negative staphylococci (46%). Treatment courses for unconfirmed LOS lasted an average of 7.8 days while confirmed patients were treated for an average of 11.4 days, these patients were primarily treated with vancomycin and gentamicin. The use of cefotaxime for unconfirmed EOS and LOS increased throughout the study period. Cefotaxime administration was associated with an increase in neonatal mortality, even when potential confounding factors were added to the logistic regression model (adjusted odds ratio 2.8, 95%CI [1.21, 6.88], p = 0.02). These results may not be generalized to all hospitals and the use of cefotaxime may be a surrogate for other factors. Given the low rate of blood culture positive diagnosis and the high exposure rate of empiric antibiotics, this patient population might benefit from improved diagnostics with reevaluation of antibiotic use guidelines.

4.
Int Immunopharmacol ; 76: 105868, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31487613

RESUMO

The use of immunoglobulins is gradually increasing. Intravenous immunoglobulins (IVIG) are used as replacement therapy for primary and secondary immune deficiencies, and as an anti-inflammatory and immunomodulatory medication for the treatment of neurologic, dermatologic, and rheumatologic diseases. The objective of this study was to analyze trends in the IVIG use in pediatric patients hospitalized to 47 US-based children's hospitals from 2007 to 2014. IVIG was used for the treatment of >2300 primary diagnoses in 53,648 unique patients. The number of IVIG admissions increased by 30.2% during the study period, while the mean rate of IVIG admissions/100,000 admissions increased only 5.8%. Most patients receiving IVIG were children and adolescents. IVIG was frequently used off-label or for the treatment of FDA-approved indications in children under two years of age and BMT patients <20 years of age. Primary immune deficiencies represented only 1.2% of all IVIG admissions. Pediatric patients with mucocutaneous lymph node syndrome (Kawasaki disease, KD) and idiopathic thrombocytopenic purpura (ITP) were two primary consumers of the IVIG. Another top-ranked indications were acute infectious polyneuritis (Guillain-Barré syndrome, GBS) and prophylaxis of infections in patients receiving antineoplastic chemotherapy. IVIG usage is a dynamic process guided by emerging evidence and FDA approval for new indications. IVIG was mostly prescribed for treatment of diseases with pathologic immune responses to foreign of self-antigens. These indications usually, require higher amounts of IVIG per admission. More studies are needed to understand whether IVIG treatments of off-label indications are effective and cost-efficient.


Assuntos
Uso de Medicamentos/tendências , Imunoglobulinas Intravenosas/uso terapêutico , Fatores Imunológicos/uso terapêutico , Adolescente , Criança , Pré-Escolar , Feminino , Síndrome de Guillain-Barré/tratamento farmacológico , Hospitais Pediátricos , Humanos , Síndrome do Coração Esquerdo Hipoplásico/tratamento farmacológico , Lactente , Recém-Nascido , Controle de Infecções , Masculino , Síndrome de Linfonodos Mucocutâneos/tratamento farmacológico , Uso Off-Label/estatística & dados numéricos , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Estudos Retrospectivos , Estados Unidos
6.
Clin Pharmacokinet ; 56(2): 107-125, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27384528

RESUMO

Systemic lupus erythematosus (SLE) is a multifactorial autoimmune disease with potentially severe clinical manifestation that mainly affects women of child-bearing age. Patients who do not respond to standard-of-care therapies, such as corticosteroids and immunosuppressants, require biologic therapeutics that specifically target a single or multiple SLE pathogenesis pathways. This review summarizes the clinical pharmacokinetic and pharmacodynamic characteristics of biologic agents that are approved, used off-label, or in the active pipeline of drug development for SLE patients. Depending on the type of target, the interacting biologics may exhibit linear (non-specific) or non-linear (target-mediated) disposition profiles, with terminal half-lives varying from approximately 1 week to 1 month. Biologics given by subcutaneous administration, which offers dosing flexibility over intravenous administration, demonstrated a relatively slow absorption with a time to maximum concentration of approximately 1 day to 2 weeks and a variable bioavailability of 30-82 %. The population pharmacokinetics of monoclonal antibodies were best described by a two-compartment model with central clearance and steady-state volume of distribution ranging from 0.176 to 0.215 L/day and 3.60-5.29 L, respectively. The between-subject variability in pharmacokinetic parameters were moderate (20-79 %) and could be partially explained by body size. The development of linked pharmacokinetic-pharmacodynamic models incorporating SLE disease biomarkers are an attractive strategy for use in dosing regimen simulation and optimization. The relationship between efficacy/adverse events and biologic concentration should be evaluated to improve clinical trial outcomes, especially for biologics in the advanced phase of drug development. New strategies, such as model-based precision dosing dashboards, could be utilized to incorporate information collected from therapeutic drug monitoring into pharmacokinetic/pharmacodynamic models to enable individualized dosing in real time.


