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Bio-profiling of TB patients with and without Type 2 Diabetes before and during anti-tuberculosis drug (ATD) therapy

dc.contributor.advisorRonacher, Katharinaen_ZA
dc.contributor.advisorKleynhans, Leanieen_ZA
dc.contributor.authorSelamolela, Mosaen_ZA
dc.contributor.otherStellenbosch University. Faculty of Medicine and Health Sciences. Biomedical Sciences: Molecular Biology and Human Genetics.en_ZA
dc.date.accessioned2017-02-09T11:27:12Z
dc.date.accessioned2017-03-29T20:53:49Z
dc.date.available2018-03-30T03:00:05Z
dc.date.issued2017-03
dc.identifier.urihttp://hdl.handle.net/10019.1/101377
dc.descriptionThesis (MSc)--Stellenbosch University, 2017.en_ZA
dc.description.abstractBackground Patients with type 2 diabetes (DM2) are three times more likely to acquire active tuberculosis (TB) compared to otherwise healthy people. TB-DM2 comorbidity is characterized by poor TB treatment outcomes, increased risk of failure and relapse. The exact mechanisms of increased susceptibility of diabetics to TB are not well understood, but it is thought that hyperglycaemia is associated with an impairment of the innate and adaptive immune response. Aim To assess soluble (cytokines) and cellular (T-cell subsets) immunological markers of treatment response in TB patients with and without DM2 and their association with glycaemic control. Materials and Methods Serum cytokine concentrations were measured by means of the Luminex assay in 14 TB and 11 TB-DM2 patients at Baseline, Month 2 and Month 6. The HO-1 levels were measured from serum samples by means of ELISA in 40 TB and 20 TB-DM2 patients at Baseline, Week 2, Month 2 and Month 6. The frequency of different T-cell subsets (central memory, naïve, effector memory and terminally differentiated effector memory T cells) was established in 8 healthy controls, 13 DM2, 18 TB and 23 TB-DM2 patients at Baseline, Month 2 and Month 6 using flow cytometry. Results Throughout treatment pro- and anti-inflammatory cytokine concentrations were increased in serum of TB-DM2 patients when compared to TB patients. Fibrinogen and Procalcitonin were higher in TB patients compared to the TB-DM2 patients at the end of treatment. Various cytokines (IL-1β, IL-4, IL-6, IL-7, IL-8, IL-9, G-CSF, GM-CSF, MCP-1(MCAF) and IFN-γ) and growth factors (VEGF and PDGF) exhibited positive correlation at baseline with HbA1c and random blood glucose, respectively. The frequencies of CD4+ naïve T cells increased from Baseline and Month 2 in TB patients. In contrast CD4+ and CD8+ naïve T cells decreased over time in the TB-DM2 patients. CD4+ T CM cells increased over time in TB-DM2 patients. Activated CD8+ naïve T cells increased over time in both TB and TB-DM2 patients while the terminally differentiated effector memory T cells decreased in both groups of study patients over time. No significant changes were observed in any CD8+ T cell subset in both groups of study patients. Conclusion The present study reveals that TB-DM2 patients have altered cytokine production at baseline and throughout treatment which may be linked to chronic inflammation associated with obesity and diabetes. Glycaemic control displays an influence in cytokine production shown in TB-DM2 patients. The frequencies of T cell subsets is altered in TB-DM2 patients and changes throughout treatment. These results show that TB-DM2 patients are characterised by changes in the adaptive immune system, which may contribute to poor treatment outcomes.en_ZA
