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1
Dillon, David. "Protective antibodies in normal pregnancy." Thesis, University of Aberdeen, 1989. http://digitool.abdn.ac.uk/R?func=search-advanced-go&find_code1=WSN&request1=AAIU028047.
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The aim of this study was to examine the maternal immune response to paternal antigens expressed by the fetus and identify the antigen inducing the response. Sera removed from responder female mice were tested for activity against paternal target cells using a cellular ELISA. Avtivity was first detectable at day 10 of a first pregnancy. The antibody detected in this way was shown to be non-cytotoxic, consisting of the IgGl subclass, directed against a class I antigen that could not be found on target erythrocytes. Sera removed at different stages of pregnancy exhibited varying degrees of cross-reactivity. To provide a source of pregnancy-induced antibody spleens from mice were removed during pregnancy and fused with rat or mouse myelomas. Antibody-secreting hybridomas were sought by means of CELISA with paternal cells as targets. Four hybridomas were isolated, producing antibody of the IgGl subclass, directed against a class I antigen and with limited cross-reactivity. The target antigen for both pregnancy sea and monoclonal antibody was examined for H-2 linkage, using the Lod score. The results obtained were unusual. Combination of the scores for four separate sera suggested an MHC-linked target. Individual scores suggested that two sera were directed against a linked and two against an unlinked antigen. Three of the monoclonal antidbodies were directed against H-2-linked antigens. Both sera and monoclonal antibody were immunoblotted against paternal, maternal and control cells. Pregnancy sera was seen to blot a 45-kD antigen present on paternal strain cells and cells from a mouse sharing the maternal haplotype. Only one hybridoma could be successfully blotted, revealing a 45-kD target. Immunisation with third-party lymphocytes has been used to treat recurrent spontaneous abortion. In twenty two couples treated in this way immunisation proved to be beneficial but there was no evidence for importance of an immune response or HLA sharing.
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Parker, Christopher S. "Effect of a codon optimized DNA prime on induction of anti-influenza protective antibodies." Worcester, Mass. : Worcester Polytechnic Institute, 2007. http://www.wpi.edu/Pubs/ETD/Available/etd-040907-100839/.
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Berry, P. R. "Production of monoclonal antibodies to Bordetella pertussis as a means of identifying protective antigens." Thesis, University of Reading, 1987. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.376819.
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Figueroa, Z. E. F. "Specificity and protective effect of polyclonal antibodies to antigens of Plasmodium berghei and Plamodium chabaudi." Thesis, Open University, 1985. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.304217.
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Czifra, György. "Identification of Mycoplasma gallisepticum antigens with diagnostic and protective properties /." Uppsala : Swedish Univ. of Agricultural Sciences (Sveriges lantbruksuniv.), 1999. http://epsilon.slu.se/avh/1999/91-576-5900-1.pdf.
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Mugyenyi, Cleopatra Kama. "The acquisition and maintenance of antibodies to merozoite antigens of Plasmodium falciparum and their role in protective immunity to malaria." Thesis, Open University, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.522224.
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Murugan, Rajagopal. "Protective memory B cell response in controlled human malaria infection." Doctoral thesis, Humboldt-Universität zu Berlin, 2019. http://dx.doi.org/10.18452/19695.
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Antikörper gegen Circumsporozoite protein (CSP), ein Oberflächenantigen von Plasmodium
falciparum (Pf), können sterile Immunität hervorrufen und dadurch die Entwicklung von
Malaria im Tierversuch verhindern. Im Menschen werden protektive B-Zell
Gedächtnisantworten gegen CSP durch natürliche Malariaerkrankung bzw. Vakzinierung
jedoch nur unzureichend erzeugt. - Für die Entwicklung von Gedächtnis-B-Zellen stellt die
Affinitätsreifung, welche durch somatische Immungobulin Hypermutation sowie der
nachfolgenden Selektion von B-Zellen mit verbesserter Antigenaffinität charakterisiert ist, eine
Schlüsselfunktion in der Generierung von protektiven Immunantworten dar. Wie
Affinitätsreifung gegen CSP im Menschen stattfindet ist jedoch nicht bekannt. In dieser Arbeit
wird die Affinitätsreifung von CSP Gedächtnis B-Zellen auf Einzelzellebene im Menschen
über drei kontrollierte Infektionen mit Pf Sporozoiten unter Chemoprophylaxe untersucht.
Durch Hochdurchsatz-Einzelzell-Sequenzierung der Immunoglobulin (Ig) gene loci und der
Produktion von rekombinanten monoklonalen Antikörpern gewährt diese Arbeit Einsicht in
die Selektion und Affinitätsreifung von humanen Gedächtnis-B-Zell Antworten gegen
komplexe Proteinantigene und identifiziert Keimbahn kodierte Immunglobulin
Charakteristika, die mit hoher CSP-Affinität und Pf-Inhibition einhergehen.
Überraschenderweise zeigen die Daten, dass initiale klonale Selektion von hochaffinen B
Zellen eine weitaus wichtigere Rolle als Affinitätsreifung in dieser Infektion spielt. Diese
Arbeit zeigt fundamentale Eigenschaften von humanen Gedächtnisantworten in einer
komplexen Parasiteninfektion und liefert die Grundlage für ein mögliches Design von
neuartigen Immunogenen um hoch-affine B-Zellen gegen CSP effizienter zu induzieren.Antibodies against the major Plasmodium falciparum (Pf) sporozoite surface protein, circumsporozoite protein (CSP), can mediate sterile immunity thereby preventing malaria disease symptoms as shown by passive transfer in animal models. However, protective anti- CSP memory antibody responses are not efficiently induced by natural Pf exposure or vaccination. Affinity maturation, i.e. the diversification of antigen-activated naïve precursor B cells by a somatic immunoglobulin (Ig) gene mutation process and the subsequent selection of B cells expressing antigen receptors with improved antigen affinity in germinal center reactions is considered key to the formation of protective memory B cell responses. However, how the anti-PfCSP memory B cell response matures in humans is not known. To address this question, the clonal evolution of the human anti-Pf CSP memory B cell response over three successive controlled Pf infections under chemoprophylaxis was assessed at single cell level by high throughput paired full-length Ig gene sequencing and recombinant monoclonal antibody production. The work provides basic insights in the longitudinal development of human memory B cell responses and identified germline-encoded Ig gene features that were associated with high anti-CSP affinity and Pf inhibitory antibody activity. The clonal selection of germline B cells expressing such antibodies, rather than affinity maturation, was associated with high quality anti-PfCSP memory B cell responses. The data provide insights into the evolution of antibody response to a complex protein antigen during infection and a strong rational for the design of novel CSP immunogens to target naïve B cell precursors expressing potent anti-CSP antibodies for the induction of protective memory B cell responses by vaccination.
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Anthony, Robert McCullough. "Characterization and function of the inflammatory response to infection by a gastrointestinal nematode parasite : new insights into protective Th2 responses /." Download the dissertation in PDF, 2006. http://www.lrc.usuhs.mil/dissertations/pdf/Anthony2006.pdf.
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Dumke, Roger, and Enno Jacobs. "Antibody response to Mycoplasma pneumoniae: protection of host and influence on outbreaks?" Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2017. http://nbn-resolving.de/urn:nbn:de:bsz:14-qucosa-213646.