Assuntos
Produtos Biológicos/farmacocinética , Produtos Biológicos/uso terapêutico , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Lúpus Eritematoso Sistêmico/metabolismo , Anticorpos Monoclonais/farmacocinética , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Linfócitos B/efeitos dos fármacos , Linfócitos B/metabolismo , Produtos Biológicos/farmacologia , Feminino , Humanos , Masculino , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismo , Resultado do Tratamento
7.
Expert Rev Anti Infect Ther ; 14(8): 731-46, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27355512

RESUMO

INTRODUCTION: Voriconazole is a broad-spectrum antifungal agent commonly used to treat invasive fungal infections (IFI), including aspergillosis, candidiasis, Scedosporium infection, and Fusarium infection. IFI often occur in immunocompromised patients, leading to increased morbidity and mortality. AREAS COVERED: The objective of this review is to summarize the pharmacodynamic properties of voriconazole and to provide considerations for potential optimal dosing strategies. Studies have demonstrated superior clinical response when an AUC/MIC >25 or Cmin/MIC >1 is attained in adult patients, correlating to a trough concentration range as narrow as 2-4.5 mg/L; however, these targets are poorly established in the pediatric population. Topics in this discussion include voriconazole use in multiple age groups, predisposing patient factors for IFI, and considerations for clinicians managing IFI. Expert commentary: The relationship between voriconazole dosing and exposure is not well defined due to the large inter- and intra-subject variability. Development of comprehensive decision support tools for individualizing dosing, particularly in children who require higher dosing, will help to increase the probability of achieving therapeutic efficacy and decrease sub-therapeutic dosing and adverse events.


Assuntos
Antifúngicos/uso terapêutico , Infecções Fúngicas Invasivas/tratamento farmacológico , Voriconazol/uso terapêutico , Antifúngicos/administração & dosagem , Antifúngicos/farmacocinética , Antifúngicos/farmacologia , Área Sob a Curva , Relação Dose-Resposta a Droga , Predisposição Genética para Doença , Humanos , Infecções Fúngicas Invasivas/genética , Infecções Fúngicas Invasivas/imunologia , Infecções Fúngicas Invasivas/microbiologia , Testes de Sensibilidade Microbiana , Modelos Biológicos , Voriconazol/administração & dosagem , Voriconazol/farmacocinética , Voriconazol/farmacologia
8.
Expert Rev Clin Pharmacol ; 9(8): 1117-27, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27171366

RESUMO

INTRODUCTION: Herbal medicines (HMs) have been well known to people of the European Union (EU) and Russia for centuries. Currently, Western HMs can be classified into two categories, plant-derived conventional medicines and dietary supplements. Interest to HMs has grown rapidly in all countries during the past two decades. AREAS COVERED: The main goal of this review article is to present the history of HMs in the EU and Russia, forms of modern HMs, including Oriental Medicines that are popular among consumers of both countries. Additional discussion points comprise safety and adulteration issues associated with HMs, including regulatory changes and new legislative measures undertaken by the authorities. Materials available from legislative and governmental websites, PubMed and news media were used. Expert commentary: Due to cultural diversities in the EU and Russia, traditional HMs of other regions, particularly Chinese Traditional and Ayurvedic medicines, are also popular. Recently, dietary supplements containing multiple herbal and other natural products have flooded the EU and Russian markets. Pharmacovigilance in these markets is challenging in terms of establishing quality and safety of ingredients, determining efficacy, and defining risks of herb-herb and herb-drug interactions. Both the EU and Russia have introduced new legislation aimed to overcome these deficiencies.


