Retinoid orphan receptor gamma t (rorγt) promotes inflammatory eosinophilia but is dispensable for innate immune-mediated colitis

by Alvaro Torres-Huerta, Katelyn Ruley-Haase, Theodore Reed, Antonia Boger-May, Derek Rubadeux, Lauren Mayer, Arpitha Mysore Rajashekara, Morgan Hiller, Madeleine Frech, Connor Roncagli, Cameron Pedersen, Mary Catherine Camacho, Lauren Hollmer, Lauren English, Grace Kane, David L. Boone

Inflammatory bowel diseases (IBD) result from uncontrolled inflammation in the intestinal mucosa leading to damage and loss of function. Both innate and adaptive immunity contribute to the inflammation of IBD and innate and adaptive immune cells reciprocally activate each other in a forward feedback loop. In order to better understand innate immune contributions to IBD, we developed a model of spontaneous 100% penetrant, early onset colitis that occurs in the absence of adaptive immunity by crossing villin-TNFAIP3 mice to RAG1^-/- mice (TRAG mice). This model is driven by microbes and features increased levels of innate lymphoid cells in the intestinal mucosa. To investigate the role of type 3 innate lymphoid cells (ILC3) in the innate colitis of TRAG mice, we crossed them to retinoid orphan receptor gamma t deficient (Rorγt^-/-) mice. Rorγt^-/- x TRAG mice exhibited markedly reduced eosinophilia in the colonic mucosa, but colitis persisted in these mice. Colitis in Rorγt^-/- x TRAG mice was characterized by increased infiltration of the intestinal mucosa by neutrophils, inflammatory monocytes, macrophages and other innate cells. RNA and cellular profiles of Rorγt^-/- x TRAG mice were consistent with a lack of ILC3 and ILC3 derived cytokines, reduced antimicrobial factors, increased activation oof epithelial repair processes and reduced activation of epithelial cell STAT3. The colitis in Rorγt^-/- x TRAG mice was ameliorated by antibiotic treatment indicating that microbes contribute to the ILC3-independent colitis of these mice. Together, these gene expression and cell signaling signatures reflect the double-edged sword of ILC3 in the intestine, inducing both proinflammatory and antimicrobial protective responses. Thus, Rorγt promotes eosinophilia but Rorγt and Rorγt-dependent ILC3 are dispensable for the innate colitis in TRAG mice.

A core outcome set for evaluating the effectiveness of mixed-diagnosis falls prevention interventions for people with Multiple Sclerosis, Parkinson’s Disease and stroke

by Nicola O’Malley, Susan Coote, Fiona McCullough Staunton, Eileen O’Connor, Amanda M. Clifford

Introduction

Clinical trials evaluating the effectiveness of falls prevention interventions for people with Multiple Sclerosis (MS), Parkinson’s Disease (PD) and stroke measure heterogeneous outcomes, often omitting those meaningful to patients. A core outcome set (COS) is a standardised set of outcomes that should be assessed in all trials within a research area. The aim of this study was to develop a COS for evaluating mixed-diagnosis falls prevention interventions for people with MS, PD and stroke in non-acute and community settings, with input from relevant stakeholder groups.

Methods

Previously published research undertaken by the team, including a qualitative study with 20 patients and a review of the literature, were used to derive a longlist of potential outcomes. Outcomes were prioritised for inclusion in the COS using a three-round online Delphi survey. A multi-stakeholder, consensus meeting was conducted to agree upon the final COS and to provide a recommendation for a single outcome measure for each outcome in the COS.

Results

Forty-eight participants were recruited across four stakeholder groups (researchers, patients, clinicians, and service-planners/policymakers). A total of 42 participants (87.5%) completed all three rounds of the surveys. Sixty-two outcomes were considered for inclusion in the COS throughout the Delphi process. A total of 15 participants attended the consensus meeting where they agreed upon the final COS and accompanying measurement instruments: fall incidence, injurious fall incidence, quality of life, falls self-efficacy, fear of falling, activity curtailment due to fear of falling, and cost-effectiveness. Attendees at the consensus meeting recommended that the proposed mechanism of impact of an intervention is considered when selecting additional outcomes outside of those in the COS to assess.

Conclusions

This study identified a COS for evaluating the effectiveness of mixed-diagnosis falls prevention interventions for people with MS, PD and stroke. It is recommended that this COS and accompanying measurement instruments be used in all future trials in this research area so that findings can be combined and compared.