Initiation and maintenance of autoimmunity in the nervous system
Project management at the University of Würzburg:
Studies on human Multiple Sclerosis (MS) and on animal models for this disease have shown that several arms of the specific immune system (CD4 T-cells, CD8 T-cells, B-cells) can participate in its pathogenesis. In order to evaluate their relative contribution in isolation as well as in a cooperative situation, a model system would be useful in which CD4 cells, CD8 cells and B-cells with homogenous antigen receptors recognising a myelin antigen are available. Since such reagents with specificity for a natural myelin antigen do not exist as a complete set, which generate a transgenic mice expressing the model antigen ovalbumin (OVA) under the control of various promoter/enhancer elements which, according to the literature, convey specificity either for the oligodendrocytes of the central nervous system (CNS) or for the Schwann cells of the peripheral nervous system (PNS).
Characterisation of the transgenic mouse lines has shown that with regard to the PNS, the desired selective expression in Schwann cells was not achieved. However, these mouse lines express OVA in other organs (lung, kidneys) leading to a partial tolerance towards OVA.
In contrast, a highly specific expression of OVA was achieved in oligodendrocytes. The immune system of these ODC-OVA mice seems to initially ignore the sequestered neo-self antigen OVA. Upon immunisation with OVA in CFA, half of the animals undergo a mild form of experimental autoimmune encephalomyelitis (EAE). Interestingly, OVA-specific CD8 T-cells, but not OVA-specific CD4 T-cells are able to induce a fulminant form of the disease. In ODC-OVA mice which express an MHC I-restricted OVA-specific T-cell antigen receptor as a second transgene, and which by consequence express OVA-specific CD8 T-cells as their major lymphocyte subset, a synchronous EAE develops already two weeks after birth. Hallmarks of this disease are a massive destruction of the cerebellum and of the white matter of the spinal cord, histopathologic findings which reflect certain subtypes of MS. We were able to prevent this fulminant disease by regulatory T-cells which were stimulated with a novel type of CD28-specific monoclonal antibody.
Projekt period: from 07.2003 to 06.2006
DFG ,Granting date: 23.06.2000