Tag Archives: TNFa

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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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.

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The Dark Side of Retinoic Acid and Interleukin-22

Salmonella species growing on XLD agar - Showing H2S production
IL-22 secretion during intestinal inflammation gives Salmonella a competitive advantage.
This week on TIBDI: Th1 cells can activate macrophages with innate signals alone, retinoic acid is no hero in Crohn’s disease, and interleukin-22 allows some pathogens to thrive.

TCRs Are Not Always Needed

Macrophages and T cells play are important in inflammatory bowel disease (IBD). Learning about how these cells interact could lead to more insight about how IBD progresses. Hope O’Donnell of the University of Minnesota has now gleaned new insights about their interactions. She looked into the mechanisms behind non-cognate stimulation of Th1 cells (non-TCR stimulation) and their ability to secrete macrophage-activating IFNγ. Using genetically manipulated mice and a Salmonella infection model, her results show that Th1 (and CD8+) cells produce plenty of IFNγ as long as they are exposed to Toll-like receptor ligands and products of activated inflammasomes like interleukin (IL)-18 and IL-33. This study underscores the flexibility and strength of the adaptive immune response.

The Pitfalls of Retinoic Acid

Retinoic acid is the current darling of those studying anti-inflammatory responses as it has been shown that retinoic acid can lead to regulatory T cell development. To determine if retinoic acid was actually lowered during Crohn’s disease (CD), Dr. Theodore J. Sanders of the Blizard Institute in London measured retinaldehyde dehydrogenase (RALDH) activity in cell samples collected from CD patients and controls. In all of the dendritic cells and macrophages tested, the RALDH activity (ability to produce retinoic acid) was increased in CD patients compared to controls. Surprisingly, blocking retinoic acid signaling actually decreased the ability of monocytes to differentiate into TNFα-producing macrophages in in vitro tests. This would suggest that retinoic acid is less helpful in CD than what one would expect.

Salmonella Exploits Interleukin-22

Interleukin-22 is a cytokine that is designed to boost immune defenses at the gut-lumen interface. It induces antimicrobial peptide release along with factors that sequester essential metal ions (like iron) that bacteria need to grow. Dr. Judith Behnsen of the University of California has now discovered that these processes can be exploited by certain pathogens, like Salmonella. She found that IL-22 deficient mice were much less susceptible to Salmonella overgrowth. The reason was that Salmonella has the ability to compensate for the loss of ambient metal ions, while this is not the situation for many commensals. This allows Salmonella to create for a rather large niche for itself, while IL-22-induced processes decimate the competition.

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NLRP3 Beats Bacteria and Anti-TNFα Needs No Help

Citrobacter freundii Gram stain
NLRP3 helps prevent intestinal colonisation of Citrobacter bacteria.
This week on TIBDI: we learn why NLRP3 polymorphisms are interesting for Crohn’s disease, and the combination treatment of anti-TNFα and methotrexate isn’t better than anti-TNFα alone.

Continue reading NLRP3 Beats Bacteria and Anti-TNFα Needs No Help

T cells in Mucosal Healing and ETS-1 in Fistulae

Crohnova nemoc
TNF and bacteria may work together to support fistulae development.
This week, we take a break from the top journals to explore other options. Interesting finds include a correlation between mucosal inflammation and naïve T cells in inflammatory bowel disease, and danger signals may increase fistula formation.

Remission Changes Mucosal T cells

In a study performed by the Karolinska Institute, it was found that the relative proportion of naïve T cells (CD4+CD45RA+) falls about 50% during mucosal healing in inflammatory bowel disease (IBD) patients. Simultaneously, there was an increase of CD4+ T cells expressing CD62L, a cell adhesion molecule that allows them to enter lymph nodes. Relative percentages of memory and early-activated T cells did not change. These observations were not correlated with a single type of treatment. Similar trends were seen with glucocorticoids and anti-TNF treated patients. The results may suggest that, during remission, a shift in naïve T cell trafficking occurs, leading to more naïve T cells entering the lymph nodes instead of the intestines.

Fistula Pathology

An unfortunate consequence of Crohn’s disease (CD) is the development of intestinal fistulae; tunnels that form between the intestines and other areas of the body. The cells lining these tunnels are called transitional cells and have characteristics of epithelial, mesenchymal and myofibroblast cells. Because this process is reminiscent of tissue remodeling, a Swiss team looked specifically at the expression of the transcription factor ETS-1, which is known to be increased in invasive breast cancers. They found that ETS-1 was increased in transitional cells, and TNF and the bacterial antigen, muramyl dipeptide, could increase its transcription.

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