Inflammatory bowel diseases (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), are chronic inflammatory immune-mediated diseases of the gastrointestinal tract. Two-thirds of IBD patients will develop severe disease, with complications that will require frequent surgeries and hospital admissions, and will seriously impair their quality of life. The ultimate clinical challenge of precision medicine in IBD is to find predictive markers to anticipate the development of severe disease and to monitor treatment in these patients.In the first part of my PhD thesis, we have carried out several studies monitoring the biologics used in IBD patients with severe disease. We have evaluated the pharmacokinetics of the following biologics used in IBD patients: infliximab, vedolizumab, and ustekinumab. We have focused on measuring trough levels (TLs) (defined as the serum drug level measured just before the next drug administration) early on after initiating biologic treatment to predict patient outcomes, including long- term responses in patients treated with infliximab and vedolizumab. In addition, we are currently conducting a prospective multicentric study that aims to design a pharmacokinetic model of infliximab at induction in IBD patients (EudraCT: CT 2015- 004618-10) (End of study expected by December 2019 but interim analysis available in the present work). Moreover, we have reported on the efficacy of ustekinumab in a large national cohort of highly refractory CD patients and have also examined the benefit of early measurement of ustekinumab TLs in these patients. Finally, we have reported novel findings on the impact of different wash-out periods (defined as the time frame between the discontinuation of one biologic and the initiation of a second biologic on the pharmacokinetics of the second-line biologic). Altogether, over the past 3 years, our data suggest the importance of measuring TLs early on during induction to predict long-term response to biologics during maintenance therapyIn the second part of my PhD thesis, we have analysed the inter-variability of the immune response in healthy subjects. Inflammation is the obvious key driver and underlying mechanism of disease severity in IBD. Therefore, the magnitude of inflammation must help define the phenotype of mild to severe disease. Delineating the inter-variability of the immune response in a healthy cohort constitutes a fundamental step to uncovering the genetic factors underlying this variability. We have performed whole blood cell cultures in a highly selected population of more than 400 healthy subjects stimulated with several Toll-like receptor (TLR) agonists and a T-cell receptor (TCR) antagonist. We found that the magnitude of the immune response (the high- or low-cytokine producer phenotype) was independent of the cytokine measured and the TLR agonists used. Thus, a donor exhibits a specific immune (cytokine) response or “immunotype” across cytokines released and TLR stimulation. Importantly, the high- or low-cytokine producer phenotype was different and did not overlap between the TLR and TCR stimulation conditions. In other words, a donor who is ahigh-cytokine producer following TLR stimulation will not be a high-cytokine producer following TCR stimulation (or the inverse). Therefore, we have defined TLR- or TCR- related Immunotypes (IT) as “a grading classification of the magnitude of the cytokine immune response” with IT1, IT2, and IT3 as low, intermediate, and high immunotypes. This suggests that two independent TLR and TCR ITs (TLR IT1 and TCR IT3) can co-exist in the same subject. We are now currently evaluating the genetic markers underlying these ITs before validating them in large cohort of IBD patients with mild-to-moderate and severe disease.This PhD thesis provides some data suggesting that the assessment of the pharmacokinetics of biologics early on at the initiation of treatment could help predict how the patient will respond in the long run. In parallel, this PhD thesis provides some advances in the understanding of the inter-variability of the immune response, a fundamental step before the identification of potential genetic markers underlying the inter-variability of inflammation and, hence, the severity of disease in IBD. / Doctorat en Sciences biomédicales et pharmaceutiques (Médecine) / info:eu-repo/semantics/nonPublished

