Objective Vedolizumab, a monoclonal antibody directed against the integrin heterodimer α4β7, is approved for the treatment of Crohn’s disease and ulcerative colitis. The efficacy of vedolizumab has been suggested to result from inhibition of intestinal T cell trafficking although human data to support this conclusion are scarce. We therefore performed a comprehensive analysis of vedolizumab-induced alterations in mucosal and systemic immunity in patients with inflammatory bowel disease (IBD), using anti-inflammatory therapy with the TNFα antibody infliximab as control.
Design Immunophenotyping, immunohistochemistry, T cell receptor profiling and RNA sequencing were performed using blood and colonic biopsies from patients with IBD before and during treatment with vedolizumab (n=18) or, as control, the anti-TNFα antibody infliximab (n=20). Leucocyte trafficking in vivo was assessed using single photon emission computed tomography and endomicroscopy.
Results Vedolizumab was not associated with alterations in the abundance or phenotype of lamina propria T cells and did not affect the mucosal T cell repertoire or leucocyte trafficking in vivo. Surprisingly, however, α4β7 antibody treatment was associated with substantial effects on innate immunity including changes in macrophage populations and pronounced alterations in the expression of molecules involved in microbial sensing, chemoattraction and regulation of the innate effector response. These effects were specific to vedolizumab, not observed in response to the TNFα antibody infliximab, and associated with inhibition of intestinal inflammation.
Conclusion Our findings suggest that modulation of innate immunity contributes to the therapeutic efficacy of vedolizumab in IBD.
Trial registration number NCT02694588
- inflammatory bowel disease
- crohn’s disease
- ulcerative colitis
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SZ, ER, CMD and KA contributed equally.
PCR, AF and SS contributed equally.
Contributors SZ, KA, CMD and ER wrote the manuscript with input from all coauthors. AA, KA, JB, BS, CC, ME, SN, SS, DS and SZ contributed to patient recruitment. UL, MM and MZ performed In-labelling of leucocytes and SPECT. A Strigli conducted immunohistochemical analyses. AA, JB, ME and SZ performed endomicroscopy. CMD, HE, SCK and MFP conducted immunophenotyping. ER and AF performed TCR sequencing. KA, WHP, NH, A Sinha and PR performed RNA sequencing. SZ, AF, PR, DK and SS coordinated the study.
Funding Work was supported by the Deutsche Forschungsgemeinschaft (DFG) (ZE814/4-1 and SCHR 512/14-1), the European Research Council (ERC Starting Grant agreement no. 336528, to SZ), the H2020 SYSCID program under the grant agreement no. 733100, the BMBF as part of the e:Med framework (‘sysINFLAME’, grant 01ZX1306), SysMedIBD EU FP7 under grant agreement no. 305564 and the DFG Excellence Clusters ExC306 ‘Inflammation at Interfaces’ (SS, AF, DK, PR, SS, SZ) and ‘Center for Regenerative Therapies’ (SZ).
Competing interests SZ: consulting fees: Biogen, Ferring, Janssen-Cilag, Takeda; Lecture fees: Abbvie, Falk, Ferring, MSD, Roche, Takeda. KA: grant support: Pfizer. AA: consulting fees: Boston Scientific; lecture fees: Boston Scientific. SS: consulting fees: AbbVie, Boehringer, Merck, Janssen, Pfizer, Takeda; lecture fees: AbbVie, Boehringer, Merck, Janssen, Pfizer, Takeda.
Patient consent Obtained.
Ethics approval The ethics committee of the Christian-Albrechts-Universität zu Kiel approved the study (A 124/14).
Provenance and peer review Not commissioned; externally peer reviewed.
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