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In humans of all ages, the cell wall-less and genome-reduced species Mycoplasma pneumoniae can cause infections of the upper and lower respiratory tract. The well-documented occurrence of major peaks in the incidence of community-acquired pneumonia cases reported world-wide, the multifaceted clinical manifestations of infection and the increasing number of resistant strains provide reasons for ongoing interest in the pathogenesis of mycoplasmal disease. The results of recent studies have provided insights into the interaction of the limited virulence factors of the bacterium with its host. In addition, the availability of complete M. pneumoniae genomes from patient isolates and the development of proteomic methods for investigation of mycoplasmas have not only allowed characterization of sequence divergences between strains but have also shown the importance of proteins and protein parts for induction of the immune reaction after infection. This review focuses on selected aspects of the humoral host immune response as a factor that might influence the clinical course of infections, subsequent protection in cases of re-infections and changes of epidemiological pattern of infections. The characterization of antibodies directed to defined antigens and approaches to promote their induction in the respiratory mucosa are also preconditions for the development of a vaccine to protect risk populations from severe disease due to M. pneumoniae.
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Dumke, Roger, and Enno Jacobs. "Antibody response to Mycoplasma pneumoniae: protection of host and influence on outbreaks?" Frontiers Media, 2016. https://tud.qucosa.de/id/qucosa%3A29946.
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In humans of all ages, the cell wall-less and genome-reduced species Mycoplasma pneumoniae can cause infections of the upper and lower respiratory tract. The well-documented occurrence of major peaks in the incidence of community-acquired pneumonia cases reported world-wide, the multifaceted clinical manifestations of infection and the increasing number of resistant strains provide reasons for ongoing interest in the pathogenesis of mycoplasmal disease. The results of recent studies have provided insights into the interaction of the limited virulence factors of the bacterium with its host. In addition, the availability of complete M. pneumoniae genomes from patient isolates and the development of proteomic methods for investigation of mycoplasmas have not only allowed characterization of sequence divergences between strains but have also shown the importance of proteins and protein parts for induction of the immune reaction after infection. This review focuses on selected aspects of the humoral host immune response as a factor that might influence the clinical course of infections, subsequent protection in cases of re-infections and changes of epidemiological pattern of infections. The characterization of antibodies directed to defined antigens and approaches to promote their induction in the respiratory mucosa are also preconditions for the development of a vaccine to protect risk populations from severe disease due to M. pneumoniae.
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Wesumperuma, Hasithri Lalanga. "Factors that affect transplacental transfer of anti-infective antibodies." Thesis, University of Liverpool, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.264020.
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Alpert, Michael. "Antibodies in Vaccine Protection against SIV and HIV-1 Infection." Thesis, Harvard University, 2011. http://dissertations.umi.com/gsas.harvard:10057.
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The properties of human immunodeficiency virus type 1 (HIV-1) and its simian counterpart SIV that enable persistent replication in the face of robust cellular, antibody, and innate immune responses have complicated efforts to develop a safe and effective vaccine. Vaccine protection against HIV-1 infection may require a combination of immune mechanisms. However, the types of immune responses that can be induced by vaccination to prevent HIV-1 infection remain unclear. The features of the viral envelope glycoprotein (Env) that confer inherent resistance to neutralization by antibodies also interfere with the development of antibody responses. We therefore vaccinated rhesus macaques with single-cycle SIV (scSIV) strains expressing Env proteins mutated to remove features that interfere with the induction of antibody responses. Antibodies capable of neutralizing Env-modified but not wild-type SIV were selectively enhanced. Identifying the immune responses underlying complete protection by live-attenuated SIV against pathogenic SIV challenge may provide guidance for HIV-1 vaccine design. To test the hypothesis that antibodies not measurable by assays for virus neutralization correlate with protection by live-attenuated SIV, we developed a novel assay for antibody-dependent cell-mediated cytotoxicity (ADCC). ADCC activity increased progressively over time after inoculation, and was measurable against viruses expressing heterologous Env proteins from independent SIV isolates when neutralization was undetectable. Two separate pathogenic \(SIV_{mac}251\) challenge experiments took advantage of either the strain specificity or the time-dependent development of immunity to overcome complete protection by live-attenuated SIV. In both experiments, macaques inoculated with live-attenuated SIV that remained uninfected by \(SIV_{mac}251\) had significantly higher ADCC activity than those that became infected. We also measured ADCC for the primary immune correlates analysis of a recent HIV-1 vaccine clinical trial in Thailand (RV144) that reported modest vaccine protection (31%). There was a nonsignificant trend towards lower risk of infection among vaccinees with high versus low relative ADCC activity. However, Env-specific IgA correlated with risk, prompting an analysis stratified by IgA levels. Among vaccinees with low Env-specific IgA, there was lower risk of infection among those with higher ADCC activity. These observations suggest that antibodies that direct ADCC may contribute to vaccine protection against SIV and HIV-1 infection.
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Rosário, Ana Paula Freitas do. "Análise dos compartimentos de linfócitos T e B de memória em animais tratados e não tratados com cloroquina durante a infecção pelo Plasmodium chabaudi AS." Universidade de São Paulo, 2008. http://www.teses.usp.br/teses/disponiveis/42/42133/tde-03062008-155929/.
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A exposição limitada ao Plasmodium chabaudi induz proeminente imunidade celular, associada à proteção de células T da apoptose. Este estudo tem como objetivo verificar a influência da carga parasitária na geração e manutenção dos linfócitos T e B de memória ao P. chabaudi. Assim, camundongos C57BL/6 foram submetidos à infecção tratada (subpatente) ou não (patente) com cloroquina após a inoculação de 106 eritrócitos parasitados (EP) e analisados nos dias 0, 20, 60, 120 e 200. Com relação à memória de linfócitos T, no dia 20, as freqüências de células CD4+ memória/ativadas e respondedoras aos EP foram significativamente maiores nos animais do grupo subpatente. Os níveis máximos de IgG2a específica foram encontrados no dia 120 em ambos os grupos. O desafio dos animais com 108 EP mostrou que a imunidade protetora declina progressivamente, mas os grupos ainda são capazes de estabelecer resposta secundária eficiente que elimine o parasita. Assim, podemos concluir que a carga parasitária influencia a fase aguda, mas não impede a geração e manutenção das células T e B de memória.One of the main characteristics of malaria is the intense policlonal activation of splenic T and B lymphocytes induced by the parasite and the consequent elimination, through apoptosis, of part of these cells. However, the limited exposure to the bloodstage malaria seems to induce a prominent cellular immunity, associated with the protection of T lymphocytes from apoptosis. With this in mind, this study aimed to verify the influence of the parasite load in the generation and maintenance of memory T and B cells specific for Plasmodium chabaudi chabaudi AS. In order to evaluate this idea, C57BL/6 mice were infected with 106 parasitized red blood cells (pRBC) and submitted to a patent (untreated) or subpatent infection (controlled with sub-curative doses of chloroquine every time parasitemia reached 1%). Splenocytes from these mice were analyzed at 20, 60, 120 and 200 days after infection, regarding the pRBC-specific T cell proliferation and the expression of surface molecules, as CD4, CD8, CD62L, CD45RB, CD44, CD45R-B220 and IgG. The parasitemia and the splenocyte phenotype were also monitored after the challenge with 108 pRBC. Regarding T cell memory, at day 20 of infection, the frequencies of effector/activated CD4+ T cells (CD62LLOW CD45RBLOW/HIGH) were significantly increased in animals from the patent group, which was strict linked with the highest cellular activation observed in these animals. On the other hand, the total numbers of pRBCproliferating T (CD4+ and CD8+) cells per spleen were approximately 3-fold increased in subpatent animals, indicating that these cells were protected from apoptosis as a result of the limited exposure to the parasite. However, in both groups, these parameters decreased to values similar to those in controls at day 200. The splenocytes from both groups produced Th1 cytokines in response to pRBC in all times of analysis, but at the early phase of infection, Th2 cytokines were also observed, but without differences between the infected groups. Regarding memory B cells, the frequency of sIgG+ cells was increased at day 20 of infection, when 11% and 9% of CD45R+ cells from patent and subpatent animals were positive, respectively. For both groups, specific IgG2a antibodies attained maximum serum levels at day 120, but at day 200, it is possible to observe a significant decrease of these levels only in the serum of patent mice. Moreover, at day 200 of infection, mice of subpatent group showed significantly higher amounts of IgG2a that recognized the intra-erythrocytic forms of the parasite and the surface of infected erythrocytes. Challenge of mice with 108 pRBC showed that protective immunity progressively decline with time and despite the higher levels of specific antibody in subpatent mice, both groups showed similar protection. In experiments of adoptive transference to CD28-/- mice, cells from 200-day infected mice were able to produce specific IgG2a antibodies, in a T CD4+ cell dependent way. In addition, we verified that CD45R+ cells of subpatent mice, when transferred to CD28-/- mice, secreted higher amounts of specific IgG2a and IgG1 antibodies, comparing to cells of patent mice. So, from this work, we can conclude that the parasite load has a great influence in the early immune response to P. chabaudi malaria and it also affects the generation and/or maintenance of memory B cells. Furthermore, according to our data, at least during the analyzed period, the loss of protective immunity against this parasite does not seem to be influenced by the acute-phase parasite load, but it can be a consequence of the progressive decline of T-cell memory response that occurs in patent and subpatent groups with time of infection.
