Gene expression in intestinal transplant patients treated with vedolizumab. An exploratory analysis.

Background: Two patients with different disease backgrounds underwent intestinal transplantation (ITx) and afterwards had either acute cellular rejection (ACR, patient 1) or chronic allograft enteropathy (CAE, patient 2). Both patients received vedolizumab, which successfully managed their rejection episodes and have been free of complaints ever since. Vedolizumab is a monoclonal antibody that targets the integrin α4β7, expressed in inflammatory cells of the intestine, and blocks the interaction with its endothelial cell receptor MAdCAM-1, preventing migration of these cells into the intestinal mucosa. This study aims to explore the effects of vedolizumab on the transcriptome of the gut mucosa in these patients. Methods: Small intestinal biopsies taken before and during treatment with vedolizumab were analysed by RNA sequencing. Nine sequential biopsies from patient 1 (five before treatment), seven from patient 2 (four before treatment), and three from another patient with ACR that received regular treatment (steroids, tacrolimus and anti-thymocyte globulin), where analysed for differential expression of their whole transcriptome associated to clinical, endoscopic, and histopathological data. Results: Twenty-one genes from the three patients were differentially expressed when treatment with vedolizumab was present. Pathway enrichment analyses showed decreased expression of genes involved in zinc homeostasis and no effect on vedolizumab targets was found. However, individual gene expression analyses showed that genes related to cell migration and adhesion were affected by treatment with vedolizumab. Patient-related effects were detected at this level on apoptosis-related genes in patient 1 and ischaemia-related genes in patient 2. Conclusion: This is the first study presenting gene transcript profiling of small intestinal biopsies of patients with ACR and CAE after ITx that were treated with vedolizumab. This drug may affect cell migration and adhesion other than, or in addition to, the α4β7-MAdCAM-1 axis. These broader effects than initially proposed may be at play to resolve rejection in these patients.