dc.description.abstractAgtergrond Pasiënte met tipe 2-diabetes (DM2) is drie keer meer geneig om aktiewe tuberkulose (TB) te ontwikkel in vergelyking met andersins gesonde mense. TB-DM2 komorbiditeit word gekenmerk deur swak TB-behandelingsuitkomste, verhoogde risiko van mislukking en terugval. Die presiese meganisme van verhoogde vatbaarheid van diabete vir TB word nie goed verstaan nie, maar dit word vermoed dat hiperglisemie ge-assosieer is met 'n beskadiging van die ingebore en aanpasbare immuunrespons. Doel Om oplosbare (sitokiene) en sellulêre (T-sel deelversamelings) immunologiese merkers van behandelingsrespons in TB-pasiënte met en sonder DM2 en hul verbintenis met glisemiese beheer te evalueer. Materiale en Metodes Serum sitokien-konsentrasies is gemeet deur middel van die Luminex-toets in 14 TB en 11 TB-DM2 pasiënte by die basislyn, Maand 2 en Maand 6. Die HO-1 vlakke is gemeet in serum monsters deur middel van ELISA in 40 TB en 20 TB-DM2 pasiënte by die basislyn, Week 2, Maand 2 en Maand 6. Die frekwensie van die verskillende T-sel deelversamelings (sentrale geheue, naïef, effektor geheue en terminaal gedifferensieerde effektor geheue T selle) is bepaal in 8 gesonde kontroles, 13 DM2, 18 TB en 23 TB-DM2 pasiënte by die basislyn, Maand 2 en Maand 6 met behulp van vloeisitometrie. Resultate Dwarsdeur behandeling is pro- en anti-inflammatoriese sitokien-konsentrasies verhoog in serum van TB- DM2 pasiënte in vergelyking met TB-pasiënte. Fibrinogeen en PCT was hoër in TB-pasiënte as in die TB-DM2 pasiënte aan die einde van die behandeling. Verskeie sitokiene (IL-1β, IL-4, IL-6, IL-7, IL-8, IL-9, G-CSF, GM-CSF, MCP-1 (MCAF) en IFN-γ) en groeifaktore (VEGF en PDGF) toon ʼn positiewe korrelasie by basislyn met HbA1c en ewekansige bloedglukose, onderskeidelik. Die frekwensies van CD4+ naïewe T- selle neem toe van die basislyn tot Maand 2 in TB-pasiënte. In teenstelling neem die CD4+ en CD8+ naïewe T selle af oor tyd in die TB-DM2 pasiënte. CD4+ T CM selle verhoog oor tyd in TB-DM2 pasiënte. Geaktiveerde CD8+ naïewe T selle verhoog oor tyd in beide TB en TB-DM2 pasiënte terwyl die terminaal gedifferensieerde effektor geheue T selle afneem in beide groepe studie-pasiënte oor tyd. Geen beduidende verandering is waargeneem in enige CD8+ T sel deelversameling in beide groepe studie-pasiënte. Gevolgtrekking Die huidige studie toon dat TB-DM2 pasiënte veranderde sitokien produksie by basislyn en dwarsdeur behandeling het wat gekoppel kan word aan chroniese inflammasie geassosieer met vetsug en diabetes. Glisemiese beheer het 'n invloed op sitokien produksie in TB-DM2 pasiënte getoon. Die frekwensies van T-sel deelversamelings is verander in TB-DM2 pasiënte en verandering geskiet regdeur behandeling. Hierdie resultate dui daarop dat TB-DM2 pasiënte gekenmerk word deur veranderinge in die aanpasbare immuunstelsel, wat kan bydra tot swak behandelingsuitkomste.af_ZA
dc.format.extent81 pages : illustrationsen_ZA
dc.language.isoen_ZAen_ZA
dc.publisherStellenbosch : Stellenbosch Universityen_ZA
dc.subjectUCTD
dc.subjectDNA profilingen_ZA
dc.subjectTuberculosis -- Case studiesen_ZA
dc.subjectType 2 diabetesen_ZA
dc.subjectTuberculosis -- Patients -- Treatmenten_ZA
dc.titleBio-profiling of TB patients with and without Type 2 Diabetes before and during anti-tuberculosis drug (ATD) therapyen_ZA
dc.typeThesisen_ZA
dc.rights.holderStellenbosch Universityen_ZA
dc.embargo.terms2018-03-30


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