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Regeneration of protective plasma cell memory after immunoablative therapy in NZB/W mice used as model of systemic lupus erythematosus

Prof. Radbruch (first supervisor), Prof. Burmester (second supervisor), Prof. Hiepe (mentor), DRFZ and Charité

For the first time, we have shown that autoreactive longlived (memory) plasma cells play a critical role in maintenance of autoimmunity and refractoriness to immunosuppressive therapies including biologics such as B cell depletion therapy. That means for new therapeutic strategies that long – lived plasma cells and their precursors (B cells) should be targeted. There is the proof of concept that immunoablation including antithymocyte globulin (ATG) can eradicate autoimmunity. The problem of this treatment is that the reconstitution of the immune system needs a long time-period with increased risk of infections. Moreover, autoimmunity including secondary autoantibody-mediated disorders can appear. We assume that empty plasma cell niches in bone marrow arising after immunoablation favor this phenomenon. Therefore, there is a need to improve the regeneration of a protective plasma cell memory, which is the aim of this project.

The project will address the following questions:

1. Is the specific depletion of B cells and plasma cells an alternative to immunoablation with ATG and does it result in a sustained depletion of pathogenic plasma cell memory?
   
2. Does the administration of protective memory B cells push on the regeneration of a protective plasma cell memory?
   
3. Does the quickening of plasma cell memory regeneration protect from anew development of autoimmunity?

The work program includes:

1. Establishment of new strategies to deplete the pathogenic plasma cell memory and to prevent its replenishment from B cells in NZB/W mice: proteasome inhibitors plus B cell depletion or cyclophosphamide, TACI-Ig plus B cell depletion or cyclophosphamide. Read-out parameters: depletion of B cells and plasma cells in bone marrow, spleen and inflamed kidneys; antibody levels; effect on lupus nephritis.
   
2. Quickening the regeneration of protective plasma cell memory after therapy as described in 1) by administration of defined protective memory B cells. Read-out parameters are reduction of infections and reappearance of autoimmunity. The following methods will be mainly used: flow cytometry, cell sorting, ELISPOT, ELISA. This project has a high impact for developing and improving cell therapies in severe autoimmune diseases.

References
Radbruch, A., G. Muehlinghaus, E. O. Luger, A. Inamine, K. G. Smith, T. Dörner, and F. Hiepe. 2006. Competence and competition: the challenge of becoming a long-lived plasma cell. Nat Rev Immunol 6:741-750.

Alexander, T., A. Thiel, O. Rosen, G. Massenkeil, A. Sattler, S. Kohler, H. Mei, H. Radtke, E. Gromnica-Ihle, G. R. Burmester, R. Arnold, A. Radbruch, and F. Hiepe. 2009. Depletion of autoreactive immunologic memory followed by autologous hematopoietic stem cell transplantation in patients with refractory SLE induces long-term remission through de novo generation of a juvenile and tolerant immune system. Blood 113:214- 223.