Assuntos
Fitoterapia/métodos , Preparações de Plantas/uso terapêutico , Plantas Medicinais/química , Animais , Suplementos Nutricionais/efeitos adversos , Suplementos Nutricionais/normas , União Europeia , Interações Ervas-Drogas , Humanos , Legislação de Medicamentos , Medicina Tradicional/métodos , Preparações de Plantas/efeitos adversos , Preparações de Plantas/normas , Federação Russa
9.
Expert Rev Clin Pharmacol ; 9(9): 1225-33, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27232545

RESUMO

INTRODUCTION: Medicinal plants, and formulations prepared from them, have been used in China and Japan for thousands of years. Nowadays, ancient formulations of Traditional Chinese and Kampo (Japanese) Medicines coexist with Western herbal medicines (HMs) and complement each other. HMs are used for the treatment of mild and chronic diseases, as an adjunct therapy, to improve wellbeing and delay aging, or as healthy (functional) foods. AREAS COVERED: This article, a third part in a series of reviews, is focusing on history, use and regulation of the traditional and modern HMs in Japan and China. Materials available from legislative and governmental websites, PubMed and news media were used. Expert commentary: HMs are heavily regulated in both countries, often in a similar manner as conventional pharmaceutical drugs. The majority of herbal formulations are sold as over-the-counter medications supplied with leaflets describing indications and appropriate dosages for patients of different ages. Medical practitioners prescribe herbal formulations that are tailored to the needs of particular patients. Both countries had problems with adverse drug reactions and toxicity of single herbs and herbal formulations that have been investigated by authorities, and some drugs have been removed from the market.


Assuntos
Fitoterapia/métodos , Preparações de Plantas/uso terapêutico , Plantas Medicinais/química , China , Medicamentos de Ervas Chinesas/administração & dosagem , Medicamentos de Ervas Chinesas/efeitos adversos , Medicamentos de Ervas Chinesas/uso terapêutico , Humanos , Japão , Medicina Tradicional Chinesa/efeitos adversos , Medicina Tradicional Chinesa/métodos , Medicina Kampo/efeitos adversos , Medicina Kampo/métodos , Fitoterapia/efeitos adversos , Preparações de Plantas/administração & dosagem , Preparações de Plantas/efeitos adversos
10.
Expert Rev Clin Pharmacol ; 9(7): 905-15, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-27070431

RESUMO

As in many developed countries, herbal medicines (HMs) are widely used in Australia and New Zealand (NZ). The popularity of HM continues to rise. Western, Asian and indigenous HMs are used, reflecting the cultural diversity of people in this region. HMs in Australia are regulated on a risk-based system with many HMs identified as being low risk. The legislation was reviewed in 2015 and proposals for change are under consideration. In NZ, it is recognised that current regulations for HMs and other natural health products (NHPs) do not adequately protect public health. NZ is entering a phase of regulatory change for this sector, and proposals for a 'light-touch' regulatory framework for NHPs are planned to be introduced into legislation during 2016.


Assuntos
Fitoterapia/métodos , Preparações de Plantas/uso terapêutico , Plantas Medicinais/química , Austrália , Humanos , Legislação de Medicamentos , Medicina Tradicional/efeitos adversos , Medicina Tradicional/métodos , Nova Zelândia , Fitoterapia/efeitos adversos , Preparações de Plantas/efeitos adversos
11.
PLoS One ; 10(3): e0121128, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25803612

RESUMO

The nicotinic acetylcholine receptor alpha7 (α7) is expressed by neuronal and non-neuronal cells throughout the body. We examined the mechanisms of the lung inflammatory response to intranasal (i.n.) lipopolysaccharide (LPS) regulated by α7. This was done in mice using homologous recombination to introduce a point mutation in the α7 receptor that replaces the glutamate residue 260 that lines the pore with alanine (α7E260A), which has been implicated in controlling the exceptional calcium ion conductance of this receptor. The α7E260A mice exhibit normal inflammatory cell recruitment to the blood in response to i.n. LPS administration. This differs from the α7knock-out (α7KO) in which upstream signaling to initiate the recruitment to the blood following i.n. LPS is significantly impaired. While hematopoietic cells are recruited to the bloodstream in the α7E260A mouse, they fail to be recruited efficiently into both the interstitium and alveolar spaces of the lung. Bone marrow reconstitution experiments demonstrate that the responsiveness of both CD45+ and CD45- cells of the α7E260A mouse are impaired. The expression of several pro-inflammatory cytokine and chemokine RNAs including TNFα, IL-1α, Ccl2 and Cxcl10 are decreased in the α7E260A mouse. However, there is a substantial increase in IL-13 expression by CD45- lung interstitial cells in the α7E260A mouse. Our results support the conclusion that α7 functional pleiotropy contributes to modulating the tissue response to an inflammatory insult through impacting upon a variety of mechanisms reflecting the individual cell composition of the lung.


