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Les cellules Natural Killer des ruminants : première caractérisation des cellules Natural Killer ovines et de bovin nouveau-né / Ruminant natural killer cells : first characterization of ovine and bovine neonate natural killer cellsEl Hmouzi-Younes, Jamila 11 December 2009 (has links)
Les nouveau-nés, dont le système immunitaire adaptatif est encore en développement sont souvent plus sensibles aux infections que les adultes. L’immunité innée constitue la première ligne de défense de l’organisme contre les agents pathogènes et en particulier les cellules Natural Killer (NK), via leur fonction cytotoxique et leur production d’interféron-gamma (IFN-?). Dans le but de pouvoir étudier, à terme, l’implication des cellules NK des ovins nouveau-nés dans un contexte infectieux, nous avons mis en place une stratégie permettant d’isoler et de caractériser ces cellules pour la première fois. En attendant que cette méthode soit mise au point, nous avons recherché les particularités des cellules NK des nouveau-nés chez les bovins pour lesquels un anticorps dirigé contre le récepteur NKp46 spécifique des cellules NK est disponible. Nous avons observé que, bien que moins nombreuses dans le sang périphérique, les cellules NK des nouveau-nés prolifèrent rapidement, sont totalement fonctionnelles et répondent fortement (cytotoxicité et production d’IFN-?) après culture en présence d’IL-15 et lors de la stimulation du récepteur NKp46 (Elhmouzi-Younes et al., 2009b). Nous avons pu caractériser les cellules NK ovines, parmi les cellules mononuclées du sang périphérique, en mettant en place une méthode basée sur l’utilisation d’anticorps dirigés contre le marqueur CD14, spécifique des monocytes, et le récepteur CD16 exprimé par les cellules NK et les monocytes. Les cellules CD16+/CD14- présentent toutes les caractéristiques morphologiques, phénotypiques et fonctionnelles fondamentales des cellules NK (Elhmouzi-Younes et al., 2009a). / Neonates are often more susceptible to infections than adults, due to their adaptive immune system still in development. Natural Killer (NK) cells are key cells of the innate immune system which provide early resistance to infections through their cytotoxic properties and production of interferon-gamma (IFN-?). In order to study the involvement of NK cells from ovine neonates during an infection we developed, a method to isolate and characterize these cells for the first time. While this method was developed, we investigated the peculiarities of bovine neonate NK cells as an antibody directed against the NKp46 receptor specific of bovine NK cells is available. On the one hand, we found that although less numerous in peripheral blood, neonate NK cells proliferated actively, were totally functional and highly responsive (cytotoxicity and IFN-? production) to IL-15 and to NKp46 receptor stimulation (Elhmouzi-Younes et al., 2009b). On the other hand, we characterized ovine NK cells, among peripheral blood mononuclear cells, after developing a strategy based on the use of antibodies against the CD14 marker, specific of monocytes, and the CD16 receptor expressed by NK cells and monocytes. We found that CD16+/CD14- cells present all the morphological, phenotypical and functional characteristics of NK cells (Elhmouzi-Younes et al., 2009a).
