Title Glikozilacija imunoglobulina G u predviđanju terapijskoga odgovora i tijekom anti-TNF terapije u Crohnovoj bolesti Title (english) Immunoglobulin G glycosylation in the prediction of therapeutic response and during anti-TNF therapy in Crohn's disease Author Maja Hanić Mentor Gordan Lauc (mentor)Mentor Irena Trbojević Akmačić (komentor)Committee member Jerka Dumić (predsjednik povjerenstva)Committee member Silvija Čuković-Čavka (član povjerenstva)Committee member Ana-Maria Šimundić (član povjerenstva)Granter University of Zagreb Defense date and country 2024-04-26, Croatia Scientific / art field, BIOMEDICINE AND HEALTHCARE Universal decimal classificationUDC ) 615 - Pharmacology. Therapeutics. Toxicology Abstract Crohnova bolest (CB) jedan je od oblika upalne bolesti crijeva koja može zahvatiti stijenku čitavog gastrointestinalnog sustava, od usta do rektuma, no najčešće je ograničena na distalni dio tankog crijeva (ileum) i debelo crijevo. Za takvu upalu kažemo da je kroničnog, diskontinuiranog i transmuralnog karaktera. Smatra se da je CB, odnosno upalna bolest crijeva općenito, posljedica pretjeranog imunosnog odgovora u probavnom traktu zbog narušene crijevne barijere, promijenjenog sastava crijevne mikrobiote i utjecaja okolišnih čimbenika kod osoba koja imaju genetičku predispoziciju za razvoj bolesti. Glavni ciljevi u liječenju CB-a jesu kontrola upale, postizanje remisije i njezino održavanje. U tu svrhu koriste se i biološki lijekovi poput antagonista faktora nekroze tumora, odnosno anti-TNF lijekovi. Ipak, takva je terapija izrazito skupa, ne mora biti prikladna za svakog bolesnika, a često dio bolesnika ne odgovora zadovoljavajuće na terapiju ili kasnije tijekom režima gubi odgovor na istu. Isto tako, mogu se razviti i nuspojave ili protutijela na sam lijek. U središtu ovog doktorskog rada jest imunoglobulin G (IgG). Istraživanja u području glikobiologije su pokazala da složeni oligosaharidi, odnosno glikani vezani na IgG imaju izravan učinak na njegovu izvršnu funkciju te da osobe oboljele od CB-a imaju drugačiji sastav ukupnih N-glikana serumskog IgG-a u odnosu na zdrave osobe. Stoga ova doktorska disertacija ima za cilj ispitati mogućnost predviđanja terapijskog odgovora na anti-TNF terapiju temeljem analize sastava N-glikoma serumskog IgG-a prije započinjanja terapije te istražiti longitudinalnu promjenu u sastavu N-glikoma serumskog IgG-a tijekom te iste terapije. Pritom je za istraživanje korišteno ukupno 1513 uzoraka krvnog seruma bolesnika s CB-om regrutiranih u sklopu studije PANTS (engl. Personalised Anti-TNF therapy in Crohn’s disease). U svrhu predviđanja terapijskog odgovora na anti-TNF terapiju korišteno je 1315 uzoraka krvnog seruma bolesnika s od CB-om, a dodatno prikupljenih 198 uzoraka krvnog seruma korišteno je kao druga vremenska točka zbog ispitivanja longitudinalne promjene u sastavu N-glikoma serumskog IgG-a kod istih bolesnika tijekom terapije. Iz uzoraka krvnog seruma pročišćen je IgG te je njegova N-glikozilacija analizirana metodom tekućinske kromatografije. Dobiveni rezultati pokazali su da tijekom primjene anti-TNF terapije dolazi do promjene u sastavu N-glikoma serumskog IgG-a bez obzira na terapijski odgovor. Preciznije, dolazi do smanjenja zastupljenosti agalaktoziliranih, a povećanja mono- i digalaktoziliranih te sijaliniziranih N-glikana IgG-a, što upućuje na smanjenje proupalnog potencijala serumskog IgG-a tijekom terapije. Nadalje, rezultati upućuju da sastav N-glikoma serumskog IgG-a prije započinjanja anti-TNF terapije ne sadrži informaciju o budućem terapijskom odgovoru te da se ne može koristiti u svrhu identificiranja bolesnika s CB-om koji neće primjereno odgovoriti na anti-TNF terapiju lijekovima.
Abstract (english) Crohn's disease is a type of inflammatory bowel disease that can affect the entire gastrointestinal system, from the mouth to the rectum. However, it most commonly affects the lower part of the small intestine (ileum) and the colon. Crohn's disease is represented by discontinued, chronic transmural inflammation of the gut. It is primarily a consequence of an exaggerated intestinal immune response, changes in the gut microbiota composition and exposure to certain environmental factors in individuals with a genetic predisposition to the disease. The main goals in the treatment of Crohn's disease are to control inflammation and to achieve and maintain remission. For this purpose, there are several therapeutic approaches available, including tumour necrosis factor antagonists (anti-TNF). However, this treatment can be quite expensive and may not be suitable for every patient. Some patients do not adequately respond to the anti-TNF therapy, lose their response over time, experience side effects or develop antibodies against the medication. The primary focus of this doctoral dissertation is on the total serum immunoglobulin G (IgG) N-glycosylation in Crohn's disease. Research in the field of glycobiology has shown that complex oligosaccharides called glycans have a direct impact on IgG effector function. Interestingly, patients with Crohn's disease have been found to have an altered composition of serum IgG N-glycans compared to healthy individuals. Therefore, this doctoral dissertation aims to study how the composition of total serum IgG N-glycans changes over time during anti-TNF therapy with infliximab and adalimumab. Additionally, it aims to explore the predictive potential of total serum IgG N-glycans in therapy response to anti-TNF drugs before initiating treatment. For those purposes, a total of 1513 serum samples were collected from CD patients as a part of the PANTS (Personalised Anti-TNF therapy in Crohn’s disease) study. From that number, 1315 serum samples were used to assess the prediction of therapy response to anti-TNF drugs. Additional 198 serum samples were collected at the second time point to explore the longitudinal change in the composition of total serum IgG N-glycome. The IgG was extracted from serum samples and its N-glycosylation pattern was analyzed using liquid chromatography. The results showed that the anti-TNF treatment in patients with Crohn's disease is associated with significant changes in the composition of total serum IgG N-glycans, regardless of therapy response. Specifically, the level of agalactosylated IgG N-glycans significantly decreased, while mono- and digalactosylated and sialylated glycans increased in their abundance, all of which suggest the reduced proinflammatory potential of serum IgG in patients with Crohn's disease during therapy. Furthermore, the results indicated that the composition of total serum IgG N-glycome at baseline does not hold predictive power to detect future non-responders to anti-TNF therapy.
Keywords
Crohnova bolest
imunoglobulin G
N-glikozilacija
anti-TNF terapija
HILIC-UHPLC-FLD
Keywords (english)
Crohn's disease
immunoglobulin G
N-glycosylation
anti-TNF therapy
HILIC-UHPLC-FLD
Language croatian URN:NBN urn:nbn:hr:163:049187 Promotion 2024 Study programme Title: Pharmceutical-biochemical sciences - doctoral study - university study Type of resource Text File origin Born digital Access conditions Open access Terms of use Created on 2024-06-14 11:44:56