Assuntos
Lipopolissacarídeos/farmacologia , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Receptor Nicotínico de Acetilcolina alfa7/metabolismo , Animais , Líquido da Lavagem Broncoalveolar , Células Cultivadas , Citocinas/imunologia , Citocinas/metabolismo , Expressão Gênica , Antígenos Comuns de Leucócito/imunologia , Antígenos Comuns de Leucócito/metabolismo , Pulmão/imunologia , Camundongos , Camundongos Knockout , Pneumonia/genética , Pneumonia/imunologia , Pneumonia/metabolismo , Mutação Puntual , Receptor Nicotínico de Acetilcolina alfa7/genética
12.
PLoS One ; 8(3): e57481, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23469197

RESUMO

How inflammatory responses are mechanistically modulated by nicotinic acetylcholine receptors (nAChR), especially by receptors composed of alpha7 (α7) subunits, is poorly defined. This includes a precise definition of cells that express α7 and how these impact on innate inflammatory responses. To this aim we used mice generated through homologous recombination that express an Ires-Cre-recombinase bi-cistronic extension of the endogenous α7 gene that when crossed with a reporter mouse expressing Rosa26-LoxP (yellow fluorescent protein (YFP)) marks in the offspring those cells of the α7 cell lineage (α7(lin+)). In the adult, on average 20-25 percent of the total CD45(+) myeloid and lymphoid cells of the bone marrow (BM), blood, spleen, lymph nodes, and Peyers patches are α7(lin+), although variability between litter mates in this value is observed. This hematopoietic α7(lin+) subpopulation is also found in Sca1(+)cKit(+) BM cells suggesting the α7 lineage is established early during hematopoiesis and the ratio remains stable in the individual thereafter as measured for at least 18 months. Both α7(lin+) and α7(lin-) BM cells can reconstitute the immune system of naïve irradiated recipient mice and the α7(lin+):α7(lin-) beginning ratio is stable in the recipient after reconstitution. Functionally the α7(lin+):α7(lin-) lineages differ in response to LPS challenge. Most notable is the response to LPS as demonstrated by an enhanced production of IL-12/23(p40) by the α7(lin+) cells. These studies demonstrate that α7(lin+) identifies a novel subpopulation of bone marrow cells that include hematopoietic progenitor cells that can re-populate an animal's inflammatory/immune system. These findings suggest that α7 exhibits a pleiotropic role in the hematopoietic system that includes both the direct modulation of pro-inflammatory cell composition and later in the adult the role of modulating pro-inflammatory responses that would impact upon an individual's lifelong response to inflammation and infection.


Assuntos
Regulação da Expressão Gênica no Desenvolvimento/imunologia , Hematopoese/imunologia , Células-Tronco Hematopoéticas/imunologia , Receptores Nicotínicos/imunologia , Transferência Adotiva , Animais , Biomarcadores/metabolismo , Linhagem da Célula/efeitos dos fármacos , Linhagem da Célula/imunologia , Cruzamentos Genéticos , Feminino , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Hematopoese/efeitos dos fármacos , Hematopoese/genética , Células-Tronco Hematopoéticas/citologia , Inflamação/genética , Inflamação/imunologia , Interleucina-12/biossíntese , Interleucina-12/imunologia , Interleucina-23/biossíntese , Interleucina-23/imunologia , Antígenos Comuns de Leucócito/genética , Antígenos Comuns de Leucócito/imunologia , Lipopolissacarídeos/farmacologia , Linfócitos/citologia , Linfócitos/imunologia , Masculino , Camundongos , Camundongos Transgênicos , Células Mieloides/citologia , Células Mieloides/imunologia , Receptores Nicotínicos/genética , Irradiação Corporal Total , Receptor Nicotínico de Acetilcolina alfa7
13.
J Steroid Biochem Mol Biol ; 126(3-5): 87-94, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21570467

