Anti-CD20 treatments and the lymphocyte membrane: pathology for therapy.
Therapeutic antibodies directed against the CD20 surface protein of B-lymphocytes are efficient means of controlling the growth and survival of malignant B-lymphocytes. The mechanisms of anti-CD20 antibody action remain in great part unexplained. However, we show that incubation of CD20+ cells with therapeutic antibodies such as Rituximab results in the redistribution of the CD20 marker in plasma membrane rafts. Rafts are specialized membrane organizations of sphingolipids and cholesterol in the plasma membrane outer leaflet that serve as signalling platforms in lymphocytes and other cells, and allow transmembrane propagation of most receptor-mediated extracellular signals. This redistribution of CD20 to rafts is not acutely toxic to lymphoma cells, but leads to long-lasting perturbations of transmembrane signalling and contributes to the progressive elimination of B-lymphoma cells. The accumulation of CD20 in rafts causes downmodulation of raft-associated protein tyrosine kinases and modifies the spatial relationships between raft lipid and protein components. Such modifications of the raft structure and function are likely to cause relatively long-lasting perturbations of the lymphoma cell physiology and contribute to the elimination of the Rituximab-targeted cells.
Borisch
B
B
Département de Pathologie, Université de Genève, Schweiz.
Semac
I
I
Soltermann
A
A
Palomba
C
C
Hoessli
D C
DC
D000595:Amino Acid Sequence; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D058846:Antibodies, Monoclonal, Murine-Derived; D018951:Antigens, CD20 / Q000276:immunology*; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001402:B-Lymphocytes / Q000276:immunology*; D014408:Biomarkers, Tumor / Q000032:analysis; D002462:Cell Membrane / Q000276:immunology; D006801:Humans; D016393:Lymphoma, B-Cell / Q000188:drug therapy*; D021962:Membrane Microdomains / Q000276:immunology; D008969:Molecular Sequence Data; D000069283:Rituximab
D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D018951:Antigens, CD20; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D000069283:Rituximab