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Vaccine ; 34(25): 2798-805, 2016 05 27.
Artigo em Inglês | MEDLINE | ID: mdl-27131285


The use of novel vaccine delivery systems allows for the manipulation of the adaptive immune systems through the use of molecular adjuvants that target specific innate pathways. Such strategies have been used extensively for vaccines against cancer and multiple pathogens such as Mycobacterium tuberculosis. In the current study we used heat killed non-pathogenic recombinant Saccharomyces cerevisiae expressing M. tuberculosis antigen Rv1886c (fbpB, mpt59, Ag85B) as a delivery system in conjunction with its ability to stimulate innate immunity to determine its ability to induce immunity. We established that the recombinant yeast induced activated antigen specific T cells are capable of reducing the mycobacterial burden. Inoculation of the recombinant yeast after vaccination with BCG resulted in a systemic alteration of the phenotype of the immune response although this was not reflected in an increase in the reduction of the mycobacterial burden. Taken together the data suggest that heat killed yeast can induce multiple cytokines required for induction of protective immunity and can function as a vehicle for delivery of M. tuberculosis antigens in a vaccine formulation. In addition, while it can enhance the effector memory response induced by BCG, it had little effect on central memory responses.

Aciltransferases/imunologia , Adjuvantes Imunológicos/administração & dosagem , Antígenos de Bactérias/imunologia , Proteínas de Bactérias/imunologia , Saccharomyces cerevisiae/imunologia , Vacinas contra a Tuberculose/imunologia , Tuberculose/prevenção & controle , Animais , Citocinas/imunologia , Feminino , Temperatura Alta , Imunização Secundária , Camundongos Endogâmicos C57BL , Mycobacterium tuberculosis , Proteínas Recombinantes/imunologia , Linfócitos T/imunologia
Immunology ; 142(1): 111-23, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24350616


In order to ensure an ample supply of quality candidate tuberculosis (TB) subunit vaccines for clinical trials, it is imperative to develop new immunostimulatory adjuvants. High Mobility Box Group 1 (HMGB1), a member of the alarmin group of immunostimulatory proteins, is released by antigen-presenting cells under various conditions and has been shown to induce T helper type 1 cytokines. We report that HMGB1 is effective as an adjuvant to enhance the protective efficacy and cellular immune response of TB subunit vaccines and that it is not dependent on the interaction between HMGB1 and receptor for advanced glycation end products, a major receptor for HMGB1. In the mouse model of TB, HMGB1 protein, when formulated with dioctadecylammonium bromide and 6000 MW early secretory antigenic target (ESAT-6), was protective as a subunit vaccine but did not protect as molecular adjuvant in an ESAT-6-based DNA formulation. We then evaluated the immunoprophylactic and protective potential of a fusion protein of HMGB1 and ESAT-6. The HMGB1-ESAT-6 fusion protein induced strong antigen-specific T helper type 1 cytokines at 30 days post-immunization. The fusion protein vaccine enhanced activated and effector memory CD4 and CD8 T-cell responses in the lungs and spleens of mice at 80 days post vaccination. Vaccination with the HMGB1-ESAT-6 fusion protein also resulted in elevated numbers of poly-functional CD4 T cells co-expressing interleukin-2, interferon-γ and tumour necrosis factor-α. The potent cell-mediated immune response generated by the fusion protein correlated with protection against subsequent challenge with Mycobacterium tuberculosis in the mouse TB model.

Adjuvantes Imunológicos/farmacologia , Antígenos de Bactérias/imunologia , Proteínas de Bactérias/imunologia , Proteína HMGB1/farmacologia , Mycobacterium tuberculosis/imunologia , Vacinas contra a Tuberculose/imunologia , Tuberculose Pulmonar/prevenção & controle , Adjuvantes Imunológicos/administração & dosagem , Animais , Antígenos de Bactérias/administração & dosagem , Proteínas de Bactérias/administração & dosagem , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/microbiologia , Linhagem Celular , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Proteína HMGB1/administração & dosagem , Proteína HMGB1/imunologia , Imunidade Celular/efeitos dos fármacos , Memória Imunológica/efeitos dos fármacos , Injeções Subcutâneas , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Recombinantes de Fusão/imunologia , Células Th1/efeitos dos fármacos , Células Th1/imunologia , Células Th1/microbiologia , Fatores de Tempo , Vacinas contra a Tuberculose/administração & dosagem , Tuberculose Pulmonar/imunologia , Tuberculose Pulmonar/microbiologia , Vacinas de Subunidades/imunologia
J Virol ; 85(10): 4898-909, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21389129