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Crohn's disease (CD) and ulcerative colitis (UC) are inflammatory bowel diseases (IBD) that result in considerable morbidity and impaired quality of life. Although IBD is ubiquitous, heterogeneity in incidence is noted geographically and among different ethnicities, presumably due to genetic and environmental factors. The incidence and prevalence of IBD has plateaued in many Western countries but are increasing in developing nations. There is a lack of data on IBD pertaining to the Chinese population. / Studies were conducted to determine the characteristics of IBD in the Chinese population. The incidence of IBD in the Chinese population is a fifth to a tenth of Western societies but has risen sharply over the past decade. Several distinct demographic and phenotypic features were noted in the Chinese IBD population. Genetically, Chinese CD patients do not harbour the NOD2/CARD15 polymorphisms unlike Caucasian CD subjects. ANCA and ASCA are serologic markers that are highly specific for UC and CD respectively in the Chinese but ANCA sensitivity in Chinese UC is significantly lower than in Caucasian UC, while quantitative IgG ASCA (and not IgA) is a moderately sensitive test for CD. These markers are useful in differentiating UC from CD. A Chinese translation of the Inflammatory Bowel Disease Questionnaire (IBDQ) was developed and validated to be reliable, sensitive to change and reproducible. A prospective cross-sectional survey of the disease-related knowledge of Chinese and Australian IBD patients identified a low level of IBD-knowledge but with a similar quality of life as Caucasians with IBD. There was a similar but high rate of use of complementary alternative medicines in both populations. / These studies were instrumental in: describing IBD in the Chinese population; developing a Chinese IBD database; acquiring techniques of investigating genetic polymorphisms and ASCA serology; devising the Chinese IBDQ to open up IBD trials to Hong Kong; and identifying knowledge deficiencies to help plan a targeted education programme. / Leong Rupert Wing-Loong. / Adviser: Joseph J.Y. Sung. / Source: Dissertation Abstracts International, Volume: 73-01, Section: B, page: . / Thesis (M.D.)--Chinese University of Hong Kong, 2004. / Includes bibliographical references. / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [201-] System requirements: Adobe Acrobat Reader. Available via World Wide Web.

Thesis (Ph. D.)--Ohio State University, 2006. / Title from first page of PDF file. Includes bibliographical references (p. 160-170).

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2007. / Härtill 4 uppsatser.

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An imbalance of the T cell immune response is observed in inflammatory bowel disease. Intestinal microbes have been linked to the disease and the disease process leads to severe mucosal injury and systemic translocation of bacterial products. Aminosalicylates, corticosteroids and immunomodulators reduce these aggressive activities but are associated with potentially serious adverse events. The aim of this work was to investigate the effects of administration of prebiotics and probiotics that modulate the gut microflora and modulate the immune response, in ameliorating severity of colitis. The prebiotic, high amylose maize resistant starch was used at two different concentrations. A number of Bifidobacterium and Lactobacillus strains were used as probiotics. BALB/c mice were administered the prebiotics and probiotics and intrarectally infused with 2.5 mg trinitrobenzene sulfonic acid (TNBS) in 45% ethanol, thereby generating colitis. Mucosal cytokine responses, colonic microbial profiles and disease activity indices were monitored. The 5% concentration of high amylose maize resistant starch delayed progression of TNBS colitis as evidenced by reduced weight loss, lesser tissue damage, abrogation of the expression and synthesis of IFN-?? and upregulation of IL-4 and IL-10. The 30% concentration of high amylose maize resistant starch exacerbated the inflammatory response with an increase in acetic acid, coliforms and endopores in the colonic contents. Three strains of bifidobacteria and 3 strains of lactobacilli were individually screened for their activity against TNBS colitis. Each strain had a distinctive effect on the course of colon inflammation. Lactobacillus fermentum VRI 003 was selected for further study as it provided most protection. The ratio of immunosuppressive cytokines to pro-inflammatory cytokines was restored closer to the normal T cell cytokine levels. It also reduced the incidence of translocation of enteric bacteria into the spleens. Dosing a minimum daily dose of 6x109 CFU L. fermentum VRI-003 to ulcerative colitis patients in remission and maintained on standard therapy for 6 months prevented the exacerbation of symptoms, including diarrhea and abdominal pain, and improved the patient general well being. It also suppressed production of IFN-?? and sustained IL-10 levels. Moreover, absence of endospores and lower numbers of coliforms were detected in the faeces of UC patients during L. fermentum VRI-003 treatment. In summary, 5% high amylose maize resistant starch and L. fermentum VRI 003 prevented colon inflammation by changing the nature of the T cell immune response and modifying the colonic microflora in the murine model. The clinical evidence supported these findings.

Thesis (Ph. D.)--University of California, Riverside, 2009. / Includes abstract. Available via ProQuest Digital Dissertations. Title from first page of PDF file (viewed March 20, 2010). Includes bibliographical references. Also issued in print.