Tag Archives: Adhesion molecules

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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The Crohn’s Disease Gender Bias and Neutrophils Disrupt the Gut

Neutrophils
Neutrophils (with purple irregular nuclei) can shed proteins that disrupt the intestinal barrier.
This week on TIBDI! Neutrophils shed a protein that disrupts the intestinal barrier, hormones and T cells are behind Crohn’s disease gender skewing, and CD31 is the newest way to make dendritic cells anti-inflammatory.

Neutrophils Bust Up the Intestinal Barrier

During inflammatory bowel disease (IBD), neutrophils gather at sites of inflammation and often migrate through the intestinal epithelial barrier. A new model described by Dr. Dominique A. Weber and Dr. Ronen Sumagin now shows how dangerous this behavior is for intestinal wound healing. They found that neutrophils shed junctional adhesion molecule-like protein (JAML) during epithelial transmigration. JAML binds to a receptor found on epithelial cells called coxsackie-adenovirus receptor (CAR), and JAML and CAR interactions cause epithelial barriers to become leaky. While this leakiness may be needed for initial efficient immune cell infiltration, shed JAML prevents the barrier from regaining normal function and stops wound closure. Experiments showed that blocking JAML-CAR interactions could lead to accelerated wound repair. This discovery could help treat IBD-induced intestinal ulcerations.

Why Crohn’s Disease Prefers Women

There is a general acceptance that the prevalence of Crohn’s disease (CD) is higher in women than in men. W.A. Goodman and R.R. Garg of Case Western Reserve University School of Medicine suspected that this gender bias might be the same in spontaneous models of CD. This is, indeed, the situation. Female SAMP1/YitFc (SAMP) mice were more predisposed to spontaneous CD and had impaired regulatory T cells with low frequencies as compared to the male SAMP mice. An investigation of the T cells revealed that male SAMP T cells responded much differently than female SAMP T cells to estrogen signals. While the male T cells responded by increasing immunosuppressive functions and expanding regulatory T cells, the female cells were resistant to these signals. Finding ways to make female T cells sensitive to estrogen signals could decrease female susceptibility to CD.

More Ways to Induce Anti-inflammatory Dendritic Cells

CD31 is expressed on many types of immune cells and endothelial cells, and it is mainly seen as an adhesion and migration molecule. Recent evidence has shown that it also has inhibitory function on T cells, which means that it might have inhibitory functions in other cells. Marc Clement of the French National Institute of Health and Medical Research (INSERM) has now found that this is, indeed, the situation with dendritic cells (DCs). Signaling via CD31 prevented DC maturation, migration and reduced pro-inflammatory signaling cascades. CD31-stimulated DC also preferentially polarized T cells towards a regulatory phenotype, and transfer of these DCs to a rodent model of multiple sclerosis delayed disease development. These results suggest that CD31 may also be potentially interesting for IBD.

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