Langerhans cell histiocytosis : clues on pathogenesis and steps towards therapy

Abstract

The aim of thesis was to increase our insight into the pathological mechanisms behind Langerhans cell histiocytosis (LCH) by studying different aspects of healthy dendritic cells (DC), LCH cells, and a mouse model of histiocytosis. Furthermore, we initiated a study to evaluate a human monoclonal antibody directed against the cell surface protein CD1a in order to find a rational therapy for LCH. Chapter 3 describes a role for transcriptionally active beta-catenin in the differentiation and maturation of monocyte-derived DC, which are a putative precursor for LCH cells. The absence of this form of beta-catenin in LCH cells might be an important factor responsible for the immature phenotype of these pathological cells. In Chapter 4 a mouse model of malignant histiocytosis (MHSV) is re-evaluated. The conclusion is that the MHSV model represents a heterogeneous neoplastic disease with characteristics of macrophage/DC sarcomas. LCH cells express the CD1a antigen. In Chapter 5, the evaluation of a completely human anti-human anti-CD1a monoclonal antibody CR2113 is described. This antibody has cytotoxic potency on CD1a expressing cells and should, therefore, be further investigated in a pre-clinical setting for its usefulness as a therapeutic agent for LCH. Chapter 6 describes significant telomere length shortening in LCH cells suggesting that a possible intrinsic and fundamental alteration, similar to neoplastic disorders, might play a role in the etiology and/or pathogenesis of LCH.