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Therapeutic potential of anti-tetanus toxoid monoclonal antibodies: application based on binding properties

dc.contributor.advisorStojanović, Marijana
dc.contributor.otherGavrović-Jankulović, Marija
dc.contributor.otherProdanović, Radivoje
dc.contributor.otherStojanović, Marijana
dc.contributor.otherGavrović-Jankulović, Marija
dc.creatorLukić, Ivana D.
dc.date.accessioned2018-12-26T14:30:29Z
dc.date.available2018-12-26T14:30:29Z
dc.date.available2020-07-03T10:14:54Z
dc.date.issued2018-09-21
dc.identifier.urihttp://eteze.bg.ac.rs/application/showtheses?thesesId=6385
dc.identifier.urihttp://nardus.mpn.gov.rs/handle/123456789/10479
dc.identifier.urihttps://fedorabg.bg.ac.rs/fedora/get/o:19075/bdef:Content/download
dc.identifier.urihttp://vbs.rs/scripts/cobiss?command=DISPLAY&base=70036&RID=50771727
dc.description.abstractTetanus toksin (TT), produkt anaerobne bakterije Clostridium tetani, je izuzetno potentan neurotoksin koji može izazvati tetanus, teško i često fatalno oboljenje. Uprkos višedecenijskom sistematskom sprovođenju vakcinacije protiv tetanusa, incidenca tetanusa još uvek nije zanemarljiva. TT-specifična antitela su ključni faktor u sprečavanju intoksikacije TT-om. Pored toga, predpostavlja se da bi ova antitela, usled ukrštene reaktivnosti, mogla doprinositi i otpornosti ka heterologim infekcijama. Kod osoba koja nemaju uspostavljen adekvatan TT-specifičan imunski odgovor, a postoji sumnja na intoksikaciju TT-om, preporučuje se imunoterapija koja podrazumeva aplikaciju TT-specifičnih antitela sposobnih da neutrališu slobodno cirkulišući TT. Duži niz godina se kao imunoterapeutici razmatraju i TT-specifična monoklonska antitela (MAt) gde se kao jedan od problema nameće pitanje kako selektovati zaštitno MAt i / ili formulisati efikasan preparat s obzirom da specifičnost ka TT ne znači nužno i zaštini potencijal. Cilj ove doktorske disertacije je da se, kroz ispitivanje vezivnih karakteristika panela TTd/TT-specifičnih MAt i njihovog zaštitnog potencijala in vivo, utvrdi na koji način i u kojoj meri vezivne karakteristike TTd/TT specifičnih antitela određuju njihovu sposobnost da spreče intoksikaciju TT-om i / ili doprinesu otpornosti ka heterologim infekcijama. Istraživanja realizovana u okviru izrade ove doktorske teze su pokazala da se zaštitni potencijal anti-TTd / TT antitela može proceniti na osnovu afiniteta ka TT-u i sposobnosti da inhibiraju TT-GD1b interakciju. TT-specifična antitela koja mogu da spreče in vivo intoksikaciju TT-om treba da vezuju TT-om sa afinitetom ≥ 1x108 M-1 i da istovremeno imaju sposobnost da inhibiraju vezivanje TT-a za GD1b gangliozide. Afinitet prema TT-u je prvi selekcioni kriterijum zaštitnih TT-specifičnih antitela, a potom njihova sposobnost da preveniraju TT-GD1b interakciju. Zaštitni potencijal TTspecifičnih antitala čiji je afinitet ka TT-u ≥ 1x108 M-1 dominantno određuje sposobnost inhibiranja TT-GD1b interakcije a ne sam afinitet...sr
dc.description.abstractis an extremely potent neurotoxin that can cause tetanus, a severe and often fatal disease. Mandatory vaccination against tetanus is introduced worldwide and it was crucial for a significant decline of tetanus cases. Nevertheless, the prevalence of the disease is not negligible, particularly in the developing world. Antibodies capable to neutralize TT are key factors in protection against tetanus disease. It is assumed that antibodies may, due to cross-reactivity, contribute to the immunity against heterologous pathogens. TT intoxications can be efficiently treated with various polyclonal antibodybased therapies. Although antibody-based therapeutics for treatment of tetanus exist on the market its production is tedious. Monoclonal antibodies (MAbs) are considered for a long time as a reagent of choice, but the core drawback is how to select a MAb and how to prepare oligoclonal MAbs-based preparation that would be safe in providing efficacious protection, since available data clearly demonstrate that the ability of a single MAb to bind TT does not necessarily mean that this MAb protects from tetanus intoxication. The aims of this thesis were to evaluate the binding characteristics and protective capacity of TTd/TT-specific MAb(s)-based preparations, to determine how these binding characteristics correlate with the observed in vivo effects and to investigate whether these preparations could contribute to the development of heterologous immunity. In this PhD thesis, we showed that the selection of protective anti-TTd/TT MAbs can be performed by the in vitro testing combining two assays: (i) the measurement of MAb affinity toward TT (ii) the evaluation of its capability to prevent TT-ganglioside interaction. TT-specific antibodies that prevent in vivo TT intoxication bind TT with affinity ≥ 1x108 M-1 and, at the same time, possess the ability to inhibit binding of TT to GD1b ganglioside. MAb’s afinity toward TT is the first selection criterion of protective TT-specific antibodies, and the second criterion is their ability to prevent TT-GD1b interaction...en
dc.formatapplication/pdf
dc.languagesr
dc.publisherУниверзитет у Београду, Хемијски факултетsr
dc.relationinfo:eu-repo/grantAgreement/MESTD/Basic Research (BR or ON)/172049/RS//
dc.rightsopenAccessen
dc.sourceУниверзитет у Београдуsr
dc.subjectmonoklonska antitelasr
dc.subjectmonoclonal antibodiesen
dc.subjecttetanus toksinsr
dc.subjectvezivne karakteristikesr
dc.subjectkooperativni efekatsr
dc.subjectzaštitni i terapeutski potencijalsr
dc.subjectunakrsna reaktivnostsr
dc.subjecttetanus toxinen
dc.subjectbinding propertiesen
dc.subjectcooperative effecten
dc.subjectprotective and therapeutic potentialen
dc.subjectcross-reactivityen
dc.titleTerapeutski potencijal anti-tetanus toksoid monoklonskih antitela: primena zasnovana na vezivnim karakteristikamasr
dc.title.alternativeTherapeutic potential of anti-tetanus toxoid monoclonal antibodies: application based on binding propertiesen
dc.typedoctoralThesis
dc.rights.licenseARR
dc.identifier.fulltexthttp://nardus.mpn.gov.rs/bitstream/id/29905/Disertacija.pdf
dc.identifier.fulltexthttp://nardus.mpn.gov.rs/bitstream/id/29906/IzvestajKomisije18636.pdf


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