Grant Awarded in 2008


A Knock-In Mouse Model Mimicking Abnormal
Langerhans Cell Trafficking in Langerhans Cell Histiocytosis


Principal Investigator
Barrett J. Rollins MD, PhD
Dana-Farber Cancer Institute, Harvard Medical School - Boston, Massachusetts USA

Date of Award
September 2008

Amount of Award
$50,000

Layperson Summary
Langerhans cell histiocytosis (LCH) is a rare disease that mainly affects children. Cells of the immune system, called Langerhans cells (LCs), accumulate in various organs and cause damage, in severe cases even leading to death. The cause of this disease and the factors leading to its progression are still unknown.

Chemokine receptors act as signposts on cells of the immune system. In healthy people the chemokine receptor CCR6 is involved in retaining resting LCs in the skin while the chemokine receptor CCR7 directs mature LCs to the lymph nodes, but they never appear at the same time on the same cells. However, in LCH both of these receptors are present on abnormal LCs. The simultaneous appearance of these receptors is probably not the cause for the disease, but could be responsible for the misguided accumulation of LCH cells in different organs. We want to test the importance of this finding in mice by genetically modifying their LCs to display these two chemokine receptors simultaneously. During this project we will assemble the tools that allow us to create these mice as well as generate the genetically modified mice and start the complex and lengthy breeding process.

Our mouse model of abnormal LC migration will help us understand the progression of LCH and other histiocytic disorders and give insight into disease mechanisms. Many pharmaceutical companies are developing drugs that block chemokine receptors.  If our work shows that these receptors contribute to the manifestations of LCH, then we can plan to test the effects of chemokine receptor blockers in patients with the disease.

Twelve Month Report
Chemokine receptors act as signposts on cells of the immune system. In healthy people the chemokine receptor CCR6 is involved in retaining resting Langerhans cells (LCs) in the skin while the chemokine receptor CCR7 directs mature LCs to the lymph nodes, but they never appear at the same time on the same cells. However, in Langerhans cell histiocytosis (LCH) both of these receptors are present on abnormal LCs. The simultaneous appearance of these receptors is probably not the cause of the disease, but could be responsible for the misguided accumulation of LCH cells in different organs. We wanted to test the importance of this finding in mice by genetically modifying their LCs to display these two chemokine receptors simultaneously. Developing a mouse model of LCH would be an important step toward being able to test new treatments in the laboratory before trying them in patients.

Although our laboratory has successfully developed many strains of genetically modified mice, this is a technically demanding process which can fail for any number of reasons. In 2007, we were supported by the Histiocytosis Association when we attempted to develop an LCH mouse model using a rather traditional approach. Unfortunately, that project was unsuccessful and so we proposed an alternative approach in the current grant application. But before we embarked on the complex process of developing the new mice, we needed to understand why the first approach failed so that we would not repeat any of the steps that might have led to that failure. After several months of work, we finally determined that there was something inherent in the genes we were trying to manipulate that was preventing their proper function in the mice we were creating. This was incredibly important information that indicated that we had to completely revise the approach we were taking to developing the mouse model.

We have since made some additional discoveries that should improve our chances for developing a reliable mouse model of LCH in the future. We will continue working in this area based on the progress we have made in our understanding of chemokine receptor expression in the mouse as a result of Histiocytosis Association funding.

Publications

 

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