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Birth Defect Amelioration and Placental Cytokine Expression in Mnu-Exposed Dams Treated With Ifn-GammaLaudermilch, Chelsea Lee 28 January 2008 (has links)
Each year, 7.9 million babies are born with birth defects. Seventy percent of those could be prevented, ameliorated, or repaired; yet 3.2 million children still die by the age of three (March of Dimes Global Report 2006). We have found that non-specific maternal immune stimulation with the cytokine interferon-gamma (IFN-gamma) can successfully ameliorate some of these defects in the C57BL/6N mouse model. We have observed a reduction in the distal limb malformations syndactyly, polydactyly, and webbing by 47%, 100%, and 63% respectively when IFN-gamma is given 2 days prior to MNU administration. We have also observed that IFN-gamma works at the placental level to protect against MNU-induced damage. Trophoblast loss and associated cytokine alterations occur in gestation day (GD) 14 placenta following GD9 MNU exposure, showing that fetal-maternal communication can be hindered due to MNU. In the labyrinthine layer of the placenta, we observed multifocal fibrinous necrosis of endothelial cells due to MNU, however IFN-gamma almost completely protected the trophoblast and endothelial cells when given to the dam as an immune stimulant. To determine the genes participating in these processes, gene microarray studies were conducted. Hepatocyte growth factor (HGF), interleukin 1 beta (IL1Β), and insulin-like growth factor 2 (IGF2) were elucidated as genes that were significantly expressed in GD12 placenta. These genes are similar in that they are all connected to the Jak-Stat signaling pathway. These findings provide a possible mechanism for birth defect reduction by maternal immune stimulation with IFN-gamma in MNU-challenged mice. / Master of Science
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A POTENTIAL STRATEGY TO MAINTAIN HSV-1 IN A LATENT STATE: USE OF IMMUNOREGULATORY PEPTIDE MIMETICSMajidi, Nasrin 22 December 2009 (has links)
No description available.
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Diagnóstico de la infección por Mycobacterium tuberculosis mediante estimulación de las células t sensibilizadas con antígenos específicosLatorre Rueda, Irene 15 April 2011 (has links)
diagnosticar precozmente y tratar a los individuos enfermos de forma apropiada. Por
otro lado, el estudio de las personas infectadas permite aplicar, medidas de prevención
y evitar que estas personas desarrollen la enfermedad.
La prueba de la tuberculina (PT) ha sido utilizada durante los últimos 100 años como
herramienta para el diagnóstico de la infección tuberculosa. Su principal inconveniente
radica en que la mayoría de proteínas presentes en el PPD no son específicas de
Mycobacterium tuberculosis. Esto provoca una disminución en la especificidad de la
prueba, ya que individuos sensibilizados por exposición previa a micobacterias no
tuberculosas (MNT) o vacunados con la BCG también responden inmunológicamente
al PPD. Además, la PT presenta una baja sensibilidad en pacientes con alteraciones
en la inmunidad celular.
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La citoquina efectora clave en el control de la infección micobacteriana para la
activación de los macrófagos y el desarrollo de la inmunidad protectora contra M.
tuberculosis es el IFN-g. Por lo tanto, un método de inmunodiagnóstico basado en la
cuantificación in vitro de la respuesta inmune celular puede ser una alternativa a la PT.
En los últimos años, se han descrito dos antígenos específicos de M. tuberculosis:
Early Secretory Antigen Target-6 (ESAT-6) y Culture Filtrate Protein 10 (CFP-10).
Estos antígenos están ausentes en la cepa vacunal de la BCG y en la mayoría de
MNT. También se ha estudiado un tercer antígeno llamado TB7.7. En este sentido han
sido desarrollados diferentes métodos de cuantificación de la respuesta inmune celular
utilizando estos antígenos específicos micobacterianos para la estimulación de las
células T sensibilizadas y para la detección in vitro de IFN-g.
En base a esta tecnología se han estandarizado dos técnicas comerciales: Quantiferon
Gold In tube (QFN-G-IT) y T-SPOT.TB. QFN-G-IT estimula los linfocitos presentes en
muestras de sangre total con los antígenos ESAT-6, CFP-10 y TB7.7 en un mismo
tubo, y determina la producción de IFN-g mediante técnica de ELISA. Por otro lado, TSPOT.
TB requiere una separación de células mononucleares para estimularlas con los
antígenos ESAT-6 y CFP-10 por separado, y el IFN-g se detecta mediante ELISPOT.
De esta forma, la Tesis se ha centrado en la estandarización y evaluación clínica de
estas técnicas inmunológicas para el diagnóstico de la infección tuberculosa y TB
activa, así como su aplicabilidad en la práctica clínica en pacientes adultos y
pediátricos (inmunocompetentes e inmunodeprimidos), y el estudio del efecto de las
MNT sobre la positividad de la PT. Finalmente, la Tesis se completa con la evaluación
de nuevos marcadores y antígenos alternativos en el diagnóstico in vitro de la TB.