RESUMO

Androst-5-ene-3ß,7ß,17ß-triol (ßAET) is an anti-inflammatory metabolite of DHEA that is found naturally in humans, but in rodents only after exogenous DHEA administration. Unlike DHEA, C-7-oxidized DHEA metabolites cannot be metabolized into potent androgens or estrogens, and are not peroxisome proliferators in rodents. The objective of our current studies was to characterize the pharmacology of ßAET to enable clinical trials in humans. The pharmacology of ßAET was characterized by pharmacokinetics, drug metabolism, nuclear hormone receptor interactions, androgenicity, estrogenicity, and systemic toxicity studies. ßAET's acute anti-inflammatory activity and immune modulating characteristics were measured in vitro in RAW264.7 cells and in vivo in murine models with parenteral administration. ßAET was rapidly metabolized and cleared from circulation in mice and monkeys. ßAET was weakly androgenic and estrogenic in immature rodents, but not bound by androgen, estrogen, progesterone, or glucocorticoid nuclear hormone receptors. ßAET did not induce peroxisome proliferation, nor was it systemically toxic or trophic for sex hormone responsive tissues in mature rats and monkeys. ßAET significantly attenuated acute inflammation both in vitro and in vivo, augmented immune responses in adult mice, and reversed immune senescence in aged mice. ßAET may contribute to the anti-inflammatory activity in rodents attributed to DHEA. Unlike DHEA, ßAET's anti-inflammatory activity cannot be ascribed to activation of PPARs, androgen, or estrogen nuclear hormone receptors. Exogenous ßAET is unlikely to produce untoward toxicity or hormonal perturbations in humans.


Assuntos
Androstenóis/farmacologia , Desidroepiandrosterona/metabolismo , Sistema Imunitário/efeitos dos fármacos , Androstenos/metabolismo , Androstenóis/metabolismo , Animais , Células CHO , Células Cultivadas , Cricetinae , Cricetulus , Relação Dose-Resposta a Droga , Feminino , Humanos , Fatores Imunológicos/metabolismo , Fatores Imunológicos/farmacologia , Macaca fascicularis , Masculino , Metaboloma/fisiologia , Camundongos , Camundongos Endogâmicos BALB C , Ratos , Ratos Wistar
14.
Pediatr Res ; 70(2): 123-9, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21505375

RESUMO

Intrauterine growth restricted (IUGR) infants have increased susceptibility to infection associated with higher risk of illness and death. Dual specificity phosphatase 1 (DUSP1), which is transcribed in the thymus, increases in quantity as T cells mature and differentiate into CD4+ cells. Little is known about how IUGR affects DUSP1 levels and T-cell subpopulations over time. We hypothesized that IUGR would decrease cell count, CD4+ and CD8+ subpopulations of T lymphocytes, and DUSP1 levels in IUGR rat thymus and spleen. Bilateral uterine artery ligation produced IUGR rats. Thymus and spleen were harvested at P0 and P21. Flow cytometry was used to compare CD4+ and CD8+ lymphocyte populations. Real-time RT-PCR and Western blotting were used to determine DUSP1 quantity. IUGR significantly decreased total cell count in P0 and P21 IUGR male and female thymus. IUGR significantly increased CD4+ cells in IUGR P0 males and females, significantly decreased CD4+ cells in P21 female thymus, and significantly altered DUSP1 levels in the IUGR female thymus at P0 and P21, although it is not yet known whether the change in DUSP1 levels is due to a change in the level per cell or to a change in cellular composition of the thymus.


