Tag Archives: IL-17A

Vedolizumab Looks Promising and PPARδ Initiates Inflammation

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.

Peyer patches MHCII-GFP mouse (2)
Even though SFB stimulate Peyer’s patches, Peyer’s patches are not needed for SFB immune responses.
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.


Anti-CD3 Control of T Cells and Milk for Immune Development

Mansion Becomes Maternity Home- Life at Brocket Hall, Welwyn, Hertfordshire, 1942 D9026
Breast milk sugars are crucial for regulating the intestinal immune responses in newborns.
This week on TIBDI! Gene expression signatures of anti-TNFα non-responders are investigated, breast milk oligosaccharides regulate developing immune responses, and an anti-CD3 antibody offers hope for T cell regulation in the gut.

Inflammatory Signatures of Anti-TNFα Non-Responders

Even though anti-TNFα therapy for Crohn’s disease (CD) patients is very effective, up to 40% of patients are or become non-responders. To find out if there were differences in gene expression between these groups of patients, Dr. Raquel Franco Leal of the Hospital Clinic in Barcelona Spain examined mRNA levels of inflammatory genes in these two populations. She found that treatment with anti-TNFα effectively regulated many cytokines and chemokine genes despite the clinical outcome. However, those that achieved a clinical remission also had a number of changes in many other genes including IL1B, S100A8 and CXCL1. In contrast, refractory patients continued to have deregulated genes associated with pathways inducing IL17A. Besides introducing new drugs targets, these results reemphasize the importance of IL-17 pathways in CD.

Developing Immune Systems Need Milk

The complex immunoregulatory mechanisms needed to protect and control the human gut are developed early after birth, and are catalyzed by the colonization of the intestinal tract with bacteria. Suspecting that breast milk may protect the early intestinal tract from unwanted inflammatory responses, Dr. Y. He and colleagues investigated human milk oligosaccharides from colostrum (cHMOSs). Using human fetal intestine explants, they were able to determine that cHMOSs significantly altered immune gene expression. Their model suggests that cHMOSs attenuate pathogen-associated receptor signaling, simultaneously lowering immune cell activation and enhancing pathways needed for clearance, regulation and tissue repair.

Anti-Inflammatory Anti-CD3

T cells likely play an important role in inflammatory bowel disease (IBD) by maintaining inflammatory responses. Finding a way to specifically reduce or deactivate these cells in IBD patients could be a possible therapy. Dr. Anna Vossenkämper, together her colleagues, experimented with this idea using a special anti-CD3 antibody called otelixizumab, which is known to induce tolerance. Using mucosal biopsies from IBD patients, she was able to determine that otelixizumab could decrease pro-inflammatory cytokine production and lower the activity of multiple immune pathways. The antibody’s effects were determined to be dependent on IL-10 expression.



New and Exciting Ways to Control Th17 Differentiation

The basic unit of chromatin organization is the nucleosome, which comprises 147 bp of DNA wrapped ar
Controlling DNA packing could be a future way to alter T cell differentiation for IBD.
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.


SIRT1 and Stress Suppress Regulatory T Cells

High traffic
Is it actually our stressful lives that are setting the stage for inflammatory bowel disease?
This week on TIBDI: Human stem cell transplantation redefines T cell repertoires, SIRT1 blocks the development of induced regulatory T cells, and stress sets the stage for intestinal inflammation.

Stem Cell Transplantation Wipes CD4+ T cell Memory

Human stem cell transplantation (HSCT) is a potential treatment for severe cases of inflammatory bowel disease (IBD). One way that HSCT works is by resetting the adaptive immune system. However, few studies have looked in depth at changes in the T cell repertoires. Dr. Paolo Muraro from the Imperial College of London has now addressed this question. In a HSCT trial for multiple sclerosis (MS) patients, he and his team used high-throughput sequencing to assess T cell receptor changes in 24 patients. They found that CD4+ and CD8+ T cells responded differently to HSCT. The patients’ CD4+ T cells were redefined and had a new repertoire of clones, while the CD8+ T cells reflected pre-HSCT clones. Resetting CD4+ T cells could be one reason why that HSCT is also successful for IBD.