En resumen, las técnicas basadas in vitro son más específicas que la PT, ya que están
menos influenciadas por la vacuna de la BCG y la sensibilización a MNT. Por lo tanto,
el uso de estas técnicas puede ayudar a reducir el número de quimioprofilaxis
innecesarias en población adulta y pediátrica. La detección de IFN-g liberado por las
células T sensibilizadas tras estimular con antígenos específicos de M. tuberculosis es
una herramienta diagnóstica alternativa en el diagnóstico de la infección tuberculosa
en población inmunocompetente e inmunodeprimida. Además, estas técnicas in vitro
pueden ayudar en el inmunodiagnóstico de la TB activa. Por otro lado, el estudio de
nuevos antígenos específicos y biomarcadores es una herramienta potencial para el
estudio de la respuesta del huésped contra M. tuberculosis durante el tratamiento y la
búsqueda de nuevos marcadores para el diagnóstico de la infección tuberculosa y TB
activa. / The bases of tuberculosis (TB) control programs consist of a diagnosis and correct
treatment of patients with active TB. An essential factor for controlling the spread of this
disease is the ability to diagnose infected individuals in their early stages before they
become infectious to others through the progression to active TB.
The tuberculin skin test (TST) has been until now the only tool available for the
diagnosis of latent tuberculosis infection (LTBI). Unfortunately, this test has some
disadvantages because of its poor specificity that lead to false positive results by the
BCG vaccine strain and nontuberculous mycobacteria (NTM) cross-reaction. Moreover,
TST has a low sensibility in groups with impaired cellular immunity giving false negative
results.
CD4 T cells represent the major players in the protection against TB. Of greatest
relevance are the T helper (Th) 1 cells, that produce IFN-g. The IFN-g cytokine
activates macrophages for the development of a protective immunity against
Mycobacterium tuberculosis. Therefore, an immunodiagnostic assay based on the in
vitro quantification of this cellular immune response could be an alternative to the TST
for the diagnosis of LTBI.
In the last years, two specific M. tuberculosis antigens have been described. These
antigens are early secretory antigenic target 6 (ESAT-6) and culture filtrate protein 10
(CFP-10), absent in BCG strain and in the majority of NTM. A new third M. tuberculosis
antigen called TB7.7 has been also studied. In vitro assays for the diagnosis of LTBI,
based on the detection of IFN-g secreted by effector T cells stimulated with these
specific antigens, have been developed.
There are two commercially available IFN-g T-cell based assays: QuantiFERON-TB
Gold In-Tube (QFN-G-IT) and T-SPOT.TB, both approved by the U.S. Food and Drug
Administration. QFN-G-IT test stimulates whole-blood with ESAT-6, CFP- 10 and
TB7.7 in the same tube, and measures the concentration of IFN-g in supernatants with
an ELISA assay. On the other hand, T-SPOT.TB assay stimulates isolated peripheral
blood mononuclear cells with ESAT-6 and CFP-10 separately, and detects number of
IFN-g producing T cells by means of an ELISPOT.
In this sense, the main objectives of this Thesis are the standardization and clinical
evaluation of these new immunological assays for the diagnosis of LTBI and active TB,
their application in clinical practice in adult and pediatric immunocompetent and
immunosuppressed population, and the evaluation of NTM effect in the LTBI diagnosis.
Finally, we study and evaluate new antigens and potential biomarkers for the diagnosis
of active TB and LTBI.
