Histiocytoses and Hematology - research projects
Hemophagocytic Lymphohistiocytosis (HLH) Clinical Studies
The mononuclear-phagocyte system comprises two major cell types, the macrophages and the dendritic cells, which are mainly antigen-presenting cells. Accordingly, histiocytoses are classified as either diseases with macrophage accumulation, including (familial) hemophagocytic lymphohistiocytosis (FHL or HLH), or disorders with the antigen-presenting Langerhans cell as the central cell, with Langerhans cell histiocytosis (LCH), previously called Histiocytosis X, as the most frequent disease.
We have a deep and long-lasting interest in this field. FHL is a rapidly fatal disease that most typically affects infants and young children, with a median survival of 1-2 months as reported in the 1980's. One arm of the studies has focused on clinical issues, such as the development of diagnostic guidelines (1991 and 2004) and therapeutic protocols. In collaboration with clinical scientists worldwide, we coordinated the international treatment protocols (HLH-94 and HLH-2004) with the major aim to improve the therapeutic results. New clinical studies on HLH treatment are in progress.
Whereas some studies focus on improved diagnostics, others focus on the outcome of stem cell transplants (SCT) and on late sequelae and more specifically CNS sequelae. Our ultimate aim is to improve the outcome, in all respects, of patients affected by HLH.
We are also interested in improving outcome for patients affected by various forms of secondary HLH, including infection-associated HLH, malignancy-associated HLH and rheuma-associated HLH.
HLH Biological studies
Based on earlier biological studies, in 1996 we suggested that FHL might be caused by an apoptosis defect, and we were able to show that FHL is caused by a deficiency in apoptosis triggering. Later, in 1999, in collaboration with other research groups, mutations in the perforin gene were revealed in a subset of FHL patients.
Our subsequent studies revealed that perforin (PRF1) mutations explain 20-40% of the FHL cases. Additional genetic studies have revealed another gene causing FHL, the gene STX11, and a deep intronic mutation and an inversion of the gene UNC13D. Interestingly, it appears as if mutations in FHL causing genes may be associated with an increased risk of developing malignancies, and we are considering whether this may be due to deficient surveillance of tumor transformed cells.
One hallmark of FHL is deficient cytotoxic activity. We are also interested in the cytotoxic cell biology in more detail, and recent studies have shown that there is defective cytotoxic lymphocyte degranulation in syntaxin 11-deficient patients.
Langerhans Cell Histiocytosis (LCH)
Langerhans cell histiocytosis (LCH) is a potentially fatal disease of unknown cause. If only one organ is involved the survival is excellent whereas the 3-year survival in multisystem LCH with risk organ involvement is around 60-70%. In addition, there is a risk of developing permanent complications to LCH. Our aims are to elucidate etiology and pathophysiologic mechanisms of LCH, and to reduce mortality and sequelae in LCH.
In very long-term follow-up studies, up to 39 years, we have shown that permanent CNS sequelae are common in LCH. With the aim to improve survival and reduction of sequelae, we try to improve monitoring of the course of the disease and evaluate clinical, laboratory and imaging tools for monitoring of disease activity. Certain cytokines have been identified in our lab as markers of disease in LCH associated to disease activity. We are eager to add novel therapeutic approaches to the treatment of this disease. We participate actively in the international multicenter study LCH-IV on treatment and natural history of pediatric LCH patients, in which we coordinate the part on CNS-LCH (“Stratum V”).