An estimated 10 million people suffer from inflammatory bowel disease (IBD) worldwide. IBD is the umbrella term for the two conditions Crohn’ disease and ulcerative colitis. They are chronic immunological diseases characterized by extended inflammation, which causes great damage in the gastrointestinal tract. To date, there is no cure.
“As IBD is a chronic immunological disease, the contribution of human immune cells and the involvement of cytokines are very well described,” says Sebastien Tabruyn, Chief Scientific Officer at TransCure bioServices. “Nowadays, patients are treated with molecules that will block the activity of human cytokines, for example, TNFα, IL-12 and IL-23.”
The treatments available today only reduce the patients’ symptoms rather than curing the disease. It is no surprise, therefore, that many companies in the biopharma industry are working to improve the current state of IBD treatments.
The humanized mouse model is the only proper way to study IBD
Although several preclinical rodent models are used by researchers in the hunt for novel IBD treatment options, many of them come with disadvantages. The most common models are either chemically induced or genetically modified. However, the expression of human cytokines or immune cells, as well as the mimicry of the human disease physiopathology, are often not a given.
“In traditional models, researchers are often restricted to studying only one particular signaling pathway, but there is no way of gaining an overview of the different human cytokines and immune cells interacting with each other,” explains Tabruyn.
For this reason, the research team at TransCure bioServices has developed a humanized mouse model that contains the full human immune system. This allows researchers to observe the different immune cells contributing to the physiopathology of IBD, such as leukocytes and macrophages, as well as the communication between these cells and cytokines.
“All of these immune cells create a unique environment that is really the cause of IBD symptoms and is therefore the main target for researchers wanting to treat patients with the disease,” says Tabruyn. “Based on the fact that we are able to reconstitute a full human immune system in our mice, we are able to see, for example, the infiltration of leukocytes within the colon and we also know that macrophages will invade the human tissue, which induces the production of cytokines and causes inflammation.”
How to induce IBD in a mouse model
The team at TransCure bioServices uses a chemical inducer, known as Dextran Sulfate Sodium (DSS), to trigger IBD in their humanized mice. Based on the concentration of DSS and the onset of treatment, the team has established two different models, one develops the acute form of IBD, the other develops a chronic form of IBD.
“DSS causes damage to the colon mucosa, resulting in the infiltration of immune cells that will not only try to resolve the damage but will also induce the inflammatory response typical for the disease,” Tabruyn explains. “The symptoms we observe, include loss of body weight, diarrhea, and bleeding in the stool. We score these three parameters to get an overall idea of the disease severity in the humanized mouse models.”
In the acute model, the research team only uses one cycle of DSS, but the symptoms of IBD remain up to 12 days after the initiation of the DSS treatment. Investigational new drugs can then be tested for their efficacy and how well they reduce the onset of the symptoms in the first phase of the disease. A drug that acts well upon the immune cells and blocks the mechanisms involved in IBD, will therefore reduce the overall scoring of characteristic symptoms.
To induce the chronic disease model, the team at TransCure bioServices uses three cycles of DSS separated by a washout phase. Whereas the first cycle of DSS induces IBD, the second and third cycles are meant to maintain the damage to the mucosa.
“The chronic model allows us to observe whether a drug will speed up the process of recovery,” Tabruyn explains. “The entire experiment for chronic models lasts about 35 days. By treating this model with immunomodulators or anti-TNFα, we can see that the recovery is sped up, and after approximately 20 to 25 days, the model is back to normal.”
Why do researchers prefer humanized mouse models?
Many of the companies working with TransCure bioServices’ humanized mouse model, want to test the efficacy, safety, and pharmacology of their drugs and compare them with Humira®, a marketed antibody that binds and inhibits TNFα to treat IBD. Others have developed drugs that modulate the T-cell response, targeting receptors expressed on the surface of T-cells.
“With this mouse model of IBD we are not only able to look at the reduction of symptoms at onset and over time, but using flow cytometry, we are also able to observe whether the target is expressed, where, and on how many cells,” Tabruyn says. “The flow cytometry technique has been developed to analyze the peripheral blood and for the analysis of the colon. By digesting the colon, we are able to analyze all the human immune cells that have infiltrated the colon after treatment.”
The team at TransCure bioServices has also developed techniques based on the endoscopy colitis scaling. “We use an endoscope designed for mouse experiments, which allows us to determine more accurately how the disease developed in the colon,” Tabruyn explains. “When we sacrifice the animal at the end of a study, we usually also measure the length of the colon. It is well known that after IBD you have a shortening of the colon, which is an important factor to see whether the therapy actually reduced this characteristic shortening.”
As a next step, the colons are either immunohistochemically analyzed to observe the overall infiltration of human immune cells, as well as the damage done to different parts of the colon. In the end, researchers will have combined results of the living animal’s clinical score and the histological and endoscopic score.
“By looking at the tissular level and by characterizing the infiltration, we can answer questions, including whether the compound triggered the recruitment of T lymphocytes in the mucosa, or whether it impaired the activation of T cells or the production of cytokines,” says Tabruyn. “Overall, the extensive results you get from this model, allow for a more realistic patient comparison and give a better idea of the studied drug’s mechanism of action.”
Are you struggling to find the right mouse model for your IBD compound? Talk to the experts at TransCure bioServices and benefit from their expertise!
Images via TransCure bioServices & header image via Lightspring/Shutterstock.com
Author: Larissa Warneck, Science Journalist at Labiotech.eu