In summary, IFN-g tests are more specific than TST because they are less affected by
BCG vaccination and NTM sensitization. So, the utilization of these assays can help to
reduce unnecessary LTBI treatment among adult and pediatric population. Therefore,
detection of IFN-g produced by T cells after M. tuberculosis specific antigen stimulation
is an alternative diagnostic tool for LTBI in immunocompetent and immunosuppressed
patients. In addition, IFN-g assays could help in the immunodiagnosis of active TB. On
the other hand, the study of new specific antigens and biomarkers is a potential tool for
studying host immune response during anti-TB therapy and finding novel diagnostic
markers for active TB and M. tuberculosis infection.
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Der Beitrag der SH2-Domäne von STAT1 zur Regulation transkriptioneller Antworten im IFN-Gamma-abhängigen Signalweg / The role of the STAT1 SH2 domain in interferon-gamma signalingGiveh Chian Zadeh, Talayeh 10 November 2014 (has links)
No description available.
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Produkce IL-1? a IFN? po stimulaci mléčné žlázy lipopolysacharidemMíka, Matěj January 2016 (has links)
This thesis was focused on the pro-inflammatory cytokines IL-1beta and IFN-gamma. Absolute and differential leukocyte count was also monitored. The experiment was conducted at 8 clinically healthy heifers, hybrids of Holstein and Czech Pied that have been housed by tethering in stalls and fed with a standard diet. The inflammatory reaction was induced by lipopolysaccharide (LPS; 5 ug in 20 ml PBS), as a control a phosphate buff-ered saline (PBS) was used. Results were measured at 1, 2, 3 and 7 days after stimulation of mammary gland by above-mentioned factors. Concentration of each cytokine was detected by a sandwich ELISA using commercially available kits. At 1 day after stimulation of mammary gland by LPS and PBS an average number of leukocytes, which was statistically significantly higher in the case of stimulation by LPS (P <0.01), was detected. After 7 days there was a significant decrease in the total number of leukocytes. There has also been a shift in the differential leukocyte count. Most abundant cell type were neutrophils, whose number was higher in the case of stimulation by LPS. Between day 1 and day 7 after challenge, there was a gradual reduction in the proportion of neutrophils. In the same period an increase in the proportion of macrophages and lymphocytes was detected. Concentration of IL-1beta also increased, 1 day after the activation a striking increase has been detected. In following days there was gradual decline of IL-1beta concentration almost to the level prior to treatment of the mammary gland. In the case of IFN-gamma similar pattern in the form of strong growth and a subsequent gradual decline in concentration to the original values was detected. There was found positive correlation between the increase in IL-1beta and IFN-gamma concentration and a shift in the differential leukocyte count in favor of neutrophils, which confirmed the important role of these pro-inflammatory cytokines in the establishment of inflammatory response and the mobilization of the components of natural and specific immunity.
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Avaliação da eficiência do antagonista seletivo de CD28, mPEG PV1-Fab´, no tratamento da uveíte autoimune experimental. / Efficacy of murine selective CD28 antagonist for the treatment of experimental autoimmune uveitis.Rosa, Pedro Henrique Papotto 08 December 2014 (has links)
A uveíte autoimune é uma doença inflamatória crônica, caracterizada pela resposta imune a antígenos oculares. É mediada por linfócitos T CD4+ com perfil TH1, e responsável por uma parcela significativa de casos de deficiências visuais e cegueira. Embora efetivos, os tratamentos disponíveis estão associados a efeitos adversos importantes. Logo, a busca de novos alvos terapêuticos mais específicos tem sido o objetivo principal no campo da imunoterapia. Nesse trabalho foi avaliada a eficiência do antagonista seletivo de CD28, mPEG PV1-Fab´(PV1), no tratamento da uveíte autoimune experimental (EAU). Camundongos tratados com PV1 exibiram menores graus de doença quando comparados a controles não tratados. Tal achado foi acompanhado de uma diminuição da ativação de linfócitos T, tanto nos olhos quanto nos órgãos linfoides periféricos desses animais. Mais ainda, o tratamento com PV1 levou a uma diminuição da população de linfócitos T reguladores e de células do tipo TH1. Portanto, concluiu-se que PV1 é eficaz no tratamento da EAU por agir em linfócitos T efetores. / Autoimmune uveitis is a T-cell mediated disease that targets mainly the posterior eye pole. Similar to human uveitis, experimental autoimmune uveitis (EAU) is mostly dependent on T cells with a TH1 phenotype. Although many treatment strategies are available, most of them focus on general immunossuppression, resulting in undesirable side effects. Thus, the development of more specific therapies is the major aim in the field of immunotherapy. Here we evaluated the efficacy of mPEG PV-1-Fab´ (PV1), a specific CD28 antagonist, in the treatment of EAU. Our results indicate that PV1 blocks T cell activation by decreasing expression of different costimulatory molecules. Furthermore, PV1 treatment led to a decrease of Treg cell population in peripheral lymphoid organs. Also, IFN-g production by CD4+ cells and TH1 lymphocytes population were decreased. Altogether, our results raise this CD28 blockade strategy as a potential tool for the treatment of autoimmune disorders in the eye, and indicate that mPEG PV1-Fab acts mainly on IFN-g production and TH1 polarization.