Variola, the causative agent of smallpox, and the related monkeypox virus are both select agents that, if purposefully released, would cause public panic and social disruption. For this reason research continues in the areas of animal model and therapeutic development. Orthopoxviruses show a widely varying degree of host specificity, making development of accurate animal models difficult. In this paper, we demonstrate a novel respiratory infection technique that resulted in "classic" orthopox disease in nonhuman primates and takes the field of research one step closer to a better animal model.

Modelos Animais de Doenças , Vírus da Varíola dos Macacos/patogenicidade , Monkeypox/patologia , Monkeypox/virologia , Infecções Respiratórias/patologia , Infecções Respiratórias/virologia , Animais , Macaca fascicularis
J Am Assoc Lab Anim Sci ; 47(5): 52-5, 2008 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-18947172


Indwelling central venous catheters are often used to facilitate frequent phlebotomy while minimizing stress and anesthetic effects on animals. However, nonhuman primates with central venous catheters must wear protective jackets. Jackets routinely are removed for aerosol exposure to agents and respiratory measurements by whole-body plethysmography (WBP) because of the potentially confounding effects of jackets on these procedures. However, removing the jacket may dislodge the catheter, making it unusable. Using each animal as its own control, we tested 12 African green monkeys to determine whether minute volume, tidal volume, respiratory rate, or accumulated volume measurements by WBP differed depending on whether the animal wore a protective jacket or not. We found no statistical differences in any measured respiratory parameter and concluded that the jackets could be left in place on the animal while undergoing plethysmography without compromising the calculations for determining the inhaled dose of aerosolized agent. In addition, this study revealed no obvious contraindications to leaving the jacket in place in other nonhuman primate species, provided that the jacket fits appropriately and that plethysmography is performed correctly.

Pletismografia Total/métodos , Animais , Chlorocebus aethiops , Feminino , Masculino
J Calif Dent Assoc ; 33(12): 951-9, 2005 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-16454238


UNLABELLED: Tooth movement results from alveolar bone resorption/deposition following application of orthodontic forces, and root resorption can be an undesirable complication associated with this process. No treatment for external root resorption is available to date. OBJECTIVE: To determine if COX-2 inhibitors like Celebrex are effective in protecting root resorption associated with orthodontic forces. METHODS: A force of 80 grams was applied to the left maxillary first molars of 7-week-old female Wistar rats using nickel titanium closed coil springs attached to the cervical area of the incisors with 0.010 stainless-steel ligature wires. Twenty animals were divided into three experimental groups: one receiving no treatment, the second receiving 25mg/kg, and the third receiving 50 mg/kg of celecoxib (Celebrex) in their drinking water. Rats were maintained on a soft diet and euthanized two weeks after initial placement of the force. Paraffin-embedded sections of the right (control) and left (experimental) maxillae were stained with H&E and the areas of root resorption were examined by counting the number of lacunaes in the roots. RESULTS: No difference in the distance of tooth movement (0.5 mm/two weeks) was seen in all three groups. The rats that received the low dose of Celebrex showed no statistically significant difference in root resorption than that of the rats that received no dose. The rats that received the high dose of Celebrex showed a lower number of lacunaes (mean = 3.5) than that of the control group (mean 10.2; p=0.02). CONCLUSIONS: Administration of Celebrex during the application of orthodontic forces does not interfere with tooth movement and appears to offer some slight protection against root resorption.

Anti-Inflamatórios não Esteroides/uso terapêutico , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Pirazóis/uso terapêutico , Reabsorção da Raiz/prevenção & controle , Sulfonamidas/uso terapêutico , Técnicas de Movimentação Dentária/efeitos adversos , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Celecoxib , Inibidores de Ciclo-Oxigenase 2/administração & dosagem , Ligas Dentárias , Feminino , Dente Molar , Níquel , Fios Ortodônticos , Pirazóis/administração & dosagem , Ratos , Ratos Wistar , Reabsorção da Raiz/patologia , Estresse Mecânico , Sulfonamidas/administração & dosagem , Titânio , Ápice Dentário/patologia , Colo do Dente/patologia , Técnicas de Movimentação Dentária/instrumentação