This proposal addresses two critical gaps in the treatment of pediatric ulcerative colitis (UC). The first gap is the need for patient-specific immunologic profiles that inform precision UC treatments to achieve remission efficiently on the safest medication. The second gap is the need to investigate therapeutic mechanisms that promote epithelial homeostasis and, thereby, improve mucosal healing, one of the best predictors of sustained remission in UC. We previously demonstrated that treatment nave pediatric UC can be distinguished from colon-only Crohn's disease by increased mucosal expression of type 2 and type 17 immune response genes, as measured by a custom real time RT-qPCR microfluidic array. Furthermore, we observed that high mucosal expression of the type 2 cytokines IL13 and IL5 was associated with 5-fold increased odds of 12-month clinical remission in pediatric UC. We have also shown that IL33, a cytokine that induces type 2 cytokine production by innate lymphoid cells (ILCs), is increased in pediatric UC and is protective in oxazolone colitis in mice, in part through preservation of mucin-producing goblet cells. Maintenance of the mucus layer is critical for epithelial barrier function and mucosal healing. Our preliminary data supports that IL33 induces goblet cell differentiation by promoting the production of IL13 by group 2 ILCs (ILC2s). Our overarching hypothesis is that the induction of mucosal type 2 cytokines by ILC2s in a subset of pediatric UC patients protects the epithelium in the setting of uncontrolled type 17 inflammation and leads to superior treatment outcomes.
In Aim 1, we will apply our array to tissues from treatment-nave patients in a large prospective pediatric UC inception cohort and validate the type 2 gene expression signature for predicting treatment-specific clinical and endoscopic outcome. We will also integrate our array data with microbiome and transcriptome data sets from this cohort to identify key associations between type 2 immunophenotype and microbial colonization/function and host epithelial homeostasis/repair pathways, respectively.
In Aim 2, we will identify ILC2s as a key source of type 2 cytokines in pediatric UC using multicolor flow cytometry and single-cell RNA sequencing. We will also determine the effect of autologous peripheral blood ILC2s on human primary colonoid growth and differentiation using a colonoid-immune cell co-culture system.
In Aim 3, we will determine the effect of ILC2s on epithelial repair and differentiation, and treatment response during chronic colitis in mice using the T cell transfer and chronic DSS models. Upon completion of Aim 1, we will have validated an assessment of UC immunophenotype for predicting clinical remission and mucosal healing in response to specific treatments in a large well-defined UC inception cohort, which will inform precision patient-specific treatment in UC. Upon completion of Aim 2 and 3, we will have determined whether ILC2s are capable of promoting epithelial growth and goblet cell differentiation in humans and relevant murine models of chronic colitis. This deliverable would support the development of therapies that promote ILC2s or ILC2 cellular therapy for advancing mucosal healing in UC.
Over 500,000 Americans, including 23,000 children, suffer from ulcerative colitis (UC) a disorder of chronic inflammation of the large intestine. This proposal will determine whether in UC activation of a certain type of immune response called a type 2 immune response predicts response to specific therapies, and whether we can use cells that promote a type 2 immune response called group 2 innate lymphoid cells to improve healing.
| Waddell, Amanda; Vallance, Jefferson E; Hummel, Amy et al. (2018) IL-33 Induces Murine Intestinal Goblet Cell Differentiation Indirectly via Innate Lymphoid Cell IL-13 Secretion. J Immunol : |