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Téllez, Sierra Aleyda. "Giardiasis in Leon, Nicaragua : prevalence and protection /." Stockholm, 2006. http://diss.kib.ki.se/2006/91-7140-999-8/.
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Speranza, Francisco Almeida Braga. "Pesquisa de anticorpos antitoxina diftérica e fenotipagem de linfócitos T em indivíduos soronegativos e soropositivos para o HIV-1 acompanhados no Instituto de Biologia do Exército Rio de Janeiro." Universidade do Estado do Rio de Janeiro, 2010. http://www.bdtd.uerj.br/tde_busca/arquivo.php?codArquivo=1508.
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Dados sorológicos sobre doenças imunopreveníveis são úteis para avaliar o sucesso de programas de imunização e a identificação de populações suscetíveis. Nos últimos 20 anos, as campanhas de imunização na infância foram eficientes no controle da difteria em muitos países. No entanto, uma taxa importante da população adulta continua suscetível à doença, uma vez que os níveis de anticorpos protetores reduzem com o passar do tempo. A infecção pelo HIV-1 leva a uma perda progressiva das funções imunes. Com o aumento da expectativa de vida dos pacientes HIV-1, e a maior incidência de infecções, torna-se importante a avaliação dos níveis de anticorpos antitoxina diftérica nestes grupos. O objetivo deste estudo foi avaliar os níveis de anticorpos antitoxina diftérica e a contagem de linfócitos T (LT) em indivíduos infectados ou não pelo HIV -1, assistidos no Instituto de Biologia do Exército (IBEx). Investigamos a correlação entre níveis de anticorpos específicos e os seguintes parâmetros dos grupos de estudo: sexo, faixa etária, categoria militar ou civil; vacinação prévia contra difteria; número de LT CD4+ e CD8+; e entre os indivíduos HIV-1 positivos a correlação com a carga viral e a terapia com antirretrovirais potentes (HAART). Para a quantificação de anticorpos antitoxina diftérica utilizou-se um kit ELISA (IBL Immuno-Biological Laboratories, Hamburg, Alemanha) e amostras de sangue de 180 indivíduos, sendo que 75 eram doadores de sangue e 105 eram pacientes positivos para o HIV-1. Aproximadamente 60% dos indivíduos estavam parcialmente protegidos contra a difteria (IgG específica ≥ 0,1 < 1,0 UI/mL). Entre os doadores de sangue, 56% dos indivíduos estavam protegidos (IgG específica ≥ 1,0 UI/mL) contra a doença, contra apenas 29 % dos indivíduos positivos para HIV-1. Em relação aos doadores de sangues de origem civil não se observou correlação entre os níveis de IgG e a idade, enquanto que, para os militares observou-se uma correlação inversa. Não houve diferença significativa na resposta de anticorpos para difteria entre os indivíduos soropositivos com CD4+ baixo ou normal. Pacientes com HAART mostraram uma resposta significativamente mais baixa de anticorpos (média geométrica de 0.39 IU/mL, n = 84) do que os pacientes não tratados (média geométrica de 0.58 IU/mL, n = 19). A diferença na idade média dos pacientes não tratados (46 anos) e tratados com HAART (35 anos) provavelmente influenciou estes resultados, já que os níveis de anticorpos contra a difteria declinam com o tempo. A existência em nossa comunidade de adultos (militares e civis) suscetíveis à difteria, incluindo os indivíduos soropositivos, reforça que a imunização a cada 10 anos e os estudos soroepidemiológicos são muito importantes e devem ser estimulados.Serologic data on diseases that are preventable by vaccine are useful to evaluate the success of immunization programs and to identify susceptible subgroups. In the last 20 years the childhood immunization program has been efficient in the control of the diphtheria in many countries. However, an important rate of adult population remains susceptible to the illness, since diphtheria protective antibodies decline with time. HIV-1 infection leads to a progressive loss of immune functions. With the increase of life expectancy of HIV-1 patients, and also the increment of infections, it is important to known the antibody levels to diphtheria toxin in these population. The aim of this study was to evaluate the IgG levels to diphtheria toxin and T lymphocytes (LT) counts in HIV-1 infected and non- infected individuals assisted at the Instituto de Biologia do Exército (IBEx), Rio de Janeiro. We investigated the correlation between specific antibody levels and the following parameters of the study groups: gender, age-group, military or civilian origin, previous diphtheria immunization, CD4+ and CD8+ counts. For HIV-1 patients, we also analysed the correlation of specific antibodies with viral load and the use of highly active antiretroviral therapy HAART. A commercial diphtheria-ELISA kit (IBL Immuno-Biological Laboratories, Hamburg, Alemanha) was used to evaluate IgG levels in serum samples of 180 individuals. Blood donors accounted for 75 individuals and 105 subjects were HIV-1 patients. About 60% of individuals were partially protected against diphtheria (specific IgG levels ≥ 0,1 < 1,0 IU/mL). About 56% of blood donors were protected against diphtheria (specific IgG > 1.0 IU/mL). Howerver, only 29% of HIV-1 patients showed the same level of protective antibodies. For the civilian blood donors, there were no correlation between specific antibody levels and age group. In contrast, a negative correlation was observed in the military group. There were no differences in diphtheria serology according to CD4+ counts of HIV-1 patients or blood donors. Interesting, HAART- treated (n = 84) patients showed a significantly lower antibody response (geomean of 0.39 IU/mL) than untreated patients (geomean of 0.58 IU/mL, n = 19). As tetanus and diphtheria antibodies tend to decrease with time, the difference in age between HAART-treated patients (mean of 46 years) and those not being treated (mean of 35 years) might introduce a bias in the study. Concluding, the existence of susceptible military and civilian adults in our community, including HIV-1 patients, reinforce that reliable seroepidemiological data and immunization campaigns should be routinely stimulated.