Assuntos
Diferenciação Celular/imunologia , Fosfatase 1 de Especificidade Dupla/metabolismo , Retardo do Crescimento Fetal/enzimologia , Retardo do Crescimento Fetal/imunologia , Linfócitos T/imunologia , Timo/metabolismo , Análise de Variância , Animais , Animais Recém-Nascidos , Western Blotting , Relação CD4-CD8 , Contagem de Células , Primers do DNA/genética , Feminino , Citometria de Fluxo , Masculino , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase Via Transcriptase Reversa
15.
J Immunol ; 186(2): 697-707, 2011 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-21148798

RESUMO

The reduced efficiency of the mammalian immune system with aging increases host susceptibility to infectious and autoimmune diseases. However, the mechanisms responsible for these pathologic changes are not well understood. In this study, we demonstrate that the bone marrow, blood, and secondary lymphoid organs of healthy aged mice possess increased numbers of immature myeloid cells that are phenotypically similar to myeloid-derived suppressor cells found in lymphoid organs of mice with progressive tumors and other pathologic conditions associated with chronic inflammation. These cells are characterized by the presence of Gr1 and CD11b markers on their surfaces. Gr1(+)CD11b(+) cells isolated from aged mice possess an ability to suppress T cell proliferation/activation and produce heightened levels of proinflammatory cytokines, both constitutively and upon activation, including IL-12, which promotes an excessive production of IFN-γ. IFN-γ priming is essential for excessive proinflammatory cytokine production and the suppressive activities by Gr1(+)CD11b(+) cells from aged mice. These cells suppress T cell proliferation through an NO-dependent mechanism, as depletion of splenic Gr1(+) cells reduces NO levels and restores T cell proliferation. Insights into mechanisms responsible for the proinflammatory and immune suppressive activities of Gr1(+)CD11b(+) cells from aged mice have uncovered a defective PI3K-Akt signaling pathway, leading to a reduced Akt-dependent inactivation of GSK3ß. Our data demonstrate that abnormal activities of the Gr1(+)CD11b(+) myeloid cell population from aged mice could play a significant role in the mechanisms responsible for immune senescence.


Assuntos
Envelhecimento/imunologia , Diferenciação Celular/imunologia , Células Mieloides/citologia , Células Mieloides/imunologia , Envelhecimento/genética , Animais , Antígeno CD11b/biossíntese , Antígeno CD11b/sangue , Antígeno CD11b/genética , Diferenciação Celular/genética , Proliferação de Células , Citocinas/biossíntese , Citocinas/fisiologia , Feminino , Inibidores do Crescimento/biossíntese , Inibidores do Crescimento/genética , Inibidores do Crescimento/fisiologia , Imunofenotipagem , Imunossupressão , Mediadores da Inflamação/metabolismo , Mediadores da Inflamação/fisiologia , Ativação Linfocitária/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Transgênicos , Células Mieloides/metabolismo , Receptores de Quimiocinas/biossíntese , Receptores de Quimiocinas/sangue , Receptores de Quimiocinas/genética , Transdução de Sinais/genética , Transdução de Sinais/imunologia
16.
Infect Immun ; 76(11): 5191-9, 2008 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-18765736

RESUMO

Immunity conferred by conventional vaccines is restricted to a narrow range of closely related strains, highlighting the unmet medical need for the development of vaccines that elicit protection against multiple pathogenic serotypes. Here we show that a Salmonella bivalent vaccine comprised of strains that lack and overproduce DNA adenine methylase (Dam) conferred cross-protective immunity to salmonella clinical isolates of human and animal origin. Protective immunity directly correlated with increased levels of cross-reactive opsonizing antibodies and memory T cells and a diminished expansion of myeloid-derived suppressor cells (MDSCs) that are responsible for the immune suppression linked to several conditions of host stress, including chronic microbial infections, traumatic insults, and many forms of cancer. Further, aged mice contained increased numbers of MDSCs and were more susceptible to Salmonella infection than young mice, suggesting a role for these cells in the immune declines associated with the natural aging process. These data suggest that interventions capable of reducing MDSC presence and activities may allow corresponding increases in B- and T-cell stimulation and benefit the ability of immunologically diverse populations to be effectively vaccinated as well as reducing the risk of susceptible individuals to infectious disease.


