Tissue specific roles of mononuclear phagocytes in health and disease

• Applicant: Professorin Barbara Schraml-Schotta, Ph.D.
• Subject Area: Immunology
• Term: from 2014 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 252386857

Mononuclear phagocytes (MPs) are innate immune cells found in lymphoid and non-lymphoid tissues that include dendritic cells (DCs), monocytes and macrophages (MØs). They are versatile controllers of the immune system with crucial roles in immune regulation and tissue homeostasis, making them attractive tools for use in vaccines and immunotherapy. MPs are known to be functionally and ontogenetically heterogeneous but it is unclear whether individual MP sub-types have unique functions in the immune system. The unresolved issues relating to the heterogeneity of MP subsets stem from the lack of in vivo models that allow the distinction and analysis of MP subsets and represent a major hurdle in understanding their biology. In the kidney, MPs form an extensive cellular network throughout the entire interstitium. During disease or injury, they are thought to contribute to immunopathology, thus promoting loss of kidney function. This is a common and costly problem, as currently few therapies exist to attenuate kidney damage or expedite the healing process. The aim of this proposal is to characterize to what extent MP functions are dictated by ontogeny versus environmental imprinting. While a particular focus is placed on functions of MPs in the kidney of mice and humans, similar questions apply to other organs. Through the recent generation of a mouse model allowing us to define DCs based on their ontogenetic descendence from a committed precursor, we are now able to reliably distinguish DCs from monocytes/MØs independent of phenotype or function. This ability provides the basis for the proposed experiments. MPs of distinct ontogeny will be identified in healthy, as well as diseased murine kidney and their functions will be assessed. In addition, the generation of novel mouse models allowing for the ablation of MPs with overlapping phenotype but distinct ontogeny will help to further define the unique functions of each cell type in immunity. The so identified subsets and functions will then be correlated to MPs in human kidney to determine the potential of targeting MPs for immunotherapy. To achieve this we will apply state of the art techniques and innovative research methodology. We anticipate that these studies will not only lead to fundamental insights into MP biology but will have significant impact on the development of immunotherapies.

• DFG Programme: Independent Junior Research Groups