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Karbach, Astrid [Verfasser], and Thomas [Akademischer Betreuer] Winkler. "Protection from Cytomegalovirus Infection by Glycoprotein-specific Monoclonal Antibodies / Astrid Karbach. Betreuer: Thomas Winkler." Erlangen : Universitätsbibliothek der Universität Erlangen-Nürnberg, 2013. http://d-nb.info/1038871204/34.
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Orhan, Sahin. "Ecology of Campylobacter Colonization in Poultry: Role of Maternal Antibodies in protection and Sources of Flock Infection." The Ohio State University, 2003. http://rave.ohiolink.edu/etdc/view?acc_num=osu1047067618.
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Rice, Rebecca. "Induction of anti-ergotamine antibodies in mice and steers and protection against fescue toxicosis in mice." Diss., This resource online, 1995. http://scholar.lib.vt.edu/theses/available/etd-06062008-155524/.
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Tan, Cheng Siang. "The role of genotype specific anti-G antibodies in protection against severe human respiratory syncytial virus infection." Thesis, University of Newcastle Upon Tyne, 2012. http://hdl.handle.net/10443/1486.
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Human respiratory syncytial virus is a leading cause of lower respiratory tract infection in infants. Current prophylaxis with Palivizumab, a humanised anti-fusion glycoprotein monoclonal antibody, has only achieved moderate success. In animal models, immunization with G glycoprotein has led to largely genotype specific immunity. This suggests the hypothesis that anti-G antibodies to the infecting virus genotype, either acquired transplacentally or induced by immunisation, may contribute to protection of the infant in the early months of life. The aim of this study has been to test this hypothesis by measuring levels of maternally acquired antibody to the G glycoprotein of the infecting virus genotype in an index group of infants with severe HRSV infection and, to the same genotype, in a comparison group of infants with no history of HRSV infection. As only 2% of infants suffer severe disease on primary HRSV infection, the comparison group are assumed to be destined to be resistant to severe infection. A deficiency of anti-G antibodies in the index group will thus indicate a protective role for these antibodies. A phylogenetic study was carried out in Newcastle upon Tyne from autumn 2007 to spring 2010 revealing three circulating genotypes of HRSV, namely GA2, GA5 and BA4 although GA5 was not detected in the third epidemic. The G genes of GA2 and BA4 and the F gene of GA2 were cloned and expressed individually in modified vaccinia Ankara virus. The recombinant proteins were used in the development of a concanavalinA capture ELISA sufficiently sensitive to detect maternal antibodies in the acute sera of infants under 6 months of age. An attempt was made to refine the assay in order to separately detect antibodies to the conserved and variable epitopes of the G glycoprotein. However, mapping of conserved and variable epitopes revealed overlap epitopes precluding the development of a differentiation in a simple ELISA assay. An index group of infants with severe HRSV infection and a comparison group of infants of similar age with no history of HRSV infection were recruited with consent by their legal carer during the epidemic of 2009/2010. The infecting virus lineage of each infant in the index group, either GA2 or BA4, was identified by reverse transciptasepolymerase chain reaction of virus recovered from nasal secretions. Sera were collected from both groups, at the acute stage of infection for the index group, and screened for ii HRSV specific IgA by ELISA. Only those without detectable IgA were included in the study. IgG maternal antibodies to the recombinant G glycoprotein of the infecting virus genotype and the F glycoprotein of the GA2 genotype were measured in the sera of index and comparison group infants whilst maternal antibody levels to both F and G glycoproteins in the sera of both index and control sera decayed at similar rates with age, the index group possessed significantly more anti-G and anti-F antibody at all ages suggesting that infants hospitalized with severe HRSV infection were not deficient in antibodies to either glycoprotein contrary to the hypothesis under test. However, mean maternal antibody levels at birth have been shown to fall across the winter epidemic and the above analysis may be susceptible to bias introduced by uneven sampling of infants across the epidemic. To avoid this potential error, anti-F/anti-G antibody ratios, which give a measure of anti-G immunity independent of age and time of collection, were also compared in the sera of index and comparison group infants. Mean ratios were not significantly different between the two groups also rejecting the hypothesis that severely affected infants have a deficiency in maternal anti-G antibodies. These studies, therefore, fail to establish a role for anti-G glycoprotein antibodies in the protection of infants against severe lower respiratory tract disease.
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Sahin, Orhan. "Ecology of Campylobacter colonization in poultry role of maternal antibodies in protection and sources of flock infection /." Columbus, OH : Ohio State University, 2003. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1047067618.
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Thesis (Ph. D.)--Ohio State University, 2003.Title from first page of PDF file. Document formatted into pages; contains xii, 177 p.: ill. Includes abstract and vita. Advisor: Qijing Zhang, Dept. of Veterinary Preventive Medicine. Includes bibliographical references (p. 152-177).
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He, Yongqun. "Induction of Protection, Antibodies and Cell Mediated Immune Responses by Brucella Abortus Strain RB51, Ochrobactrum Anthropi and Recombinants Thereof." Diss., Virginia Tech, 1999. http://hdl.handle.net/10919/11276.
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Although it is known that cell-mediated immunity (CMI) plays a key role in protection against brucellosis, the exact immune mechanisms leading to protection are still not fully understood. Better understanding of the mechanisms would help in the development of a human Brucella vaccine and help in improving animal vaccines. In this research, B. abortus strain RB51 and a closely-related, nonpathogenic Ochrobactrum anthropi (strain 49237) bacterium were used to study the immune response against brucellosis in mice. Both O. anthropi strain 49237 and recombinant strain 49237 expressing Brucella protective antigen copper-zinc superoxide dismutase (Cu/Zn SOD) induced a mix of Th1 and Th2 type immune responses but failed to provide protection against virulent Brucella challenge. After changing the immune response to a predominantly Th1 type of response using CpG oligonucleotides as an adjuvant, both strains provided protection with the recombinant strain inducing significantly higher protection. It was also demonstrated that vaccination with strain RB51 induced Th1 immune responses characterized by high interferon-gamma (IFN-g) production with no interleukin-4 (IL-4) secretion as well as high IgG2a and minimal IgG1 production. A colorimetric cytotoxic T lymphocytes (CTL) assay was developed to demonstrate that strain RB51 induced an antigen-specific CTL reaction that probably plays an important role in protection. The results suggest that optimal protection against brucellosis requires IFN-g-secreting T cells and antigen-specific CTLs. Recombinant strain RB51 overexpressing Brucella Cu/Zn SOD and simultaneously expressing mycobacterial 85A antigen induced higher IFN-g production and CTL activity than the parent RB51 strain. The combined results suggest that the recombinant O. anthropi strain could be used as a human vaccine against brucellosis and that the recombinant RB51 strain could be used as an effective vaccine against both brucellosis and tuberculosis in animals.Ph. D.
