Grants Awarded

Role of the Granzyme Inhibitor Proteinase Inhibitor-9 (PI-9) in Langerhans Cell Histiocytosis

Principal Investigator
Carl Friedrich Classen MD
University Childrens Hospital Rostock – Duisburg, Germany

Date of Award
December 2007

Amount of Award

Layperson Summary
Langerhans cell histiocytosis (LCH) is a disease characterized by irregular proliferation of Langerhans cells – a subgroup of dendritic cells (DC) – with a broad spectrum of clinical manifestations, ranging from small solitary bone lesions to multi-organ diseases which may be fatal despite extensive therapeutical efforts. The mechanisms by which the disease develops, however, is largely unknown.

In several malignant diseases, especially lymphomas, it has been found that expression of a protein called Proteinase inhibitor 9 (PI-9) is correlated to a bad prognosis. PI-9, which is highly expressed in normal Langerhans cells, is the only known endogenous antagonist of the protein granyzme B (GrB). GrB is a cytotoxic protease, by which cytotoxic T-lymphocytes (CTL) kill their targets, like malignant or virus-infected cells.

The normal function of Langerhans cells and other DC is antigen presentation to T-lymphocytes, leading to activation of specific immune responses. In this context, PI-9 protects cells – both the cytotoxic lymphocytes themselves and the antigen-presenting cells – from misdirected GrB. Thus, it is involved in normal immune regulation. However, it is completely unknown whether PI-9 is also expressed in LCH, and whether it may contribute to the disease course, e.g. by conferring resistance towards cytotoxic T-lymphocytes.

In the present work, we want to analyze PI-9 expression retrospectively in specimens of LCH patients with different clinical course. Further, regulation of PI-9 upon in-vitro stimulation will be studied in normal Langerhans cells, Langerhans cells induced in vitro, and fresh tumor cells from LCH patients.

The aim is first to define a possible relationship between PI-9 expression and LCH subtype, second to identify the role of PI-9 in the development and prognosis of LCH, and finally to find out whether this might represent an aim for new, targeted therapy modalities.