טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
Ph.D Thesis
Ph.D StudentMaimon Naama
SubjectHigh-Dimensional Characterization of Inflammatory Bowel
Disease Tissue and its Reflection in the Periphery
Yields New Approaches for Disease
Management
DepartmentDepartment of Medicine
Supervisors PROF. Yehuda Chowers
ASSOCIATE PROF. Shai Shen-Orr
Full Thesis textFull thesis text - English Version


Abstract

Despite the intensive research and the developments of new biological treatments for inflammatory bowel disease (IBD), it is still an incurable disease with a significant influence on patient quality of life. The overall goal of these studies was to better characterize disease pathogenesis and response to drug therapy. We applied an in-depth analysis of peripheral blood and intestinal tissues from IBD patients and healthy controls and generated novel understanding of gene and cell changes leading to abnormal immune activity. 

In the first part of the work we used a combined statistical deconvolution and meta-analysis methodology of anti-TNFα-naive IBD patients, to identify biomarkers for anti-TNFα response. The first biomarker was on the cellular level, where abundances of plasma cells and inflammatory macrophages in pretreatment intestinal biopsies were different in anti-TNFα responders versus non-responders. High plasma-cell numbers in non-responders were validated in two independent real-life cohorts of IBD patients, naive to anti-TNFα therapy. At the gene level, pathway analysis of the cell-adjusted differentially expressed genes in biopsy between response groups suggested an upregulation of the triggering receptor expressed on myeloid cells 1 (TREM-1) and chemokine receptor type 2 (CCR2)-chemokine ligand 7 (CCL7) axes in non-responders. TREM-1 expression in blood of patients with Crohn‘s disease (CD) was predictive of anti-TNFα response with very high accuracy.

In the second part we investigated the functional relationship between the peripheral blood and intestinal mucosa, since we observed that the CCR2-CCL7 axis was upregulated in colon tissues of non-responders, although their upstream regulator TREM was downregulated in the peripheral blood. We aimed to characterize how peripheral measurements reflect immunity of the mucosa using high-resolution immunopheotyping.  Such insights can be useful for future prediction studies and understanding IBD pathogenesis. We observed different cell content in each immune compartment and a role for NK cells in the regulation of inflammation between and within each compartment, in association with the previously identified plasma cell-macrophage axis. 

In the last part we characterized immune differences between segments along the gut mucosa. Location-based IBD subtypes have distinct differences in disease presentation and risk for progression or complications, but most of the attention was so far focused on presence or absence of ileal involvement, with less attention to within-colon variation, despite the fact that the reason for segmental colonic involvement is poorly understood. We used protein and gene expression analyses in 3 independent cohorts consisting of over 400 intestinal biopsies, allowing a high-resolution overview on the importance and consequences of immune biogeography in the intestine. We found a previously unappreciated variation in cell composition and function within the colon, implying novel stratification of location-based IBD phenotypes, that may explain clinical phenomena and should be considered during disease management.

Collectively, our work utilizes high-resolution in-house and external data with advanced analytic methods to unmask and better interpret signals not previously appreciated that may improve personalized IBD therapy.