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Stenmark, Stephan. "Cutaneous resistance against Francisella tularensis." Doctoral thesis, Umeå : Infectious diseases, Department of clinical microbiology, Umeå university, 2004. http://publications.uu.se/umu/theses/abstract.xsql?dbid=329.
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Maung, Nang H. "Intranasal Colonization by Streptococcus Pneumoniae Induces Immunological Protection from Pulmonary and Systemic Infection: A Dissertation." eScholarship@UMMS, 2011. https://escholarship.umassmed.edu/gsbs_diss/570.
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Given that Streptococcus pneumoniae can cause life-threatening pulmonary and systemic infection, an apparent paradox is that the bacterium resides, usually harmlessly, in the nasopharynx of many people. Humoral immunity is thought to be the primary defense against serious pneumococcal infection, and we hypothesized that nasopharyngeal colonization of mice results in the generation of an antibody response that provides long-term protection against lung infection. We found that survival of of C57L/6 mice after intranasal inoculation with wild-type serotype 4 strain TIGR4 pneumococci required B cells but not T cells, suggesting that nasopharyngeal colonization elicited a protective humoral immune response. In fact, intranasal inoculation resulted in detectable pneumococcal-specific antibody responses, and protected mice against a subsequent high-dose S. pneumoniae pulmonary challenge. B cells were required for this response, and transfer of immune sera from i.n. colonized mice, or monoclonal antibodies against phosphorylcholine, a common surface antigen of S. pneumoniae, was sufficient to confer protection. IgA, which is thought to participate in mucosal immunity, contributed to but was not absolutely required for protection from pulmonary challenge. Protection induced by i.n. colonization lasted at least ten weeks. Although it was partially dependent on T cells, depletion of CD4+ T cells at the time of challenge did not alter protection, suggesting that T cells did not provide essential help in activation of conventional memory cells. Peritoneal B1b cells and radiation-resistant, long-lived antibody secreting cells have previously been shown to secrete anti-pneumococcal antibodies and mediate protection against systemic infection following immunization with killed bacteria or capsular polysaccharide [1, 2]. We found that peritoneal cells were not sufficient for colonization-induced protection, but sub-lethally irradiated mice largely survived pulmonary challenge. Thus, our results are consistent with the hypothesis that nasopharyngeal colonization, a common occurrence in humans, is capable of eliciting extended protection against invasive pneumococcal disease by generating long-lived antibody-secreting cells.
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Chaillon, Antoine. "Glycoprotéines d'enveloppe du virus de l'immunodéficience humaine (VIH) : contribution à l'étude des propriétés biologiques et des mécanismes de protection par anticorps neutralisants." Thesis, Tours, 2012. http://www.theses.fr/2012TOUR3312/document.
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La problématique de la neutralisation par les anticorps constitue un enjeu majeur dans la perspective de la conception d’un vaccin efficace contre le VIH et les connaissances récemment acquises conforte NT l’absolue nécessité de maintenir une recherche cognitive fondamentale sur le sujet. L’un des objectifs de ce travail de thèse a été de documenter les propriétés biologiques en terme de sensibilité à la neutralisation de variants présents chez certains patients asymptomatiques à long terme (ALT) et présentant des caractéristiques particulières. Nous avons pu identifié certains déterminants moléculaires associés à la sensibilité ou à la résistance à l’anticorps monoclonal 2G12 tels le site potentiel de glycosylation (PNGS) en position N302 et la longueur de la boucle V1V2 du gène env. Nous avons ensuite caractérisé la relation entre l’évolution du gène env et la sensibilité à la neutralisation dans un contexte d’évolution tardive chez un patient ALT. Ces travaux ont permis de mettre en évidence une poursuite de l’évolution du gène env plus de 10 ans après l’infection et ceci malgré la présence d’anticorps largement neutralisants et d’une réponse autologue croissante au cours du temps. Le contexte de la transmission mère enfant (TME) constitue un modèle de choix afin d’étudier le rôle des anticorps neutralisants. Afin d’identifier d’éventuels corrélats de protection, mon travail a consisté à étudier la réponse neutralisante dans une population de 114 couples mères-enfants. Nous avons pu confirmer que le spectre de neutralisation des sérums maternels n’était pas associé à une moindre TME du VIH-1, mais que les anticorps neutralisant certains isolats pourraient constituer des indicateurs d’intérêt associé à un moindre risque de transmission. L’ensemble de ces travaux souligne à nouveau la complexité et la pertinence à poursuivre les investigations relatives à l’identification d’éventuels corrélats de protectionBasic research on neutralizing antibodies. still remains relevant in term of HIV vacccine development. One of the aim of this thesis was to document the neutralization sensitivity of particular HIV-1variants from long term non progressor (LTNP) patients. We first identified molecular signatures associated with sensitivity to 2G12, such as a potential N-linked glycosylation site (PNGS) at N302 and a longer V1V2 loop of gp120. We also studied the relationship between long-term evolution of the virus and neutralization sensitivity in a LTNP patient. We showed that HIV-1 may continue to evolve in presence of both broadly neutralizing antibodies and increasing autologous neutralizing activity more than 10 years post-infection. Mother-to-child transmission provides a natural model for studying the role of neutralizing antibodies. In previous studies, we showed that the presence or high titers of neutralizing antibodies against a CRF01_AE strain, MBA, was associated with a lower rate of HIV-1 intrapartum transmission in Thailand (Barin et al., 2006; Samleerat et al., 2009). In order to confirm this observation and to identify potential correlates of protection in the MTCT context, we examined the breadth and levels of neutralizing antibodies in 57 transmitting and 57 non-transmitting untreated HIV-1 infected mothers. Our study confirmed that the breadth of maternal neutralizing antibodies was not associated with protection of infants from infection, but that neutralizing antibodies to particular strains might be associated with a lower rate of MTCT of HIV-1
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Costa, Andréa da. "Avaliação da imunidade e proteção induzida em modelos experimentais por extrato solúvel de taquizoítos de Toxoplasma gondii irradiado por 60CO." Universidade de São Paulo, 2014. http://www.teses.usp.br/teses/disponiveis/42/42135/tde-18072014-103422/.
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A toxoplasmose afeta 1/3 da população humana e só existe uma vacina para uso veterinária. A radiação gama altera as proteínas tornando-as mais imunogênicas, por oxidação e melhor apresentação de antígenos na ausência de adjuvantes. Irradiamos extrato solúvel de taquizoítos da cepa RH de T. gondii (AgTg), e avaliamos seu uso como vacina em camundongos BALB/c. Doses abaixo de 500Gy não afetavam e doses acima de 2000Gy destruíam o extrato, sendo que animais imunizados com extrato irradiado a 1000, 1500 e 2000Gy tinham mais IgG especifica de maior avidez, comparado ao AgTg nativo (p<0.05). Animais imunizados pelo AgTg 1500Gy tiveram aumento da proliferação de esplenócitos, fenotipados como CD3+CD4+, CD3+CD8+ e de linfócitos B, comparados com animais imunizados pelo AgTg nativo. Animais imunizados pelo AgTg 1500Gy após desafio com cepa ME-49 cistogênica apresentaram menor numero de cistos cerebrais e maior sobrevida pós-desafio com cepa virulenta RH. A radiação ionizante em extratos de T.gondii aumenta a resposta imune e a memória imunológica na ausência de adjuvantes.Toxoplasmosis affects 1/3 of the human population and only a vaccine for veterinary use. Gamma radiation alters the proteins making them more immunogenic by oxidation and better antigen presentation in the absence of adjuvants. Radiate soluble extract of RH strain tachyzoites of T. gondii (AgTg ) , and evaluate its use as a vaccine in BALB/c . Doses below 500Gy not affected and destroyed 2000Gy doses above extract, whereas animals immunized with irradiated extract at 1000, 1500 and 2000Gy had more of specific IgG avidity, compared to native AgTg (p < 0, 05). AgTg 1500GY the immunized animals had increased proliferation of splenocytes, phenotyped as CD3+CD4+,CD3+CD8+ and B-lymphocytes immunized animals compared to the native AgTg . Animals immunized by AgTg 1500GY after challenge with strain ME- 49 cystogenic showed lower number of brain cysts and greater survival after challenge with virulent RH. Ionizing radiation in extracts of T. gondii increases the immune response and immune memory in the absence of adjuvants.
