Although pharmacologic advances have improved the care of patients with IBD, up to one third of patients have refractory disease with significant morbidity. Mucosal healing is a major clinical endpoint in achieving deep remission and there is a clinical need for better mechanistic understanding of this process to support diagnostic and therapeutic strategies. The recent discovery of IL-23 responsive lymphocytes along with genome- wide association studies (GWAS) identification of single nucleotide polymorphisms (SNPs) in the IL-23R gene locus associated with IBD have highlighted a critical role for IL-23-dependent immunity in IBD. IL-23 responsive innate lymphoid cells (called group 3 ILCs or ILC3) have been identified to play a key role in promoting mucosal healing. GWAS have also identified genetic variants in TNFSF15 that strongly associate with IBD and stratify therapeutic response to biologic therapy. My K08 funded research led to the discovery that CX3CR1+ mononuclear phagocytes produce TNFSF15/TL1A and play a critical role in regulating ILC3 effector cytokine production. These findings place TL1A as a central molecule regulating the effector function of mucosal ILC3, but a better mechanistic understanding of the cells and molecules involved in mediating the ILC3 response is required to develop genetic diagnostics and therapeutic strategies to promote healing. To this end, this proposal will: (A) generate novel mouse models to evaluate the role for TL1A in specific intestinal cell populations in mouse models of colitis; (B) evaluate the microbial pathways contributing to intestinal CX3CR1+ mononuclear TL1A expression in vitro and in vivo. Findings from this work have the potential to translate into novel therapeutic targets to promote mucosal healing in IBD. !
Inflammatory bowel disease (IBD) affects over 1 million Americans, resulting in significant morbidity and mortality. This proposal aims to provide a mechanistic understanding of the cells and molecules involved in the mucosal immune response and will provide new insight into diagnostic and therapeutic strategies for IBD. !
|Castellanos, Jim G; Woo, Viola; Viladomiu, Monica et al. (2018) Microbiota-Induced TNF-like Ligand 1A Drives Group 3 Innate Lymphoid Cell-Mediated Barrier Protection and Intestinal T Cell Activation during Colitis. Immunity 49:1077-1089.e5|