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.
This week on TIBDI we get an overload on new Th17 research including Th17 induction via segmented filamentous bacteria and dendritic cells, the role of methyltransferases during T cell differentiation, and, my own article describing how TLR6 stimulation in the gut leads to increased Th17.
Segmented Filamentous Bacteria, DCs and Th17
It is already well described that segmented filamentous bacteria (SFB) are associated with the induction of Th17 cells in the gut, and that Th17 is associated with inflammatory bowel disease (IBD). However, the mechanisms behind the induction were not entirely clear. Yoshiyuki Goto and Casandra Panea of Columbia University Medical Center worked together to answer these questions, and found that dendritic cells (DCs) were the missing link. They determined that DCs presented SFB via MHC class II molecules to T cells, and induced SFB-directed Th17 cells. These interactions were not limited to areas of lymphoid tissue, but also happened in the small intestinal lamina propria. Interestingly, RORγt+ innate lymphoid cells simultaneously played an inhibiting role also via MHC class II molecules.
TLR6 Involved with Intestinal Inflammation
Pattern recognition receptors, like those from the Toll-like Receptor (TLR) family, alert the immune system when pathogens enter areas of the body. While this system is essential for fighting infection, the same receptors also induce inflammation during IBD. To learn more about TLR6 in intestinal inflammation, Dr. M.E. Morgan of Utrecht University in the Netherlands and her colleagues looked at immune responses induced in the gut both in vitro and in vivo. They found that stimulation of TLR6 in the gastrointestinal-associated lymphoid tissue supported the induction of Th1 and Th17 cells, and oral feeding of TLR6 ligands induced Th17 cells. Mice deficient in TLR6 had lower numbers of Th1 and Th17 cells, and were also protected from experimental colitis suggesting that TLR6 could be an interesting candidate for future IBD therapeutics.
Chromatin Control of T Cell Differentiation
Histone methyltransferases modify histones (by adding methyl groups to lysine residues) to control DNA packing and gene accessibility. These kinds changes could impact IBD. Recent research has indicated that the methyltransferase G9A controls a repressive modification called H3K9me2 that influences T cell differentiation. Dr. Frann Antignano of the University of British Columbia in Canada now sheds more light on this process. She found that G9A dynamically inhibited the differentiation of regulatory T cells and Th17, and that loss of G9A specifically led to more activity of the Foxp3 and Rorγt genes, which are the master transcription factor of regulatory T cells and Th17 cells respectively. Specifically eliminating G9A from T cells transferred during the T cell transfer colitis model increased regulatory T differentiation and lowered disease. This could mean that targeting histone methyltransferases could be a potential IBD therapy.