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Langel, Stephanie Mary Neal. "Defining the Gut-Mammary Gland-Secretory IgA Axis in Porcine Epidemic Diarrhea Virus Infected Gilts and its Impact on Lactogenic Immune Protection of Neonatal Suckling Piglets." The Ohio State University, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=osu1542041868304033.
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"Monoclonal antibodies as protective medications for drug abuse during pregnancy." UNIVERSITY OF ARKANSAS FOR MEDICAL SCIENCES, 2009. http://pqdtopen.proquest.com/#viewpdf?dispub=3340141.
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Leysath, Clinton Edward. "Structure and engineering of neutralizing antibodies to anthrax toxin." 2008. http://hdl.handle.net/2152/9707.
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Recombinant antibodies have increased in prominence as therapeutics and diagnostic tools since their introduction to the market in the mid-1980s. They are used to treat diverse conditions from Crohn's disease to cancer. Since the Anthrax letter attacks of 2001, a great deal of work has been carried out to develop therapeutics to this disease, and antibodies that neutralize the toxic action of Bacillus anthracis are prominent among them. This dissertation describes the elucidation of the structure of the 14B7 family of neutralizing antibodies directed at protective antigen (PA) of B. anthracis and the complex of PA domain 4 (PAD4) with an ultra-high affinity neutralizing antibody (M18), and then utilizes this information to aid in the engineering of the antibody to various ends. Chapter 2 presents the structure of the M18-PAD4 complex and of the 14B7 family of antibodies, which aids in the understanding of the affinity maturation process for this antibody family. Chapter 3 describes the affinity maturation of M18 to a PA variant by applying the knowledge gained from the complex structure. This previously intractable challenge was met by employing saturation mutagenesis in highly focused libraries to M18 directed by the complex structure to the area of variation on PA. These results indicate that this could be a generalizable method for the engineering of M18 to natural and deliberate variation of PA. Chapter 4 reports work toward the development of a reversible, photoresponsive antibody using small molecule and polymer-protein conjugates. The results indicate that a probable site on M18 was located for placement of the polymer appendage, although further work is necessary to empirically refine the properties of the photoresponsive polymer. Chapter 5 presents an unrelated project, which was to confirm the existence of a proposed RNA thermosensor in the 5' untranslated region of LcrF from the pathogenic bacterium Yersinia pestis, the causative agent of plague. Overall, these studies reveal the power of structure-based engineering in this antibody-antigen system. In addition, the structural elucidation of the M18-PAD4 complex and the 14B7 family of antibodies furthers our basic understanding of protein-protein interactions and the process of affinity maturation of antibodies.text
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Chia-HuiHuang and 黃佳慧. "The protective effects provided by antibodies against chimeric dengue virus nonstructural protein 1." Thesis, 2010. http://ndltd.ncl.edu.tw/handle/90648716945776858666.
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碩士國立成功大學
微生物及免疫學研究所
98
Patients infected by dengue viruses (DV) may display dengue fever, dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS). Hemorrhagic syndromes of DHF/DSS include thrombocytopenia, coagulopathy and vasculopathy, which are related with dysfunction of endothelial cells and platelets. Previous studies in our laboratory showed that antibodies (Abs) against DV nonstructural protein 1 (NS1) cross-react with human endothelial cells and induce apoptosis. Platelet dysfunction and bleeding tendency are also induced by anti-DV NS1 Abs. Using sequence homology analysis, we found that the C-terminal region of DV NS1 protein contains cross-reactive epitopes shared with self-antigens. For safety in vaccine development, the cross-reactive epitopes of DV NS1 protein should be deleted or modified. We have generated the chimeric NS1 protein, which consists of N-terminal DV NS1 (a.a. 1-270) and C-terminal JEV NS1 (a.a. 271-352) (designated DJ NS1). The anti-DJ NS1 Abs showed lower binding activity to human endothelial cells and platelets than that of anti-DV NS1 Abs. In the murine model, DV NS1 immunization caused prolonged bleeding time, but DJ NS1 immunization did not. Passive immunization with anti-DV NS1 or anti-DJ NS1 Abs could reduce DV-induced prolonged bleeding time and hemorrhage on the local skin. KU812 basophil/mast cell line was susceptible to DV infection without enhancing Abs. Anti-DJ NS1 Abs induced DV-infected KU812 cells to undergo apoptosis. Moreover, the expression of MIP-1 alpha and MIP-1 beta in DV-infected KU812 cells was also reduced by anti-DJ NS1 Abs. According to these findings, DJ NS1 may provide a strategy for dengue vaccine development.
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Chia-YiHung and 洪嘉依. "Evaluation of the protective efficacy of anti-dengue virus nonstructural protein 1 monoclonal antibodies." Thesis, 2016. http://ndltd.ncl.edu.tw/handle/662xr2.
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Saliba, Tony. "The development and characterization of murine monoclonal antibodies raised to recombinant protective antigen toxin of Bacillus anthracis." 2005. http://hdl.handle.net/1993/18104.
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Lu, Yi-Tien, and 盧怡恬. "Evaluation of protective effects provided by antibodies against dengue virus nonstructural protein 1 lacking cross-reactive epitopes." Thesis, 2009. http://ndltd.ncl.edu.tw/handle/92852149464044613497.
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碩士國立成功大學
微生物及免疫學研究所
97
Dengue virus (DV) infection causes diseases ranging from mild dengue fever to life-threatening dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). Several mechanisms are suggested to be involved in the pathogenesis of DHF/DSS progression, including antibody-dependent enhancement (ADE) and abnormal host immune responses. Recent reports have demonstrated DV induced autophagy in human hepatoma cell lines and peripheral blood monocytes which promote viral replication. Mast cells are susceptible to ADE-mediated DV infection. We have also detected autophagosome vesicles in DV-infected mast cells under transmission electron microscopy. In the presence of DV-enhancing antibodies, there were higher amounts of autophagosomes in each infected cell than in cells infected with DV without enhancing antibodies. Our results also showed an increase of the LC3-II/LC3-I ratio in DV-infected mast cells. The percentages of DV-infected cells, with or without enhancing antibodies, were reduced by the autophagy inhibitor 3-MA. In addition, our previous studies showed that antibodies against DV nonstructural protein 1 (NS1) cross-reacted with human platelets and endothelial cells. Based on the sequence analysis, the N- and C-terminal regions of DV NS1 possess cross-reactive epitopes which are shared between NS1 and self-antigens. We compared the effects of NS1,delta C NS1 (deletion of amino acids 271-352) and delta NC NS1 (deletion of amino acids 1-35 and 271-352) in DV infection using animal models and cell cultures. Results showed that the binding activity of delta NC NS1 antibodies to endothelial cells and platelets was lower than those of NS1 and delta C NS1 antibodies. We found that these three antibodies all induced DV-infected cell apoptosis. In the murine model, NS1 immunization caused prolonged bleeding time, while delta C NS1 and delta NC NS1 immunization did not cause a similar effect. In a passive immunization model, the binding abilities of anti-delta C NS1 and anti-delta NC NS1 antibodies to platelets were much lower than that of anti-DV NS1 antibodies. The effects of antibodies against NS1 or truncated NS1 on DV-induced autophagy, apoptosis, and viral replication require further investigation. This study offers insights into the potential protective effects provided by delta C NS1 and delta NC NS1 antibodies in DV infection.
