Immunological characteristics in UC patients that predict response on Vedolizumab

Inflammatory Bowel Diseases (IBD) is a heterogeneous group of diseases
regarding clinical presentation and treatment response. Incidence is increasing
and disease burden is high due to the young age at onset and the chronic nature
of the disease. Pathogenesis is complex and multifactorial based on
interactions between genetic and environmental factors, gut microbiota and the
immune system, leading to intestinal inflammation.

Alterations in T-cell subsets and homing of lymphocytes to gut mucosa were
shown to play an important role in the pathogenesis of IBD1, causing
inflammation primarily in the intestine but also in extra-intestinal tissues.
The therapeutic arsenal is directed to suppress this immune mediated
inflammatory reaction.
We previously reported different T-cell maturation profiles in the ileum/colon
mucosa of newly diagnosed IBD patients which consist of mainly naïve T cells
(Tn cells) and central memory T cells (Tcm cells) versus mainly effector memory
T cells (Tem cells). Higher frequencies of Tn cells in patients with Crohn*s
Disease (CD) were associated with a more extended and penetrating disease,
reflecting a more aggressive initial presentation.2 Furthermore we recently
identified several serum markers associated with disease activity and disease
course (s-TNF R1, s-TNFR2, sIL2R, MMP1) in newly diagnosed Crohn*s disease
patients.3

Migration of Tn * and Tcm cells to the gut is thought to be facilitated by
tertiary lymphoid organs (TLOs) containing high endothelial venules (HEVs). The
migration of T cells through HEVs is guided by different vascular addressins,
such as MAdCAM-1 and peripheral lymph node addressin (PNAd). Differences in
HEVs density and TLOs between newly diagnosed IBD patient with active disease
has been recently described.4 Increased density of colonic extrafollicular HEVs
in the early phase of disease was associated with more Tn- and Tcm cells in the
inflamed gut mucosa, which could be responsible for maintaining a continuous
inflammatory process. In patients with a lower density of HEVs (HEVlow) there
is increased infiltration of effector memory T cells in the gut mucosa. Tem
cells are known to express adhesion markers such as gut-homing markers *4*7 and
CCR9. Targeting T-cell migration to the inflamed gut in IBD patients is gaining
more and more interest.

Vedolizumab is a humanised IgG1 monoclonal antibody to *4*7 integrin approved
for the treatment of Ulcerative colitis (UC) and CD5. Our aim is to investigate
if there are immunological characteristics in UC patients that predict the
response on Vedolizumab treatment. Our hypothesis is that HEVlow patients with
more influx of *4*7+ Tem lymphocytes benefit more from Vedolizumab (anti- *4*7)
treatment compared to HEVhigh patients. We will evaluate clinical en endoscopic
activity in both UC groups on Vedolizumab.

Determine if there are immunological or patient characteristics in UC patients
that predict the endoscopic response on Vedolizumab treatment.

The study will be a prospectively observational pilot study that will be
performed at the Departments of Gastro-enterology and Hepatology, Microbiology
and Immunology and Pathology of the Rijnstate Hospital in Arnhem.

Sigmoidscopy with biopsies is a standard examination in patients with suspicion
of exacerbation. Collection of biopsies during the endoscopy, ie without
interventions like polypectomy, is a safe procedure (bleeding, perforation
<0,001). In the regular clinical practice, different endoscopists take a
variable number of biopsies (4-10) from sites of interest. The intervention in
this study comprises taking 4 additional biopsies on top of the regular
histological biopsies for immunological examination.
We take a venous bloodsample during a regular labcontrol.
At the week 16 during sigmoidscopy and blood checks the same additional samples
will be taken as at baseline.
The burden and risks for patients are minimalized and comparable to the risk
related to the regular care procedures