Project Title:

GENOME-WIDE DETECTION OF POSSIBLE CHROMOSOMAL IMBALANCES IN LCH LESIONAL CELLS USING BAC MICROARRAYS
 

Investigator:

Nicola Elizabeth Annels, MD

Leiden University Medical Center; Leiden - The Netherlands

Amount:

$40,000

Length:

One year

Summary

Langerhans cell histiocytosis is not only a disease of unknown cause but also there is still a lot of controversy about whether this is a malignant disease. Defining what a tumor is is not easy. However, in LCH there is clearly a dividing clonal cell population, a feature widely considered to be characteristic of a malignant tumor. Further evidence that a cell is a tumor cell is that it has genetic abnormalities. Genetic studies carried out to date in LCH have given conflicting or inconsistent results. Thus, this project aims to provide a comprehensive study that will show whether there is indeed a genetic cause behind LCH. Due to the fact that the disease process underlying LCH has so far remained unknown, many current treatments for LCH are empirical. Thus, only once the nature of the disease has been resolved can a rational approach to treatment be achieved.

Project Title:

IDENTIFICATION OF LYTIC GRANULE EXOCYTOSIS-RELATED CANDIDATE GENES INVOLVED IN PATHOGENESIS OF HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS

Investigator:

Sasa Radoja, PhD

Children's Research Institute - Washington, D.C.

Investigator:

E. Marion Schneider, MD

University of Ulm - Ulm, Germany

Amount:

$40,000

Length:

One year

Summary

Hemophagocytic lymphohistiocytosis (HLH) is a life threatening immune disorder that usually presents during infancy or early childhood.  Dysfunction of a particular type of immune cells, called "killer cells" is thought to be the basis for development of HLH. By comparing the blood samples from HLH patients and healthy individuals, our goal is to find new genes that are responsible for altered function of the killer cells in HLH patients. We believe that findings originating from the studies proposed in this application will allow us to better understand how this disease develops and eventually help us find more efficient ways for its treatment.

Project Title:

CIGARETTE SMOKING AND TSLP IN THE PATHOGENESIS OF PULMONARY LCH

Investigator:

Robert Vassallo, MD

Pulmonary and Critical Care Medicine, Mayo Clinic - Rochester, Minnesota

Amount:

$40,000

Length:

One year

Summary

Although numerous studies suggest that tobacco smoke causes, or induces pulmonary LCH, the mechanisms by which this happens are not known. The this application, we will investigate a number of mechanisms by which smoking, together with a new factor called thymic stromal lymphopoietin (TSLP), lead to the formation of pulmonary LCH. The reason we have chosen to look at the role of TSLP in LCH is because of recent studies in patients with allergic dermatitis - an allergic inflammatory condition of the skin which is associated with many Langerhans cells infiltrating the skin - produces human TSLP. In these patients, biopsy of skin shows many Langerhans cells infiltrating at the site of production of TSLP protein. This was an important observation because TSLP is a very potent stimulant and regulator of Langerhans cell function.

Since the airways of the lung (air-conducting passages), are lined by cells similar to those found in the skin (airway epithelial cells), and because of the fact that normal Langerhans cells in the lung are located just beneath this layer of epithelial cells, we formulated the hypothesis that smoking induces airway epithelial cells to produce TSLP. This TSLP protein causes Langerhans cells in the vicinity to become activated, and induce other inflammatory cells to accumulate, leading to the early lesion of pulmonary LCH. Another factor produced by Langerhans cells from bony LCH lesions is prostaglandin E2 (PGE2). PGE2 may play an important role in this disease because it can alter the way in which Langerhans cells interact with T cells (another major culprit cell found in the LCH lesion). We propose that smoking stimulates the production of PGE2 by Langerhans cells. In doing so, smoking favors the production of certain factors (cytokines) that lead to further recruitment of inflammatory cells in the lungs.

The theories proposed are supported by many lines of experimental and published evidence and will be tested by a number of experimental approaches that will proceed independently of each other. Understanding how pulmonary LCH occurs in smokers is essential in the quest for new treatments. In addition to smoking cessation, new targets for therapy may include inhibitors of TLSP and/or PGE2. These studies are also essential to help us sort out how pulmonary LCH differs from other forms of LCH that are not associated with cigarette smoking. The support provided by this grant will also be of critical importance to enable continued investigation in the natural history, long-term prognosis,
and other ongoing pulmonary LCH research at the Mayo Clinic.

Project Title:

GENE EXPRESSION IN LANGERHANS CELL HISTIOCYTOSIS

Investigator:

Kenneth L. McClain, MD, PhD

Baylor College of Medicine, Texas Children's Cancer Center - Houston, Texas

Amount:

$40,000

Length:

One year

Summary

Better therapies for Langerhans cell Histiocytosis cannot be designed until we understand what causes the disease to occur. It is known that several genes that regulate the immune system are making their products at much higher levels than normal immune cells. However, the number of genes studied so far is rather limited, less than 20.

We have developed a method to isolate the individual immune system cells that are in the diseased tissues of patients with LCH and study the genetic information that is being used from 96 genes. Our methods allow us to measure the amount of each gene and compare that number to cells from different patients. The importance of this is that differences in the kinds and amounts of genes being used in LCH patients with only bone or skin lesions can be compared to those with liver, spleen, lung, or bone marrow LCH. The latter group of patients typically is harder to treat and only about half of them survive. By understanding the differences between these two groups of patients we will be able to concentrate on a few of the most important genes and learn why they are working in abnormal ways.

Another goal of the project is to identify patients early in their treatment who have too high a chance of not being cured by current treatments and giving them additional therapy early so they may have a better chance of survival.

Project Title:

STUDY OF DENDRITIC CELL-DERIVED MULTINUCLEATED GIANT CELLS IN LANGERHANS CELL HISTIOCYTOSIS

Investigator:

Christine Serve-Delprat, PhD

Molecular Immunobiology Clinic; INSERM - Lyon, France

Amount:

$40,000

Length:

One year

Summary

LCH may affect any age group, from the newborn to the elderly, but clinical features, pathogenesis, and treatment outcome derives from the pediatric experience. The incidence for LCH of around 1:200,000 children per year, peaks at 1-3 years. LCH is an 'orphan' disease that belongs to the Histiocytoses. Besides visceral organ involvement, 80% of patients with multisystem disease develop bone lesions; the cells that resorb bone are myeloid-derived multinucleated giant cell (MGC) called osteoclasts.

The course of LCH is often unpredictable, varying from spontaneous regression and resolution to rapid progression and death or repeated recurrence and recrudescence with a considerable risk of permanent sequelae since tumors destroy the tissue where they grow. Inside tumors, multinucleated giant cells (MGC) express different phenotypes, depending on the tissue they colonize. The origin and the functions of these MGC are unknown. However we demonstrated that normal DC are able to fuse and transdifferentiate into osteoclasts. It is thus reasonable to propose that MGC observed in LCH lesion come from the fusion of pathogenic DC and are able to destroy tissues, especially bone matrix. MGC would consequently be responsible for the sequelae associated to this disease, sometimes leading to a fatal issue.

The objective is to study the DC-derived multinucleated giant cells in LCH. The aim is to design therapeutic agents able to prevent DC fusion and their transdifferentiation into osteoclasts. Thus, monoclonal antibodies able to block formation and/or function of DC-derived MGC will be produced. The hope is that preventing MGC formation from LCH-DC will abrogate or at least reduce tissue destruction in all LCH lesions.