An interspecies translation model implicates integrin signaling in infliximab-resistant inflammatory bowel disease

Abstract

Anti–tumor necrosis factor (anti-TNF) therapy resistance is a major clinical challenge in inflammatory bowel disease (IBD), due, in part, to insufficient understanding of disease-site, protein-level mechanisms. Although proteomics data from IBD mouse models exist, data and phenotype discrepancies contribute to confounding translation from preclinical animal models of disease to clinical cohorts. We developed an approach called translatable components regression (TransComp-R) to overcome interspecies and trans-omic discrepancies between mouse models and human subjects. TransComp-R combines mouse proteomic data with patient pretreatment transcriptomic data to identify molecular features discernable in the mouse data that are predictive of patient response to therapy. Interrogating the TransComp-R models revealed activated integrin pathway signaling in patients with anti–TNF-resistant colonic Crohn’s disease (cCD) and ulcerative colitis (UC). As a step toward validation, we performed single-cell RNA sequencing (scRNA-seq) on biopsies from a patient with cCD and analyzed publicly available immune cell proteomics data to characterize the immune and intestinal cell types contributing to anti-TNF resistance. We found that ITGA1 was expressed in T cells and that interactions between these cells and intestinal cell types were associated with resistance to anti-TNF therapy. We experimentally showed that the α1 integrin subunit mediated the effectiveness of anti-TNF therapy in human immune cells. Thus, TransComp-R identified an integrin signaling mechanism with potential therapeutic implications for overcoming anti-TNF therapy resistance. We suggest that TransComp-R is a generalizable framework for addressing species, molecular, and phenotypic discrepancies between model systems and patients to translationally deliver relevant biological insights.

Computational Interspecies Translation Between Alzheimer’s Disease Mouse Models and Human Subjects Identifies Innate Immune Complement, TYROBP, and TAM Receptor Agonist Signatures, Distinct From Influences of Aging

“…To perform cross-species analysis, we utilized a modified version of the translatable component regression (TransComp-R) modeling methodology ( Brubaker et al, 2020 ). The integrative analysis tool involves a multi-part workflow that is conceptually illustrated in Figure 1 .…”

“…We hypothesize that many of our findings could be validated in RNA-sequencing datasets and that additional signatures beyond the limit of detection for microarray data could be inferred using RNA-sequencing datasets. Additionally, the initial TransComp-R study ( Brubaker et al, 2020 ) involved concomitant analysis of proteomic and transcriptomic data. This study demonstrated that TransComp-R is effective for other omics data not highlighted in our study, as the computational workflow does not mathematically preclude its application to various data types.…”

“…TransComp-R is a method for concomitant evaluation of two different datasets that was previously developed in the lab ( Brubaker et al, 2020 ). Code from the initial study is available via MATLAB File Exchange 1 , and the TransComp-R-specific analyses in this study were also conducted using MATLAB (2018b).…”

“…In this study, we aimed to conduct cross-species analysis that leverages existing mouse model datasets by modeling human and mouse data concomitantly in integrated manner. We employed an interspecies analysis method previously developed in our group, Translatable Components Regression (TransComp-R; Brubaker et al, 2020 ). Using TransComp-R, we concurrently analyzed transcriptomic data from human postmortem brain and traditional amyloid AD mouse model hippocampi to identify pathway-level signatures present in human patient samples yet predictive of mouse model disease status.…”

Facing the urgency of therapies for progressive MS — a Progressive MS Alliance proposal

“…On the contrary, the need for a deep and rigorous biological assessment in early phase clinical trials (similar to what may occur in preclinical studies) has been less emphasized and seldom put into practice [32][33][34][35][36] . This is surprising since a major leap in the entire drug development pipeline (the transition from animal to human biology) takes place when early phase trials are initiated 37 (interestingly, to help cope with these difficulties, interspecies translation models are under development in autoimmune diseases 38 ).…”