Biologische Effekte eines CD82-spezifischen monoklonalen Antikörpers auf die normale und maligne Hämatopoese

Tetraspanins are a family of transmembrane proteins with a typical structure, expressed in a wide range of human cells. They have been implicated in a multitude of biological processes but their distinct function remains unclear. One of the main functions seems to be the regulation of interactions between cells by stabilization of multimeric protein complexes on the cell-surface. There is little information about their role in hematopoiesis. The tetraspanin CD82 is known for an inhibition of metastasis of cancer-cells in several solid tumors. Also it has the ability to deliver coactivation signals to T-lymphocytes. Even though CD82 is strongly expressed on hematopoietic progenitors and leukemic cells its relevance for hematopoiesis was unclear. Therefore the aim of this study was to provide new insight into the relevance of expression of CD82 in normal and malignant progenitors. Because no natural ligand is known for CD82 an antibody model was used. A CD82-specific activating monoclonal antibody, 50F11, was made up for a ligand for the transmembrane CD82 molecule. In spadework adhesion and changes in cell-morphology could be induced in normal hematopoietic progenitors by this model. Within this study could be shown that malignant cells have a deficiency in CD82-induced biological effects compared to normal progenitor cells and that normal progenitor cells show distinct biological effects as a result of CD82-activation. In the first line there was CD82-induced adhesion and changes in cell-morphology as well as CD82-specific regulations of cell-adhesion molecules, especially the VLA-4 integrin. In leukemic cells these effects were significantly affected. In cDNA-array analysis Hox-D3 was identified as a possible target gene of CD82-induced signal transduction. Finally could be shown for the first time that CD82-activation by the monoclonal antibody lead to a significant reduction of LTC-IC-frequency. That means that CD82 seems to be a regulator of the earliest human hematopoiesis. In conclusion CD82 is a novel antigen involved in the regulation of the biology of hematopoietic progenitor cells and its functions are reduced in leukemic cells. The data of this study should prompt to further investigation of the role of CD82 in hematopoiesis.