Assuntos
Anticorpos Antibacterianos/imunologia , Células Mieloides/imunologia , Salmonelose Animal/prevenção & controle , Vacinas contra Salmonella/imunologia , Salmonella/imunologia , Envelhecimento/imunologia , Animais , Reações Cruzadas , Células HeLa , Humanos , Memória Imunológica , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Linfócitos T/imunologia
17.
Appl Environ Microbiol ; 74(6): 1757-66, 2008 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-18245251

RESUMO

The global trend toward intensive livestock production has led to significant public health risks and industry-associated losses due to an increased incidence of disease and contamination of livestock-derived food products. A potential factor contributing to these health concerns is the prospect that selective pressure within a particular host may give rise to bacterial strain variants that exhibit enhanced fitness in the present host relative to that in the parental host from which the strain was derived. Here, we assessed 184 Salmonella enterica human and animal clinical isolates for their virulence capacities in mice and for the presence of the Salmonella virulence plasmid encoding the SpvB actin cytotoxin required for systemic survival and Pef fimbriae, implicated in adherence to the murine intestinal epithelium. All (21 of 21) serovar Typhimurium clinical isolates derived from animals were virulent in mice, whereas many (16 of 41) serovar Typhimurium isolates derived from human salmonellosis patients lacked this capacity. Additionally, many (10 of 29) serovar Typhimurium isolates derived from gastroenteritis patients did not possess the Salmonella virulence plasmid, in contrast to all animal and human bacteremia isolates tested. Lastly, among serovar Typhimurium isolates that harbored the Salmonella virulence plasmid, 6 of 31 derived from human salmonellosis patients were avirulent in mice, which is in contrast to the virulent phenotype exhibited by all the animal isolates examined. These studies suggest that Salmonella isolates derived from human salmonellosis patients are distinct from those of animal origin. The characterization of these bacterial strain variants may provide insight into their relative pathogenicities as well as into the development of treatment and prophylactic strategies for salmonellosis.


Assuntos
Salmonella enterica/genética , Salmonella enterica/patogenicidade , ADP Ribose Transferases/genética , Animais , Gastroenterite/microbiologia , Humanos , Mucosa Intestinal/microbiologia , Camundongos , Reação em Cadeia da Polimerase , Infecções por Salmonella/microbiologia , Salmonella enterica/classificação , Sorotipagem , Virulência/genética , Fatores de Virulência/genética
18.
Vaccine ; 26(5): 601-13, 2008 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-18178294

RESUMO

Cathelicidin production by human myeloid cells stimulated through toll-like receptor (TLR) 2/1, the migration of human CD8+ T cells to inflamed skin sites, and the ability of murine dendritic cells (DCs) to migrate from skin sites of vaccination to mucosal lymphoid organs all occur via calcitriol-dependent mechanisms. Herein, we report that murine DCs exposed to TLR3/TLR4 ligands upregulate their expression of 1 alpha-hydroxylase, the enzyme that converts circulating 25(OH)D3 to calcitriol, the active form of vitamin D3. TLR3/TLR4 ligands injected subcutaneously affect DC migration in vivo, allowing their trafficking to both draining and non-draining systemic and mucosal lymphoid organs. Subcutaneously delivered vaccines containing TLR3/TLR4 ligands and antigen stimulate the induction of both systemic and mucosal immune responses. Vaccines containing TLR9 ligands fail to stimulate 1 alpha-hydroxylase protein expression, are incapable of redirecting DC migration into Peyer's patches and do not induce mucosal immune responses. These findings support a hypothesis that active metabolites of vitamin D3 produced locally are able to affect various aspects of innate and acquired immune responses.


Assuntos
Calcitriol/metabolismo , Colecalciferol/metabolismo , Células Dendríticas/fisiologia , Receptor 3 Toll-Like/metabolismo , Receptor 4 Toll-Like/metabolismo , Vacinação , Animais , Proteínas de Bactérias/administração & dosagem , Proteínas de Bactérias/imunologia , Movimento Celular , Células Cultivadas , Hidrolases/metabolismo , Imunidade nas Mucosas , Injeções Subcutâneas , Ligantes , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C3H , Camundongos Transgênicos , Nódulos Linfáticos Agregados/imunologia , Receptores de Antígenos de Linfócitos T/deficiência , Receptores de Antígenos de Linfócitos T/genética , Regulação para Cima
19.
J Bacteriol ; 189(13): 4708-17, 2007 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-17468250

