P061 Response to anti-α4β7 therapy in Ulcerative colitis is associated with lymphoid aggregate attrition through impaired recruitment of naïve lymphocytes
Canales-Herrerias, P.(1)*;Uzzan*, M.(1);Seki*, A.(1);Czepielewski, R.S.(2);Verstockt, B.(3);Dunn, A.(1);Dai, D.(1);Ko, H.M.(4);Furtado, G.C.(5);Tokuyama, M.(1);Tankelevich, M.(1);Meringer, H.(1);Cossarini, F.(1);Jha, D.(1);Paulsen, J.D.(6);Nakadar, M.Z.(6);Wong, J.(6);Sharma, K.(1);Rosenstein, A.(1);Dawson, T.(7);Singh, H.(1);Lim, J.(8);Lira, S.A.(5);Yajnik, V.(9);Reboldi, A.(10);Petralia, F.(11);Vermeire, S.(3);Polydorides, A.D.(6);Randolph, G.J.(2);Colombel , J.F.(1);Mehandru, S.(1);
(1)Icahn School of Medicine at Mount Sinai, Gastroenterology, New York, United States;(2)Washington University School of Medicine, Pathology & Immunology, St. Louis, United States;(3)University Hospitals Leuven, Gastroenterology and Hepatology, Leuven, Belgium;(4)Columbia University, Pathology, New York, United States;(5)Icahn School of Medicine at Mount Sinai, Immunology, New York, United States;(6)Icahn School of Medicine at Mount Sinai, Pathology- Molecular and Cell Based Medicine, New York, United States;(7)Icahn School of Medicine at Mount Sinai, Human Immune Monitoring Center, New York, United States;(8)Icahn School of Medicine at Mount Sinai, Microbiology, New York, United States;(9)Takeda Pharmaceuticals, Gastroenterology, Boston, United States;(10)UMass Chan Medical School, Pathology, Worcester, United States;(11)Icahn School of Medicine at Mount Sinai, Genetics and Genomic Sciences, New York, United States;
Vedolizumab (VDZ) is a frontline drug for Ulcerative colitis (UC) and Crohn’s disease (CD) that targets integrin α4β7, a gut-homing receptor. Despite significant use, the mechanism(s) of action (MOA) of VDZ remain unclear.
Peripheral blood mononuclear cells (PBMC) from UC patients (n=43) and paired intestinal biopsies in a subset (n=12) were examined at week 0 (pre-infusion) and 14, by multiparameter flow cytometry (FC). TNF inhibitor (TNFi)-treated UC patients served as controls. Drug MOA was further examined in detail in murine models using single-cell RNA-seq, FC, conventional and immunofluorescent microscopy (IF). Photoconvertible (Kikumi) mice were used to study cellular trafficking after anti-α4β7 (DATK32) antibody (mAb) administration. Two distinct UC cohorts (n=42 and n=21 respectively) were used to correlate GI immune alterations following VDZ with mucosal healing.
A significant decrease of colonic and ileal naïve B and T cells was noted in VDZ- but not in TNFi-treated patients (Fig 1A), while total T cell-frequencies were unchanged. Circulating gut-homing plasmablasts (β7+) were significantly decreased post-VDZ.
Peyer’s patches (PP) in anti-α4β7-treated mice showed a rapid loss of cellularity associated with decreased follicular naïve B cells (Fig 1B). Single-cell RNA-seq also demonstrated a significant loss of follicular B cells, including a unique population of epithelium-associated B cells following anti-α4β7 mAb. In Kikumi mice, anti-α4β7 mAb impaired non-photoconverted follicular B cells and T cells into photoconverted PPs (Fig 1C) demonstrating that loss of PP cellularity was due to impaired cellular ingress.
In VDZ-treated (but not TNFi-treated) UC patients, lymphoid aggregate (LA) size was significantly reduced in treatment responders compared to non-responders (defined by absence of histological inflammation). A distinct validation cohort further confirmed that reduced lymphoid aggregate size was associated with response to VDZ-therapy (Fig 1D).
VDZ is associated with impaired ingress of naïve B and T cells, resulting in attrition of intestinal LA. Reduced LA size is associated with VDZ response. Immune inductive site targeting represents a novel MOA of VDZ in patients with UC.