SIRT1 Suppresses Suppressor Induction

Regulatory T cells (Tregs) are known to be important in IBD, and work from animal models shows that they can regulate the severity of symptoms. Previous work by Dr. Tatiana Akimova and her colleagues at the Children’s Hospital of Philadelphia demonstrated a connection between SIRT1 and Tregs. To investigate this more in induced Tregs, they used SIRT1 deficient cells in the T cell transfer model of colitis. Loss of SIRT1 increased the induction of Tregs and effectively attenuated colitis development. This result was mirrored in dextran sodium sulfate colitis using an inhibitor of SIRT1 (EX-527). It will be interesting in the future to see if targeting SIRT1 will work in a therapeutic setting.

Stress Hinders Regulatory T Cells

Most IBD patients are quite aware that stress plays a role in their disease progression. However, the connection between stress and IBD remains shaky. Dr. Wei Wu of Tongji University considered that the missing link could be Treg function. To test this concept, they stressed mice and investigated the Tregs both in vitro and in vivo. Tregs from stressed mice were unable to function as normal, and some expressed IL-17 and TNFα. Prolactin, a stress mediator, mediated this change via dendritic cells. Stressed mice were highly susceptible to colitis, however, blocking prolactin reduced colitis. The authors feel that stress and prolactin set the stage for IBD development by the conversion of Tregs from effective suppressors to harmful pro-inflammatory T cells.


Lost Faecalibacteria in IBD and IL-10 Influences Inflammasomes

Lab mouse
Mice deficient in IL-10 have over active inflammasomes, which cause colitis.
This week on TIBDI: A new review is published on the gut microbiome, IBD patients have less butyrate-producing bacteria, and IL-10 deficient mice are inflamed by inflammasomes.

Healthy Gut Microbiome in the Spotlight

The state of the intestinal microbiome, in essence the microbiota genome, is proving to be an important factor during disease development and progression. However before in depth studies are done to define disease-related microbiome profiles, it’s essential to also have an idea of what profiles define a healthy state. Dr. Emily B. Hollister of the Baylor College of Medicine and Texas Children’s Hospital reviewed the current literature. In general, the gut microbiome has approximately more than 10 million non-redundant genes, and a more diverse microbiome is healthier than less diverse one. Not everyone has the same types of populations of bacteria; most healthy microbiomes can be classified into three basic enterotypes. The influence of the microbiome extends to the immune system, cellular nutrition, cellular protection, metabolic processes and the functioning of the nervous system.

Lost Faecalibacteria in IBD

Many researchers are searching for the right probiotics to treat inflammatory bowel disease (IBD). To support this kind of search, simultaneous research investigating the microbiota in IBD patients as compared to healthy ones is also necessary. Wei Wang of Wuhan University recently published evidence that some major changes in the IBD microbiota are an increase in Bifidobacteria and Lactobacilli along with a loss of Faecalibacterium prausnitzii. The loss of F. prausnitzii was especially considerable in patients with active Crohn’s disease (CD). F. prausnitzii is known to produce butyrate, which is especially important for the formation of regulatory T cells in the colon. The author suggests that instead of focusing on common lactic acid producing probiotics in IBD, patients may be better served by looking at butyrate-producing probiotic species.

IL-10 Deficient Mice Inflamed by Inflammasomes

An interesting model of IBD is the interleukin (IL)-10 deficient mouse, which develops spontaneous colitis. Dr. J. Zhang of the Medical University of South Carolina found evidence that inflammasomes play a role in this model by promoting chronic intestinal inflammation. He found that loss of IL-10 increased the levels of NLRP3 and contributed to more inflammasome activity. This caused higher amounts of active IL-1β to be produced in gut tissues, which also led to increased colitogenic Th17. Blocking inflammsome activation successfully improved the colitis of the IL-10 deficient mice, suggesting that similar strategies could be useful in IBD.