Category Archives: Crohn’s disease

Macrophages Like IL-10 and DNA Methylation Regulates Tregs

This week on TIBDI, we see a plethora of interesting articles including a parallel publication about the necessity of IL-10 conditioning for gut macrophages and the ways that DNA methylation influences colon Treg proliferation.

IL10 Crystal Structure.rsh
IL-10 is an important conditioning factor for gut macrophages.
Intestinal Macrophages Need IL-10 Conditioning: Parallel Publication

Macrophages are an important immune cell of the intestines. For instance, CX3CR1hi macrophages capture antigens from the lumen by extending dendrites up through the epithelial layer and into the mucus to interact with passing bacteria. In the latest set of publications by the journal Immunity, parallel articles examine the relationship between macrophages and the anti-inflammatory cytokine interleukin (IL)-10. Using two different approaches, Dr. Ehud Zigmond of the Weizmann Institute of Science in Israel and Dr. Dror S. Shouval of Harvard Medical School in the United States were able to make similar conclusions.

Dr. Zigmond, using macrophage-restricted Il-10-/- and Il-10ra-/- mice, determined that macrophages with deficient IL-10 secretion were not nearly so harmful to the gut as macrophages not being able to respond to IL-10. Losing the ability to be conditioned by IL-10 made the macrophages more pro-inflammatory and led to spontaneous colitis. Dr. Shouval approached his research by creating bone-marrow chimeras with Rag2-/-Il-10rb-/- bone marrow and using the T cell transfer model of colitis. He found that loss of IL-10 signaling in innate immune cells led to colitis development. His work, unlike that of Dr. Zigmond, revealed that IL-10 conditioned macrophages are needed for proper regulatory T cell (Treg) development, and mucosal immune tolerance. He also found that pediatric inflammatory bowel disease (IBD) patients with mutations in their IL-10 receptors also had more pro-inflammatory macrophages. This work may lead to insights about why IBD develops.

Colonic Treg Proliferation Needs Uhrf1

Finding the ways that epigenetic mechanisms control T cell function and numbers is an exciting new field of research. One of the latest Nature Immunology articles adds fuel to the fire by publishing the work of Dr. Yuuki Obata of the University of Tokyo in Japan. She found that the DNA-methylation adaptor Uhrf1 was needed for Treg proliferation in the colon. This was determined by profiling genes activated in proliferating Treg after colonization with bacteria. This was then confirmed using T cell-specific Uhrf1-/- mice. Loss of Uhrf1 led to hypomethylation of a cell-cycle gene and a loss of Treg division in the colon. As a consequence of the low Treg numbers, Uhrf1-/- mice developed spontaneous colitis. It will be interesting to see if the same results can be found in the human setting.

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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.

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Notch for Oral Tolerance and Integrin Targeting in Crohn’s Disease

This week on TIBDI! Notch signaling is needed for the development of antigen sampling macrophages, and blocking integrins on T cells leads to less migration and colitis.

Macrophage
Notch signaling appears to be necessary for the development of cells that sample luminal antigens.
Notch and Intestinal Antigen Samplers

Recent literature has brought to light that macrophage-like cells expressing the chemokine receptor CX3CR1 and the integrin CD11c are needed to continually survey the antigen contents of the intestinal lumen. However, very little was known about how these cells develop. In a new publication, Dr. Chieko Ishifune of The University of Tokushima Graduate School in Japan shows that Notch signaling is involved. The Notch family is a highly conserved set up receptors designed for local cell communication, and they are involved in immune cell development. Using targeted knock-out mice, the researchers found that the downstream transcriptional regulator Rbpj was necessary for CD11c+CX3CR1+cells. Moreover, Notch1 and Notch2 were also needed. These results will help scientists learn more about oral tolerance, which could play a role in IBD.

Integrin Targeting Supported for Crohn’s Disease

The integrin α4 is suspected to be important for the recruitment of T cells to intestinal tissues. This concept is supported by the success of two blocking antibodies, Natalizumab and Vedolizumab, in Crohn’s disease (CD) clinical trials. To precisely examine the role of integrins on T cells during colitis, Dr. Elvira Kurmaeva of Louisiana State University Health Sciences Center transferred CD4+ T cells with a targeted deletion of α4 or β1 to induce colitis in immunodeficient mice. Her results indicated that loss of α4β7 lowered colitis severity. Further analysis of the colons showed that the mice had lower amounts of infiltrating CD4+ T cells, which matched results found in CD patients treated with Natalizumab. Interestingly, the migration problems were only apparent during inflammation, and didn’t affect T cell polarization.

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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.

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B Cells and Lactate Slow Down the Immune Response

Sodium lactate
A simple injection of sodium lactate can influence inflammasome activation.
This week on TIBDI: IL-35-secreting B cells inhibit immune responses; lactate interferes with inflammasome activation; and mucus and microbiota link nature and nurture.

New Inhibitory B Cells

B cells, known more for their antibody producing potential, also have a regulatory function when they secrete the anti-inflammatory cytokine interleukin (IL)-10. In a recent publication of Nature, Ping Shen and Toralf Roch of the German Rheumatology Research Center (DRFZ) in Germany discovered that IL-35-secreting B cells also play a similar role. They found that triggering co-stimulatory receptors on B cells induced IL-35 production and that IL-35-deficient B cells both hindered the recovery from a model of autoimmune disease (multiple sclerosis) and increased the immune response to an intestinal pathogen (Salmonella). Given the widespread influence of IL-35 producing B cells during infection and inflammatory disease, it will be interesting to see if they also are important for inflammatory bowel disease (IBD).

Lactate Slows Down Inflammasomes

Previous literature has indicated that the NLRP3 inflammasome is associated with Crohn’s disease (CD), and may be needed to induce protective immune responses against invading bacteria. Inflammasomes in macrophages are activated, in part, by danger signals. While danger signals mainly induce pro-inflammatory cytokine production, they also stimulate metabolic pathways, and one product that is produced is lactate. According to results produced by Rafaz Hoque of Yale University, lactate can function as a negative regulator of inflammasome activation. The team at Yale found that stimulation of the lactate receptor GPR81 could modify Toll-like receptor 4 signaling and lower subsequent NLRP3 activation. In vivo, lactate was effective at reducing acute organ injury in models with potent inflammasome activation, such as hepatitis and pancreatitis. This could mean that lactate modulates NLRP3 responses in Crohn’s disease as well.

Nature, Nurture and Mucus Production

Intestinal mucus has the important function of preventing bacterial contact with the epithelial surface. In fact, TMF-/- mice lacking a specific Golgi-associated protein (TMF/ARA160), which produce thick mucus, are generally protected from experimental colitis. However, Shai Bel of the Bar Ilan University in Israel has found that the protection is not derived from mucus alone. The intestinal microbiota are also important. The team found that the microbiota of TMF-/- mice is different from that of wild-types, and has larger populations of bacteria from the Firmicutes phylum. Even more importantly, transfer of these populations to normal mice, by co-housing, also transferred the colitis protection. This underscores the potential role of microbiota manipulation in lowering IBD susceptibility despite genetic predisposition.

Q: What’s your opinion about microbiota manipulation for IBD prevention? Feel free to contribute your thoughts here or on the LinkedIn discussion group.

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