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Tsou, Yung-Ta, and 鄒永達. "Neuraminidase-inhibiting antibodies and protective immunity elicited by recombinant neuraminidase proteins of H5N1 and pH1N1 Influenza A Viruses." Thesis, 2013. http://ndltd.ncl.edu.tw/handle/14193320467066262354.
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Lin, Chia-Ying, and 林佳瑩. "Novel Neuraminidase Mutants Proteins to Enhance Heterosubtypic NA-Inhibiting Antibodies and cross-protective immunity against influenza A virus." Thesis, 2014. http://ndltd.ncl.edu.tw/handle/y39zz4.
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Yu-ChangChang and 張育菖. "Study on the protective effects of antibodies against C-terminal region-modified dengue virus nonstructural protein 1 in mouse model." Thesis, 2012. http://ndltd.ncl.edu.tw/handle/10941142057045350817.
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碩士國立成功大學
微生物及免疫學研究所
100
Dengue virus (DV) is a mosquito-transmitted virus which may cause dengue fever, dengue hemorrhagic fever, and dengue shock syndrome. Dengue patients show symptoms with plasma leakage, thrombocytopenia, bleeding tendency, and elevated cytokines. Over 50 million cases of DV infection occur each year, but there is still no approved antiviral treatment or vaccine available. Our previous studies showed that antibodies (Abs) against DV nonstructural protein 1 (NS1) cross-reacted with human endothelial cells and platelets and induced endothelial cell apoptosis and platelet dysfunction. Based on sequence analysis, the C-terminal region of DV NS1 protein contains homologous sequences with self-antigens. For safety concerns of vaccine development, we generated a C-terminal region (amino acid 271-352)-truncated DV NS1 protein or replaced the C-terminal region with JEV NS1 protein, designated C NS1 and DJ NS1, respectively. Anti-C NS1 Abs and anti-DJ NS1 Abs showed lower binding activity to human endothelial cells and platelets than that of anti-DV NS1 Abs. We further established a DV infection model in STAT1-/- mice which are more susceptible to DV as compared with the wild-type mice. Results showed that DV infection in STAT1-/- mice caused prolonged bleeding time, splenomegaly, and elevated levels of serum cytokines and chemokines. The therapeutic effects of anti-C NS1 Abs and anti-DJ NS1 Abs were further investigated in this mouse model. DV2-infected mice treated with anti-C NS1 Abs and anti-DJ NS1 Abs showed significant reduction of prolonged bleeding time and serum interleukin-6 and macrophage inflammatory protein-1 production, which were associated with disease severity. In addition, anti-C NS1 Abs and anti-DJ NS1 Abs also reduced DV3-induced prolonged bleeding time and monocyte chemotactic protein-1 production both in serum and local infection sites. Furthermore, macrophage infiltration to the local infection site was also inhibited in DV3-infected mice by treatment with anti-C and anti-DJ NS1 Abs. Taken together, these studies show not only the therapeutic effects of anti-C and anti-DJ NS1 Abs in DV2-infected mice but also cross-protective effects in DV3-infected mice. The results also provide important information for DV vaccine development.
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Wan-ShanChou and 周琬軒. "Study on the protective effects of chimeric dengue virus nonstructural protein 1 antibodies both in vitro and in active immunization mouse model." Thesis, 2011. http://ndltd.ncl.edu.tw/handle/71470336640185467486.
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黃韻儒. "Removal of N-linked glycan(s) in the stem region of influenza A virus hemagglutinin proteins to elicit heterosubtypic neutralizing antibodies and cross-protective immunity." Thesis, 2013. http://ndltd.ncl.edu.tw/handle/53004753703006004625.
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Moodley-Govender, Eshia S. "Cellular immunity, immune activation and regulation in HIV-1 infected mother-child pairs : what are the determinants of protective immunity." Thesis, 2011. http://hdl.handle.net/10413/9871.
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Background: Prevention of Mother-to-child transmission (PMTCT) of human
immunodeficiency virus (HIV) remains a significant challenge in resource-poor settings despite the advances in antiretroviral (ARV) treatment. HIV-1 infected individuals are able to achieve viral control naturally, however the underlying mechanisms of immunological control in children remains poorly understood. This study was conducted from 2006 to 2010 to investigate correlates of immune control in HIV-1 clade C infected mother-child pairs in the absence of ARVs. Genotypic and phenotypic viral characteristics, cellular immune responses to HIV-1 and host genetics were characterized and correlated with clinical markers
of disease progression. Materials and Methods: To achieve the objectives of the study, three cohorts of mother-child pairs were investigated. The first cohort included 60 untreated mother-child pairs and a further ten uninfected children as controls. The second cohort comprised of ARV treated
pairs (n=60). The third cohort consisted of 374 mothers and 374 children (infected, exposed uninfected, HIV negative). Plasma viral loads and absolute CD4+ T cell counts were routinely performed in all three cohorts. HIV-specific CD8+ T cell responses were analyzed by interferon gamma (IFN-γ) enzyme linked immunosorbent spot (ELISpot) assays. Viral
replicative fitness was assessed using a green fluorescent protein reporter cell line (GFP).Multi-parameter flowcytometry allowed for the investigation of T cell regulation, exhaustion and activation using CD127/CD25, TIM-3/PD-1 and HLA-DR/CD38 markers respectively. IL-10 promoter single nucleotide polymorphisms (SNPs) at positions -592 and -1082 were
determined by TaqMan allelic discrimination assays. Plasma IL-10 levels were measured using a luminex assay. Results: To describe the CTL responses elicited to various regions of the HIV proteome in
HIV-infected treatment naïve children. Sixty children under one year of age in the untreated cohort were analyzed for CTL responses spanning the HIV genome, for which only 30 had detectable responses. There was no significant difference in viral load between respondersand non-responders (p=0.2799). The responders predominantly targeted Nef (49%), Gag
(17%) and Env (14%) regions. Markers of T cell exhaustion and regulation and theirrelationship to markers of disease progression, were next investigated as these parameters may explain the inability of T cells to effectively control HIV infection. T cell phenotyping compared treated, untreated and uninfected subgroups. In infected children, CD8+ T cells
were significantly higher for both the inhibitory marker TIM-3 (p=0.001) and exhaustion marker PD-1 (p=0.0001) compared to uninfected children. Median expression of TIM-3 was higher on CD8+ T cells (46%) compared to CD4+ T cells (20%). TIM-3 and PD-1 expression on T cells were maintained at high levels over time. The frequency of absolute Tregs (p=0.0225) were found to be significantly higher in untreated compared to treated children.
