Therapeutic targeting of the intestinal barrier in inflammatory bowel disease and graft-versus-host disease

Published on December 31, 2015   19 min
0:00
Hello, my name is Sam Nalle, I'm a postdoctoral fellow at Genentech, and I'll be discussing therapeutic targeting of the intestinal barrier in inflammatory bowel disease and graft-versus-host disease.
0:14
In this lecture I will compare and contrast inflammatory bowel disease, IBD, and graft-versus-host disease, GVHD. I'll take a detailed look at the intestinal barrier in IBD and GVHD and I will discuss therapeutic targeting of the intestinal barrier in IBD and GVHD. The goal of this lecture is to understand the biological basis for rational therapeutic targeting of the intestinal barrier in IBD and GVHD.
0:41
Starting with inflammatory bowel disease, IBD is comprised of Crohn's disease and ulcerative colitis. Ulcerative colitis involves only the colon whereas Crohn's disease can affect the entire gastrointestinal tract. Symptoms include malabsorption, nausea, bloody or mucoid diarrhea, and weight loss. Etiology involves a combination of genetic and environmental factors, and IBD is more prevalent in developed countries in North America and Europe.
1:08
I'll give the histology of Crohn's disease for some more detailed description of IBD. Inactive IBD is characterized by crypt architectural distortion, fibrosis, or epithelial metaplasia, but no active inflammatory infiltrates such as neutrophils or eosinophils. Mild activity is characterized by rare intraepithelial neutrophils or eosinophils, and increased numbers of neutrophils or eosinophils within the lamina propria. Moderate activity contains frequent intraepithelial neutrophils or eosinophils, lamina propria distortion, and markedly increased numbers of neutrophils or eosinophils within the lamina propria. Finally, severe activity is characterized by numerous crypt abscesses, erosions or ulcerations and focal sheets of neutrophils or eosinophils within the lamina propria.
1:51
Turning to graft-versus-host disease, GVHD is the major complication associated with hematopoietic stem cell transplantation, or HSCT. HSCT is the term used with humans and BMT is the more general term that is often used in animal model studies. The transplantation procedure involves a harvest of donor stem cells, either directly from the bone marrow or by mobilization of stem cells by injection with G-CSF and harvesting peripheral blood, followed by infusion into a conditioned recipient. Prior to transplant, the recipient is treated with chemotherapy and/or radiation, which acts to immunosuppress the recipient to prevent graft rejection, reduce the number of tumor cells if applicable, reduce the number of recipient hematopoietic cells or to make space. A pre-transplant regimen is absolutely essential to the transplantation process but it contributes to GVHD, and that's a point I will discuss in more detail a little bit later in the lecture.
2:42
As I said, the main complication associated with HSCT, BMTs, is GVHD. It can lead to rash, malabsorption, nausea, weight loss, diarrhea, idiopathic pneumonia syndrome, and oral mucositis. The target organs for GVHD are the intestine, liver, skin, and lung. Histologically in the gut, it is different than IBD. In GVHD there's crypt cell apoptosis, and sparse lamina propria infiltrate. Liver involvement is much more common in GVHD than IBD. And histological features include portal inflammation, and bile duct damage.
3:17
This figure broadly compares IBD and GVHD. In GVHD the involvement of the target organs mentioned such as the skin, liver, and lung, in addition to the intestine, is common. Additionally, the characteristic intestinal GVHD histopathology includes crypt cell apoptosis and sparse lamina propria infiltrate. In IBD the liver and skin can be involved but it is not common. Histologically, IBD is characterized by crypt abscesses and dense lamina propria and lymphoplasmacytic infiltrate as mentioned previously. Because of the shared pathological mechanisms, IBD and GVHD have similar therapeutic strategies as well. I'll discuss this in more detail towards the end of the lecture.
3:56
So this is a busy slide, but the important point to take away from here is that there are many similarities between IBD and GVHD. These include shared genetic associations at microbial-sensing loci, immunological aspects, barrier dysfunction, a role for the gut microbiota and some of the extraintestinal manifestations. What I want to emphasize here is the role of barrier dysfunction in both IBD and GVHD. And this is something that I will focus on in the following slides. There's a role for barrier dysfunction in IBD and GVHD in the sense that there's a correlation with disease severity in patients and experimental models. It is required for disease in MHC-matched GVHD experimental model, which I will provide details on later. And also that the proinflammatory milieu modulates tight junction components which can affect the paracellular permeability of epithelial cells in the intestine.
4:50
Taking a closer look at the intestine epithelial barrier, here's an H&E showing the polarized epithelial layer that separates the outside, the lumen of the gut and the inside of the body. The blue portion of the epithelial cells is the apical junctional complex which regulates paracellular flux between neighboring epithelial cells. An electron micrograph in the middle shows the junctional complex of an intestinal epithelial cell. I'd like to highlight the tight junction which is the very apical portion of the cell, and forms a paracellular seal between epithelial cells. The components of the tight junction are critical for regulating the permeability of the intestinal epithelial barrier.
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Therapeutic targeting of the intestinal barrier in inflammatory bowel disease and graft-versus-host disease

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