VEDOLIZUMAB REDUCES IGG+ PLASMA CELLS AND FCγR SIGNALLING IN TREATMENT RESPONDERS

Introduction
Vedolizumab (VDZ) is a monoclonal antibody that targets the gut-homing receptor α4β7. Despite its widespread use as a frontline therapy for ulcerative colitis (UC) and Crohn’s disease, its mode of action (MOA) remains unclear. Previously, we documented that response to VDZ associated with size loss of gut-associated lymphoid tissues (GALT) (1). To further understand drug MOA, here we aimed at defining the relationship between GALT attrition and resolution of inflammation.

Methods
Tissue immunofluorescence (IF) was performed on two independent cohorts of UC patients (n=60, n=21) studied longitudinally pre- and post-VDZ. Peripheral blood mononuclear cells from UC patients (n=56) were examined at week 0 (pre-VDZ) and 14 (post-VDZ) by flow cytometry, while intestinal biopsies were analyzed in a subset of patients. Transcriptomic analyses were performed in a third cohort of 401 UC patients and 243 controls where bulk RNA-sequencing was performed on intestinal biopsies (2). Finally, data from a fourth validation cohort (n=31) was examined pre- and post-VDZ (3).

Results
IF analysis of follicular IgD⁺ naïve B (FB) cells, BCL6⁺CD3^- GC B cells and total CD3⁺ T cells, led to the identification of three GALT types: organized aggregates with readily visible GC and demarcated B/T cell zones, organized aggregates without GC, and poorly organized aggregates (Fig1A). When comparing pre- and post-VDZ, responders (R) had a significant reduction in GALT organization, while no change was seen in non-responders (NR). The number of FB cells was reduced post-VDZ in R but not NR (Fig1B), while no change was seen in T cells (Fig1C). The reduction in FB cells was validated by means of transcriptomics (Fig1D). To explore potential consequences of GALT attrition, we analyzed GALT-derived circulating β7⁺ plasmablasts (PB) and control β7^- plasmablasts. The frequencies of β7⁺IgG⁺ and β7⁺IgA⁺ PBs were reduced post-VDZ in R but not NR (Fig1E). No change was observed in β7^- PBs post-VDZ (Fig1F). Among β7⁺ PBs, there was a greater reduction in IgG⁺ PBs compared to IgA⁺ PBs (Fig1G). Furthermore, colonic IgG⁺ plasma cells (PC) were significantly reduced post-VDZ in R but not in NR (Fig1H). To evaluate IgG-mediated proinflammatory function, we studied the expression of FcγR-pathway genes in colonic biopsies. Importantly, the FcγR-pathway was enhanced in inflamed tissues from UC patients (Fig1I-J) and was significantly reduced in R but not NR post-VDZ (Fig1K).

Conclusions
Our work demonstrates a novel effect of anti-α4β7 blockade that results in intestinal lymphoid aggregate attrition through impaired recruitment of naïve B cells, leading to the suppression of IgG-driven immune responses and proinflammatory FcγR signaling. These data highlight the targeting of GALT as a novel therapeutic paradigm in IBD.

(1) Canales-Herrerias 2023 (Preprint)
(2) Argmann 2023
(3) Arijs 2018