In the first funding period (07/2015- 06/2019), the “IMPATH paradox” has proven its biological and clinical relevance, both in terms of guiding research in individual projects as well as in providing an integrative platform for the overall consortium.
In the second funding period (07/2019 – 06/2023), we plan to focus increasingly on the molecular mechanisms determining the impaired immune reaction and the ensuing immune-mediated pathology. For this, we will build on the evolving interactions among the different projects that favour the development of common areas of experimental exploration. The CRC will now be structured in sections, providing a framework for the specific areas of research that have emerged during the first funding period.
Area A will focus on the impaired immune reaction and its reconstitution in human disease models of T cell-mediated immunopathology.
Area B will use human and mouse models to study signals and cells regulating extent and time course of immune-mediated pathology.
Area C will employ mouse models to study innate control of immune-mediated pathology.
Area A: The impaired immune reaction and its reconstitution
In the disease situations analyzed in area A, cells expressing viral or autoantigens stimulate immune cells, but due to partial functional exhaustion or genetic lack of effector mechanisms, the immune cells fail to eliminate the source of immune stimulation. This leads to immunopathology caused by residual immune cell functions such as cytokine production, cytotoxicity and aberrant cellular infiltration. Area A will focus on the impaired immune reaction and its reconstitution in human disease models of T cell-mediated immunopathology. Mechanistic studies will focus on effector functions of T cells that are impaired either by genetic lesions or by T cell exhaustion. A translational project will exclusively focus on immune reconstitution by gene therapy as a promising therapeutic approach to treat immunopathology.
Area B: Signals and cells regulating immunopathology
The common denominator of projects in Area B is the focus on signals and cells regulating the effector phase of the immune-mediated pathology. The first group of projects focuses on B cells and analyses how various signals impair BCR responses but at the same time favour autoantibody-mediated immunopathology.
The second group of projects focuses on impaired cellular regulation of pathological T cell effector responses, not only through regulatory T cells, but also through IEL, neutrophils or CD4 T cells/B cells.
Area C: Innate control of immune-mediated pathology
Area C explores innate immune mechanisms controlling immune-mediated pathology. Molecular mechanisms of impaired virus control, inflammasome homeostasis or metabolic homeostasis that lead to uncontrolled immune stimulation will be investigated. Macrophages and epithelial cells are the main cell types used for experimentation in these projects.