Prof. Dr. Andreas Radbruch

Deutsches Rheuma-Forschungszentrum Berlin
Ein Institut der Leibniz Gemeinschaft
Charitéplatz 1
10117 Berlin  

Tel. +49 (0) 30 28460 601
radbruch@drfz.de

Dr. Hyun-Dong Chang

Deutsches Rheuma-Forschungszentrum Berlin
Ein Institut der Leibniz Gemeinschaft
Charitéplatz 1
10117 Berlin  

Tel. +49 (0) 30 28460 683
chang@drfz.de

Project summary:

Deciphering the survival code of memory plasma cells and memory B cells

Two essential components of antibody-mediated immunity are memory plasma cells and memory B cells. Both, memory plasma cells and memory B cells, can be maintained over decades and provide the basis for longterm protection against recurrent pathogens but also for therapy-refractory immunopathology in autoimmune diseases. For memory plasma cells, it has been shown that their survival in bone marrow is conditional on provision of multiple survival signals in dedicated niches organized by bone marrow stromal cells.

In the last funding period, we have been able to establish for the first time a synthetic niche which provides the plasma cells with their physiological survival signals and allows us to maintain and study memory plasma cells ex vivo.

In the current funding period, we will elucidate the molecular signalling network which governs differentiation of precursors into memory plasma cells and their survival. We will use the synthetic niche for memory plasma cells to (1) determine which molecular networks determine the competence for a short-lived plasma blast to become a long-lived memory plasma cells, and (2) decipher redundant and non-redundant survival signals, and determine how their signals are integrated. Lastly, we will (3) also characterize the survival niche of memory B cells and establish a synthetic niche for memory B cells, to elucidate the signals required for memory B cell maintenance.

Deciphering the survival code of memory plasma cells and memory B cells
Fig. 1
Publications P 16:

Zehentmeier S, Roth K, Cseresnyes Z, Sercan O, Horn K, Niesner RA, Chang HD, Radbruch A, Hauser AE. Static and dynamic components synergize to form a stable survival niche for bone marrow plasma cells. Eur J Immunol. 2014 Apr 28. [Epub ahead of print].

Shinoda, K., Tokoyoda, K., Hanazawa, A., Hayashizaki, K., Zehentmeier, S., Hosokawa, H., Iwamura, C., Koseki, H., Tumes, D.J., Radbruch, A., and Nakayama, T. (2012). Type II membrane protein CD69 regulates the formation of resting T-helper memory. Proc Natl Acad Sci U S A 109:7409-14.

Tokoyoda, K., Hauser, A.E., Nakayama, T., and Radbruch, A. (2010). Organization of immunological memory by bone marrow stroma. Nat Rev Immunol. 10:193-200.

Tokoyoda K, Zehentmeier S, Chang HD, Radbruch A. (2009). Organization and maintenance of immunological memory by stroma niches. Eur J Immunol. 2009 Aug;39(8):2095-9.

Tokoyoda, K., Zehentmeier, S., Hegazy, A.N., Albrecht, I., Grün, J.R., Löhning, M., and Radbruch, A. (2009). Professional memory CD4+ T lymphocytes preferentially reside and rest in the bone marrow. Immunity 30:721-30.

Lexberg, M.H., Taubner, A., Förster, A., Albrecht, I., Richter, A., Kamradt, T., Radbruch, A., and Chang, H.D. (2008). Th memory for interleukin-17 expression is stable in vivo. Eur J Immunol 38:2654-64.

Chang, H.D., Helbig, C., Tykocinski, L., Kreher, S., Koeck, J., Niesner, U., and Radbruch, A. (2007). Expression of IL-10 in Th memory lymphocytes is conditional on IL-12 or IL-4, unless the IL-10 gene is imprinted by GATA-3. Eur J Immunol 37:807-17.

Hebel, K., Griewank, K., Inamine, A., Chang, H.D., Müller-Hilke, B., Fillatreau, S., Manz, R.A., Radbruch, A., and Jung, S. (2006). Plasma cell differentiation in T-independent type 2 immune responses is independent of CD11c(high) dendritic cells. Eur J Immunol 36:2912-9.

Muehlinghaus, G., Cigliano, L., Huehn, S., Peddinghaus, A., Leyendeckers, H., Hauser, A.E., Hiepe, F., Radbruch, A., Arce, S., and Manz, R.A. (2005). Regulation of CXCR3 and CXCR4 expression during terminal differentiation of memory B cells into plasma cells. Blood 105:3965-71.

Cassese, G., Arce, S., Hauser, A.E., Lehnert, K., Moewes, B., Mostarac, M., Muehlinghaus, G., Szyska, M., Radbruch, A., and Manz, R.A. (2003). Plasma cell survival is mediated by synergistic effects of cytokines and adhesion-dependent signals. J Immunol 171:1684-90.

Hauser, A.E., Debes, G.F., Arce, S., Cassese, G., Hamann, A., Radbruch, A., and Manz, R.A. (2002). Chemotactic responsiveness toward ligands for CXCR3 and CXCR4 is regulated on plasma blasts during the time course of a memory immune response. J Immunol 169:1277-82.

Cassese, G., Lindenau, S., de Boer, B., Arce, S., Hauser, A., Riemekasten, G., Berek, C., Hiepe, F., Krenn, V., Radbruch, A., and Manz, R.A. (2001) Inflamed kidneys of NZB / W mice are a major site for the homeostasis of plasma cells. Eur J Immunol 31:2726-32.

Manz, R.A., Löhning, M., Cassese, G., Thiel, A., and Radbruch, A. (1998). Survival of long-lived plasma cells is independent of antigen. Int Immunol 10:1703-11.

Manz, R.A., Thiel, A., and Radbruch, A. (1997). Lifetime of plasma cells in the bone marrow. Nature 388:133-4.