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Avaliação da eficiência do antagonista seletivo de CD28, mPEG PV1-Fab´, no tratamento da uveíte autoimune experimental. / Efficacy of murine selective CD28 antagonist for the treatment of experimental autoimmune uveitis.Pedro Henrique Papotto Rosa 08 December 2014 (has links)
A uveíte autoimune é uma doença inflamatória crônica, caracterizada pela resposta imune a antígenos oculares. É mediada por linfócitos T CD4+ com perfil TH1, e responsável por uma parcela significativa de casos de deficiências visuais e cegueira. Embora efetivos, os tratamentos disponíveis estão associados a efeitos adversos importantes. Logo, a busca de novos alvos terapêuticos mais específicos tem sido o objetivo principal no campo da imunoterapia. Nesse trabalho foi avaliada a eficiência do antagonista seletivo de CD28, mPEG PV1-Fab´(PV1), no tratamento da uveíte autoimune experimental (EAU). Camundongos tratados com PV1 exibiram menores graus de doença quando comparados a controles não tratados. Tal achado foi acompanhado de uma diminuição da ativação de linfócitos T, tanto nos olhos quanto nos órgãos linfoides periféricos desses animais. Mais ainda, o tratamento com PV1 levou a uma diminuição da população de linfócitos T reguladores e de células do tipo TH1. Portanto, concluiu-se que PV1 é eficaz no tratamento da EAU por agir em linfócitos T efetores. / Autoimmune uveitis is a T-cell mediated disease that targets mainly the posterior eye pole. Similar to human uveitis, experimental autoimmune uveitis (EAU) is mostly dependent on T cells with a TH1 phenotype. Although many treatment strategies are available, most of them focus on general immunossuppression, resulting in undesirable side effects. Thus, the development of more specific therapies is the major aim in the field of immunotherapy. Here we evaluated the efficacy of mPEG PV-1-Fab´ (PV1), a specific CD28 antagonist, in the treatment of EAU. Our results indicate that PV1 blocks T cell activation by decreasing expression of different costimulatory molecules. Furthermore, PV1 treatment led to a decrease of Treg cell population in peripheral lymphoid organs. Also, IFN-g production by CD4+ cells and TH1 lymphocytes population were decreased. Altogether, our results raise this CD28 blockade strategy as a potential tool for the treatment of autoimmune disorders in the eye, and indicate that mPEG PV1-Fab acts mainly on IFN-g production and TH1 polarization.