RESUMO

Salmonella enterica serovar Typhimurium that lacks the DNA adenine methylase (Dam) ectopically expresses multiple genes that are preferentially expressed during infection, is attenuated for virulence, and confers heightened immunity in vaccinated hosts. The safety of dam mutant Salmonella vaccines was evaluated by screening within infected mice for isolates that have an increased capacity to cause disease relative to the attenuated parental strain. Since dam mutant strains are sensitive to the DNA base analog 2-aminopurine (2-AP), we screened for 2-AP-resistant (2-AP(r)) isolates in systemic tissues of mice infected with dam mutant Salmonella. Such 2-AP(r) derivatives were isolated following intraperitoneal but not oral administration and were shown to be competent for infectivity via intraperitoneal but not oral infection of naïve mice. These 2-AP(r) derivatives were deficient in methyl-directed mismatch repair and were resistant to nitric oxide, yet they retained the bile-sensitive phenotype of the parental dam mutant strain. Additionally, introduction of a mutH null mutation into dam mutant cells suppressed the inherent defects in intraperitoneal infectivity and nitric oxide resistance, as well as overexpression of SpvB, an actin cytotoxin required for Salmonella systemic survival. These data suggest that restoration of intraperitoneal virulence of dam mutant strains is associated with deficiencies in methyl-directed mismatch repair that correlate with the production of systemically related virulence functions.


Assuntos
Reparo de Erro de Pareamento de DNA , Mutação , Salmonelose Animal/genética , Salmonella/genética , DNA Metiltransferases Sítio Específica (Adenina-Específica)/genética , Animais , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Ácidos e Sais Biliares/farmacologia , Western Blotting , Farmacorresistência Bacteriana/genética , Fígado/microbiologia , Camundongos , Camundongos Endogâmicos BALB C , Boca/microbiologia , Mucosa Bucal/microbiologia , Óxido Nítrico/farmacologia , Cavidade Peritoneal/microbiologia , Reação em Cadeia da Polimerase , Salmonella/patogenicidade , Salmonelose Animal/metabolismo , Salmonelose Animal/microbiologia , DNA Metiltransferases Sítio Específica (Adenina-Específica)/metabolismo , Baço/microbiologia , Transcrição Genética , Virulência/genética
20.
Vaccine ; 25(7): 1236-49, 2007 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-17092617

RESUMO

The mucosal immune system provides the host with a first line of adaptive immune defense against invasion by many species of pathogenic microorganisms and their secreted products. Calcitriol, the active form of Vitamin D3 (VD3), promotes the induction of mucosal immunity in mice when added to subcutaneously administered vaccine formulations. Dendritic cells (DCs) activated at vaccination sites where VD3 is present gain the capacity to bypass sequestration in the draining lymph node and traffic to the Peyer's Patches (PP) of immunized animals. By employing protocols that allow the effective tracking of endogenous or adoptively transferred myeloid DCs in vivo, we found that VD3 influences on the trafficking of fully differentiated immature DCs were temporary, and occur without negative effects to antigen processing or peptide presentation to CD4+ T cells. In contrast, DCs differentiated from hematopoietic precursors in the presence of VD3 (conditioned DCs), were markedly compromised in their antigen presenting properties, while manifesting clear alterations to their trafficking properties in vivo. Similar to the recent finding of VD3-mediated enhancement of innate immune protection, our findings suggest that VD3 could also play an important role in controlling the types of immune effector responses elicited subsequent to either infection or vaccination.


Assuntos
Adjuvantes Imunológicos , Apresentação do Antígeno/efeitos dos fármacos , Apresentação do Antígeno/imunologia , Colecalciferol/farmacologia , Células Dendríticas/imunologia , Células Mieloides/imunologia , Animais , Células da Medula Óssea/imunologia , Linfócitos T CD4-Positivos/imunologia , Quimiotaxia de Leucócito/imunologia , Células Dendríticas/efeitos dos fármacos , Feminino , Imunidade nas Mucosas/imunologia , Imunoterapia Adotiva , Tecido Linfoide/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C3H , Camundongos Transgênicos , Células Mieloides/efeitos dos fármacos , Receptores CCR7 , Receptores de Quimiocinas/biossíntese , Receptores de Quimiocinas/genética , Pele/citologia , Pele/imunologia
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