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Michael Bachmann
Tumorimmunology
Previous and current research
Our major goals are to develop and optimize novel tools for reprogramming of the immune system. These tools will be helpful for modulation of wanted and unwanted immune responses including (i) activation of the immune system against tumor cells or virus infected cells, (ii) destruction of autoreactive cells in an antigen specific manner, and (iii) modulation of immune responses including the induction of antigen-specific tolerance.(1) We have developed a novel modular cell targeting system allowing us to reprogram immune effector cells including dendritic cells, T-cells and NK cells. The modular system bases on bispecific antibodies and suitable linker molecules. Both together form a novel platform which allows us to engage target cells (e.g. tumor cells, virus infected cells) directly with immune effector cells. T cell engagement is mediated via CD3, NK cells are engaged via activating receptors such as ULBP2. Blood dendritic cells (DCs) are targeted via a unique sugar structure on their surface. In case of DCs the targeting system does not only deliver an antigen cargo but also the genetic information for maturation of the DCs. For this purpose multigene expression vectors were developed. This targeting strategy will allow us to either upregulate or downregulate an immune response in an antigen specific manner. In order to optimize the targeting tools in vitro/vivo maturation approaches are developed to improve the specificity and affinity of recombinant antibody derivatives. For this purpose Cre-loxP based vectors were developed allowing us to repeatedly turn on and off the expression of up to four living colour labelled genes (e.g. the AID gene).
(2) In previous studies we have detected a mutation in one of the nuclear autoantigens of patients with systemic autoimmune diseases such as systemic lupus erythematosus (SLE) or primary Sjögren’s syndrome. The antigen is known as the La antigen. This protein which shuttles between the nucleus and the cytoplasm is an RNA chaperon and plays a major role including for example in transcription termination of RNA polymerase III, tRNA processing, RNA quality control, regulation of cap-indepenent translation of cellular mRNAs (e.g. MDM2, XIAP, VEGF) or viral mRNAs (e.g. poliovirus, hepatitis C, HIV), and translation of 5‘-TOP mRNAs. The knock out of the La antigen is lethal in stem cells. The mutation exists in about 30% of anti-La positive patients. Most of interest, mice transgenic for the mutant form of La develop a SLE-like phenotype including anti-nuclear antibodies and an immunecomplex nephritis while mice transgenic for the native form of La are healthy. Presently, we investigate the molecular mechanisms leading to the autoimmune phenotype of the mutant La transgenic mice. For this purpose novel mice are constructed allowing a Cre-loxP based regulation of expression of the mutant La form.
Future prospects and goals
Our modular targeting system is an open system and a series of novel targets and targeting molecules are on the way to be included into the system. Presently, we try to develop more efficient expression systems which are the prerequisites for our final goal the translation of our preclinical data into the clinic.
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Selected publications
Dudek, N.L., Maier, S.M., Chen, Z., Mudd, P.A., Mannering, S.I., Jackson, D.C., Zeng, W., Cavill, D., Keech, C.L., Hamlin, K., Pan, Z., Davis-Schwarz, K., Workman-Azbill, J., Bachmann, M., Gordon, T.P., McCluskey J. and Farris, A.D. (2007): T cell epitopes of the La/SS-B autoantigen in humanized transgenic mice expressing the HLA class II haplotype DRB1*0301/DQB1*201. Arthritis Rheum., in press.
Bachmann, M., Bartsch, H., Gross, J.A., Maier, S.M., Gross, T., Workman, J., James, J.A., Harley, J.B.H., Conrad, K., Schmitz, M., Jung, B., Buyon, J.P., Semsei, I., Farris, A.D., Harley, J.B. and Rieber, E.P. (2006): Autoimmunity as the result of escape from RNA surveillance. J. Immunology 177, 1698-1707.
Tröster, H., Metzger, Th., Semsei, I., Schwemmle, M., Winterpacht, A., Zabel, B. and Bachmann, M. (1994): One gene two transcripts.: Isolation of an alternative transcript encoding for the autoantigen La/SS-B from a cDNA library of a patient with primary Sjoegrens' syndrome. J. Exp. Med. 180, 2059-2067.
Schwemmle, M., Clemens, M., Hilse, K., Tröster, H., Müller, W.E.G., und Bachmann, M. (1992): Comparison of the localization of EBER RNAs in mitotic and interphase cells. Proc. Natl. Acad. Sci. USA 89, 10292-10296.
Bachmann, M., Pfeifer, K., Schröder, H.C. and Müller, W.E.G. (1990): Characterization of the autoantigen La as a nucleic acid dependent ATPase/dATPase with melting properties. Cell 60, 85-93.