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Die Rolle von IFN Gamma in der ImmunregulationEulenburg, Katharina zu 14 March 2007 (has links)
In der vorliegenden Arbeit wurde die Rolle des Zytokins IFN-gamma in einer Th1-vermittelten Entzündungsreaktion untersucht. Ausgangspunkt war die Beobachtung, dass die Blockade des als proinflammatorisch beschriebenen Zytokins IFN-gamma zu einer chronischen Entzündung führte. Ziel war also das Erkennen und Verstehen der Regulationsmechanismen, sowie die Identifizierung beteiligter Zelltypen und beteiligter Moleküle. Mit Hilfe von Knochenmarkschimären konnte gezeigt werden, dass die Zelle, die von Th1-Zellen sekrektiertes IFN-gamma erkannte, haematopoietischen Ursprungs war. Zum weiteren Verständnis der Regulationsmechanismen wurden Tiere unter IFN-gamma-Blockade mit Tieren, die einen Kontrollantikörper erhielten, verglichen. Mittels Immunhistochemie konnte in Kontrolltieren eine starke Expression von iNOS am Ort der Entzündung nachgewiesen werden, während in Tieren, in denen IFN-gamma blockiert wurde, keine iNOS Expression nachzuweisen war. Mit Hilfe von iNOS-defizienten Mäusen konnte gezeigt werden, dass NO tatsächlich funktionell essentiell in der IFN-gamma abhängigen Selbstlimitation der Th1-vermittelten Entzündungsreaktion war. Weitere Charakterisierung der iNOS-exprimierenden Zellen mittels FACS-Analyse ergab, dass iNOS-produzierende Zellen den Oberflächenmarker CD11b exprimierten. Diese iNOS-produzierenden Zellen waren fast ausschließlich am Ort der Entzündung zu finden. Die funktionelle in vitro Charakterisierung dieser Zellen nach ex vivo Isolierung ergab, dass diese Zellen die Proliferation von CD4+ T-Zellen supprimierten und deshalb als Myeloide-Suppressor-Zellen bezeichnet werden können. Der hier untersuchte IFN-gamma vermittelte Regulationsmechanismus scheint auf andere T-Zell-Systeme übertragbar zu sein, da IFN-gamma Blockade in einer durch CD8+ Effektor-T-Zellen vermittelten Entzündung auch zu einer Verlängerung der Entzündung führte. Zusammenfassend konnte gezeigt werden, dass das Zytokin IFN-gamma während der Effektorphase einer Immunreaktion wichtig für die Selbstlimitation ist. / The aim of the work was to understand the role of the cytokine IFN-gamma in a Th1 dependent inflammation. Starting point was the observation that the blockade of IFN-gamma, which is generally regarded as a proinflammatory cytokine, led to a more severe inflammation. We were therefore aiming at a better understanding of the mechanism of regulation, the identification of important cell types and downstream effector molecules. With the help of bone marrow chimeras we could show that the host cell which recognises IFN-gamma is of haematopoietic origin. For further understanding we compared animals under IFN-gamma neutralisation with control animals. Immunohistochemical staining revealed a strong expression of the enzyme iNOS in control animals whereas iNOS was merely detectable under IFN-gamma neutralisation. With the help of iNOS deficient animals we could show, that NO is indeed essential as downstream effector molecule. Further characterisation via FACS analysis showed that iNOS production was only observed among CD11b+ cells, roughly half of the iNOS expressing cells were also positive for GR-1. iNOS expression could only be detected at the site of inflammation. Functional in vitro characterisation of these cells after ex vivo isolation revealed that they suppressed the proliferation of CD4+ T cells. They can therefore be regarded as myeloid suppressor cells. To study whether the observed mechanisms of regulation are of any general importance, we looked at a DTH response mediated by CD8+ effector T cells and indeed we could observe a more severe inflammation under IFN-gamma neutralisation, although the effect was not quite as strong as in the Th1 mediated inflammation. In summary we could show, that the cytokine IFN-gamma is important in the limitation of the effector phase of an ongoing immune response.
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Évaluation quantitative de l'oxyde nitrique produit par les neutrophiles sanguins de chevaux sainsLapointe Corriveau, Capucine January 2004 (has links)
Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.
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