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.
This week on TIBDI: NOD2 and IFNγ work together to recruit cells to the small intestine, and a microRNA offers an interesting way to control Th17 differentiation.
NOD2 Behind Intestinal T Cell Recruitment
One of the most important receptors involved with Crohn’s disease (CD) is NOD2, a pattern recognition receptor that recognizes bacterial cell walls. Dr. Xingxin Wu of the Yale University School of Medicine investigated its involvement in an acute intestinal disease model induced by systemic anti-CD3. His results provide unique insight into infiltration dynamics of the characteristic CD8+ T cells found in the small intestine of this model. He discovered that NOD2 stimulation was needed for optimal infiltration. Without these signals, chemokines, specifically CXCR3-ligands, were not secreted by macrophages, dendritic cells and stromal cells. This prevented CD8+ T cells from leaving the circulation and entering the intestinal lamina propria. Moreover, the loss of CD8+ T cells in the small intestine led to reduced IFNγ, which also plays a role in stimulating immune cell chemotaxis.
Unexpected MicroRNA Control of Th17
During low oxygen conditions, immune cells upregulate transcription factors that turn on genes that help them cope with the hypoxia. One of these transcription factors, HIF-1α, also contributes to the differentiation of Th17 cells, which are important in the pathogenesis of inflammatory bowel disease (IBD). In an extremely interesting Nature Immunology publication, Dr. Haopeng Wang of the University of California in San Francisco described how the microRNA Mir210 inhibited HIF-1α expression and Th17 differentiation. MicroRNAs are small RNAs that prevent gene expression. By controlling the abundance of Mir210, he was also able to influence the numbers of Th17 T cells differentiated in vitro. Using the T cell transfer model of colitis with genetically manipulated T cells, which lacked Mir210 expression, he found that Mir210-deficient T cells caused increased numbers of Th17 and worsened symptoms. The authors suggest that drugs that function similarly to Mir210 could be interesting therapeutics.
Wang, H., Flach, H., Onizawa, M., Wei, L., McManus, M. T., & Weiss, A. (2014). Negative regulation of Hif1a expression and T. Nature Immunology, 1–10. doi:10.1038/ni.2846
Wu, X., Lahiri, A., Haines, G. K., Flavell, R. A., & Abraham, C. (2014). NOD2 Regulates CXCR3-Dependent CD8+ T Cell Accumulation in Intestinal Tissues with Acute Injury. The Journal of Immunology. doi:10.4049/jimmunol.1302436
This week on TIBDI: Soluble CD83 may be a useful anti-inflammatory factor, bacterial proteomics reveals new Crohn’s disease biomarkers, and GATA3 is an important transcription factor for group 3 innate lymphoid cells.
Soluble CD83, the Anti-Inflammatory Molecule
In order to control signals of membrane-bound receptors, the body often employs soluble versions that act as ligand sponges, preventing signaling on the stationary, active molecule. This is also the case with the pro-inflammatory, co-stimulatory molecule CD83, which is expressed on activated dendritic cells as well as activated T and B cells. The researcher Jenny Eckhardt, located at the University Hospital Erlangen in Erlangen, Germany, realized that this process might be involved in controlling intestinal inflammation and sought more answers with her team. They found that administration of soluble CD83 prevented colitis in a mouse model of inflammatory bowel disease. This was associated with improvements in many inflammatory mediators. They also determined that the positive effects of soluble CD83 were induced by indoleamine 2,3-dioxygenase, which is known to have immunosuppressive properties.
Metaproteomics for Crohn’s Disease Monitoring
Catherine Juste of the French National Institute for Agricultural Research (INRA) has zeroed in on new molecular parameters for Crohn’s disease (CD), which may impact future diagnosis, monitoring and treatment. While many have focused on categorizing the intestinal microbiota signatures of CD patients, her team went one step further and looked at the microbial protein signature. They found that many proteins from Bacteroides species were over represented. Many of the over-expressed proteins were for the invasion and breaching of the mucosa. This unique method of looking at bacterial proteins could lead to new targets to help treat CD.
GATA3’s New Identity
GATA3 is a transcription factor most well known for its role in inducing T cell differentiation towards Th2. However, Nicolas Serafini of the Pasteur Institute and French Institute of Health and Medical Research (INSERM) has now found that GATA3 has many more uses including the induction of group 3 innate lymphoid cells (ILC3). ILC3 are essential for generating a wave of epithelial cell-activating IL-22 after intestinal bacteria infection. ILC3 are also characterized by the expression of the Th17-associated transcription factor RORγt. GATA3 was necessary for these cells during development, and their loss led to a reduced resistance against an intestinal bacterial pathogen.