This week’s TIBDI update discusses new evidence showing a gut specific role for Vedolizumab, the role of PPARδ in intestinal inflammation, and the interesting ability of segmented filamentous bacteria to induce lymphoid tissues.
Vedolizumab Demonstrates Gut Specificity
Vedolizumab is an antibody that blocks the α4β7 integrin, and the literature suggests that this leads to gut-specific inhibition of T cell infiltration during inflammation. This is an important characteristic because other Crohn’s disease (CD) therapies, which lead to systemic changes in immune responses, are associated with harmful infections. To further investigate this property, Dr. Tim Wyant of Takeda Pharmaceutical International coordinated a phase I trial with healthy volunteers. Each volunteer was given a dose of Vedolizumab and then subjected to either an injected hepatitis B vaccination, an oral cholera vaccination, or a matched placebo. Volunteers given Vedolizumab and vaccinated for hepatitis B had similar amounts of protective antibodies as the placebo group. However, in the groups given the oral cholera vaccination, the Vedolizumab-treated volunteers had significantly reduced amounts antibodies. This further supports the concept that Vedolizumab has selective effects on the gastrointestinal immune response.
PPARδ and Intestinal Inflammation
The transcription factor Peroxisome proliferator-activated receptor δ (PPARδ) is highly expressed in the intestinal tract, and is believed to be involved with chronic inflammation. However, mouse studies looking at its involvement in colitis were not entirely conclusive. To shed more light on its role in colitis and colorectal cancer, Dr. Dingzhi Wang of Arizona State University engineered a PPARδ-deficient mouse. With this tool, he found that loss of PPARδ lowered the severity of the dextran sodium sulfate colitis model and reduced cellular infiltration and cytokine expression. PPARδ-deficiency also significantly reduced the emergence of colitis-associated tumor growth. Further experimentation demonstrated that PPARδ-deficiency reduced COX-2 expression and PGE2 production. PPARδ could be an interesting target for future inflammatory bowel disease (IBD) drugs.
Segmented Filamentous Bacteria Builds Its Own Centers
In a recent post, an article from the journal Immunity discussed the role of segmented filamentous bacteria (SFB) and dendritic cells in T helper 17 (Th17) cell development. This article was not alone. The journal also published a related article from another laboratory in the same issue. The companion article describes work by Dr. Emelyne Lécuyer of the Universite ́ Paris Descartes-Sorbonne. She looked at the relationship between SFB-dependent immune responses and gastrointestinal-associated lymphoid tissues. She found that lymphoid tissues generated during gestation and shortly after birth weren’t necessary for SFB-dependent responses. SFB; unlike a nonpathogenic, control bacteria; could induce tertiary lymphoid structures, which were capable of supporting both Th17 cell development and IgA responses.
- Lécuyer, E., Rakotobe, S., Lengliné-Garnier, H., Lebreton, C., Picard, M., Juste, C., et al. (2014). Segmented filamentous bacterium uses secondary and tertiary lymphoid tissues to induce gut IgA and specific T helper 17 cell responses. Immunity, 40(4), 608–620. doi:10.1016/j.immuni.2014.03.009
- Wang, D., Fu, L., Ning, W., Guo, L., Sun, X., Dey, S. K., et al. (2014). Peroxisome proliferator-activated receptor δ promotes colonic inflammation and tumor growth. Proceedings of the National Academy of Sciences of the United States of America. doi:10.1073/pnas.1324233111
- Wyant, T., Leach, T., Sankoh, S., Wang, Y., Paolino, J., Pasetti, M. F., et al. (2014). Vedolizumab affects antibody responses to immunisation selectively in the gastrointestinal tract: randomised controlled trial results. Gut. doi:10.1136/gutjnl-2014-307127