HLA-DR+CD38+ on CD8+ T cells were significantly up-regulated in untreated children compared to treated (p=0.002) and uninfected children (p=0.0177). HLA-DR+CD38+ was also significantly higher in children less than 6 months compared to older children on CD4+ (p=0.0437) and CD8+ T cells (p=0.00276). Interestingly, we observed a significant negative
correlation between magnitude of CTL response and CD25+CD127- (p=0.0202; r=-0.7333) as well as HLA-DR+CD38+ (p=0.0408; r=-0.5516) on CD8+ T cells. IL-10 is an important immunoregulatory cytokine that has been shown to affect the outcome of chronic viral infections. IL-10 polymorphisms have previously been associated with IL-10 levels and
HIV-1 outcomes in adults. Polymorphisms associated with different levels of IL-10 production and their relationship with transmission, markers of disease progression and immune responses were next investigated in this mother-child HIV transmission setting. Genetic analysis of IL-10 in cohort three revealed that HIV-1 acquisition was not associated with either IL10 -592 (AA/CA vs CC) or IL10 -1082 (AA/AG vs GG) single nucleotide polymorphisms (SNPSs). There was a significant association between IL10 -1082 and HIV-1 transmission (p=0.0012). No correlation was observed between IL10 -592 (p=0.4279) or IL10 -1082 SNPs (p=0.6361) and mortality rates in children. IL10 -592C was associated with an elevated magnitude of IFN-γ CD8+ T cell response compared to IL10 -529A (p=0.0071). We found a significant positive correlation between IL-10 plasma levels and viral loads (p=0.0068; r=0.4759) and the ages of the children (p=0.0312; r=0.1737). Conclusion: CD8+ T cell responses and viral fitness did not explain differences in disease progression in selected HIV-1 untreated clade C transmission pairs. T cell activation and regulatory markers influence CTL immune responses resulting in poor clinical outcome. IL10 -1082 polymorphisms may be used as a predictor of HIV-1 transmission. The association between increased IL-10 plasma levels and high viral loads suggest that IL-10 contributes to immune dysfunction in paediatric HIV-1 infection. This study has extended our understanding of immunological and genetic correlates of mother-to-child transmission and
disease outcome in ARV naïve (naturally controlling) and HIV treated infected children.Thesis (Ph.D.)-University of KwaZulu-Natal, Durban, 2011.
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"The role of antibodies in Dengue virus infection: Understanding protection and pathogenesis." Tulane University, 2013.
Find full textAbstract:
Profound vascular leakage in conjunction with elevated viremia is the hallmark of Dengue Hemorrhagic Fever/Dengue Shock Syndrome (DHF/DSS). Antibody (Ab)-dependent enhancement (ADE), in which pre-existing, cross-reactive Abs enhance virus infectivity, is thought to be responsible for increased viremia, while loss of endothelial cell (EC) barrier integrity is the precursor to plasma leakage. However, the relationship between viremia and vascular leak has not been established. The objective of this dissertation project was to determine the involvement of antibodies in the pathogenesis of vascular leak syndrome associated with DHF/DSS by establishing a relationship between Ab-mediated increase in viremia and changes in vascular permeability, the hallmark of DHF/DSS. Our approach focused on characterization of human monoclonal antibodies (hMAbs) from a previously dengue virus (DENV)-infected patient for their ability to both neutralize and enhance infection and increase vascular permeability in vitro. Our results revealed that the human antibody response to DENV E protein elicited by natural infection is predominantly comprised of broadly cross-reactive antibodies targeting domain II epitopes. Using a multiplex cytokine immunoassay, qRT-PCR, and plaque assay, we demonstrated an association between viral load and cytokine production in DENV-infected FcγR-bearing K562 cells, and determined that DENV infection of K562 cells in the presence of hMAb resulted in a modulated inflammatory cytokine response with an overall pro-inflammatory profile. Using human microvascular ECs (HMEC-1), we further demonstrated an association between viral load, cytokine production, and the onset of permeability changes via an indirect mechanism in which inflammatory mediators released by DENV-infected K562 cells altered HMEC-1 barrier function and observed a synergistic effect between active DENV infection and release of inflammatory mediators by both K562 and HMEC-1 that increased permeability. Collectively, our results support the multifactorial nature of the pathogenesis underlying vascular leak, involving a complex interaction between ECs and FcγR-bearing cells, and a synergistic relationship between enhanced viremia and inflammatory mediators leading to increased permeability. Our use of hMAbs provided a novel approach to understanding how Abs impact the vasculature during DENV infection and enable identification of Ab characteristics that may trigger vascular leak, a crucial concern for DENV vaccine design.acase@tulane.edu
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HanLee and 李涵. "Protection of Anti-Dengue Virus Nonstructural Protein 1 Antibodies in the Wild Type and Humanized Mouse Models." Thesis, 2014. http://ndltd.ncl.edu.tw/handle/16788569457957022981.
Full textAbstract:
碩士國立成功大學
微生物及免疫學研究所
102
Dengue virus (DENV) infection may cause dengue fever or even life-threatening dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). Currently, there are no approved vaccines or antiviral therapies. We previously found that the anti-nonstructural protein 1 (NS1) antibodies (Abs) could cross-react with endothelial cells and platelets and cause their dysfunction due to a molecular mimicry with host self-antigens. The Abs against C-terminus-deleted NS1 provided protective effects both in cell culture and in mice. This NS1 with a deletion at C-terminal amino acids 271-352 was designated ΔC NS1. In addition, the Abs against consensus envelope protein domain III (cEDIII), of which the amino acid sequences are consensus among four serotypes and which was developed by our collaborators, had neutralizing activity against all the four serotypes of DENV. We, therefore, developed a recombinant NS1 by fusing cEDIII and ΔC NS1. We immunized mice with cEDIII-ΔC NS1 proteins encapsulated in the polymer-based nanocomplex as adjuvant. The cEDIII-ΔC NS1 proteins did not cause acute toxicity or prolonged bleeding in mice. An ELISA-based assay showed that the immunization provoked a higher Ab response for cEDIII-ΔC NS1 than ΔC NS1. In addition, anti-cEDIII-ΔC NS1 Abs could neutralize DENV infection in a plaque reduction test. Anti-cEDIII-ΔC NS1 Abs also provided therapeutic effect in DENV-infected wild type (WT) mouse model. We further demonstrated that monoclonal antibody (mAb) 2E8, which did not recognize the C-terminal region of DENV NS1, could provide therapeutic effects in DENV-infected WT mice. So far, there is no ideal animal model for dengue disease studies. Because mice are not natural host for dengue, the advantages of using humanized mice include higher susceptibility to DENV and enhanced opportunity to investigate human cell responses to DENV infection. We have established two models of humanized mice. The NOD/SCID IL2Rγnull mice were reconstituted with human hematopoietic stem cells (HSCs) or human peripheral blood mononuclear cells (PBMCs). Passive immunization with anti-ΔC NS1 Abs could reduce DENV-induced mouse-tail prolonged bleeding time in human HSC-engrafted mice. In human PBMC-engrafted mice, DENV infection induced severe hemorrhage in local skin. Importantly, passive immunization with mAb 2E8 reduced hemorrhage. Taken together, the cEDIII-ΔC NS1 protein and mAb 2E8 are potential candidates to provide protection against DENV infection.