Philipp Lachenmann: DELPHI Rationale


Avrion Mitchison Prize 2008

Dr. Kirsten Neubert

Dermatology Clinic at the University of Erlangen, Department Biology of Arborescent Cells

"The proteosome inhibitor bortezomib depletes plasma cells and protects mice with lupus-like disease from nephritis"

In spite of intensive efforts, the treatment of antibody-mediated autoimmune diseases still poses a great challenge. The currently available and partly very aggressive therapeutic possibilities can improve the symptoms, but frequently fail to effect a lasting cure. The reason for this seems to be long-lived plasma cells which are involved in maintaining the humoral immunity by permanently secreting antibodies. In the case of autoimmune diseases, these cells, however, secrete large amounts of pathogenic antibodies, so-called auto-antibodies, which cause damage to tissues and organs. So far, long-lived plasma cells have been resistant to conventional drugs and radiation treatment. Therefore, the development of new selective and better tolerated therapy concepts is urgently necessary.

Systemic lupus erythematosus represents the prototype of an antibody-mediated autoimmune disease. This chronic inflammatory disease is characterized by the production of autoantibodies that cause a variety of organ damages.

In two mice models, Dr. Kirsten Neubert investigated the impact of Bortezomib on the autoantibody titer and the course of the disease. The preventive and therapeutic use of Bortezomib could prevent or at least substantially improve the lupus disease of NZB/W F1- and MRL/lpr-mice. The treatment led to a significant reduction in autoantibodies, a strong decrease of proteinuria and a dramatic increase in life expectancy without obvious side effects.

In addition, Neubert noted that Bortezomib can eliminate the largely therapy-resistant, long-lived plasma cells more effectively than conventional therapeutics. The biologist could also show that plasma cells, due to their markedly increased antibody production, respond better to Bortezomib than other cells of the immune system. This finding is another important argument in favor of the clinical use of Bortezomib. Since the established treatments are relatively unspecific and come with severe side effects, the preferential elimination of the plasma cell population could limit the range of side effects.

These findings show that Bortezomib is a promising new option for treating antibody-mediated autoimmune diseases. Since Bortezomib is already used successfully to treat multiple myeloma, relevant studies on the treatment of other antibody-mediated diseases could thus be initiated and performed more easily.



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