Final Activity Report Summary - MACRORIEN (Renal macrophages as natural biosensors and therapeutic targets)
The Macrorien project was an FP6 Marie Curie Excellence Chair awarded to Professor Andrew Rees that enabled him to translocate from Aberdeen (UK) where he was Regius Professor of Medicine to the Clinical Institute of Pathology at the Medical University of Vienna, headed by Professor Dontscho Kerjaschki. The project had two principal objectives: first that Professor Rees establish a new translational renal immunology research programme in Vienna combining his immunological and clinical expertise with Professor Kerjaschki's in renal cell biology and pathology; and second develop an outstanding training programme in renal immunology to complement it.
The Macrorien research group has the ultimate goal of devising better treatments for pauci-immune focal necrotising glomerulonephritis (piFNGN) a severe autoimmune kidney disease that commonly causes kidney failure. The disease is caused by autoantibodies known as anti-neutrophil cytoplasmic antibodies (ANCA) that recruit circulating white blood cells (leukocytes) to the kidney where they are activated to cause tissue damage. Research undertaken has provided new information both about the antibodies that cause piFNGN and the signalling pathways that control the function of macrophages perhaps the most important of the infiltrating leukocytes because they can be activated to be either M1 macrophages that cause injury or to M2 macrophages that promote healing.
Notable achievements in macrophage research included identifying an essential role for the suppressors of cytokine signalling (SOCS) family protein SOCS3 in the development of tissue damaging M1 macrophages in a rat model of FNGN (Liu et al. J Immunol. 1;180:6270-8, 2008) whilst SOCS1 expression is essential for development of M2 macrophages that promote healing (Whyte et al. 2010. Submitted); quantifying macrophages SOCS 1 and SOCS 3 expression in biopsies from patients and showing it is a useful clinical biomarker with marked differences between piFNGN and more indolent disease and that predicts the response to chemotherapy and eventual outcome in breast cancer treated with adjuvant chemotherapy (Heys et al, 2010. In preparation). However, the autoantibody studies provided some of the most novel data first by linking antibodies to lysosome associated membrane protein-2 (LAMP-2) to the pathogenesis of piFNGN and then by showing that the patients' autoantibodies cross-react with the bacterial protein FimH and can be induced by molecular mimicry to it (Kain et al. 2008. Nature Medicine.14:1088-96). Thus FimH triggered autoimmunity to hLAMP-2 provides a novel molecular mechanism for the initiation and development of injury in piFNGN that will revolutionise understanding of piFNGN if confirmed by others.
Macrorien established a robust training programme based on the close supervision of doctoral students complemented with a small group interactive course that teaches early stage researchers the generic skills they will require. A particular aim of the course was to develop the students' ability to prepare grant applications, manuscripts and theses and to write them clearly in English. The programme also included a series of advanced lectures on different types of glomerulonephritis. The training programme will continue funded by a Marie Curie ITN coordinated by Professor Rees.
Macrorien also had two secondary objectives aimed at the wider European renal community. First Professor Rees organised two international multidisciplinary meetings designed to enhance European research in renal immunology. One was held in September 2008 and was restricted to established investigators; the second was held March 2010 and mixed established and more junior investigators. The second initiative was to develop a public awareness program about the threats posed by on kidney disease. This has been developed collaboratively with the European Kidney Alliance (chaired by Professor Rees) and concentrates on European politicians and opinion formers.
The Macrorien research group has the ultimate goal of devising better treatments for pauci-immune focal necrotising glomerulonephritis (piFNGN) a severe autoimmune kidney disease that commonly causes kidney failure. The disease is caused by autoantibodies known as anti-neutrophil cytoplasmic antibodies (ANCA) that recruit circulating white blood cells (leukocytes) to the kidney where they are activated to cause tissue damage. Research undertaken has provided new information both about the antibodies that cause piFNGN and the signalling pathways that control the function of macrophages perhaps the most important of the infiltrating leukocytes because they can be activated to be either M1 macrophages that cause injury or to M2 macrophages that promote healing.
Notable achievements in macrophage research included identifying an essential role for the suppressors of cytokine signalling (SOCS) family protein SOCS3 in the development of tissue damaging M1 macrophages in a rat model of FNGN (Liu et al. J Immunol. 1;180:6270-8, 2008) whilst SOCS1 expression is essential for development of M2 macrophages that promote healing (Whyte et al. 2010. Submitted); quantifying macrophages SOCS 1 and SOCS 3 expression in biopsies from patients and showing it is a useful clinical biomarker with marked differences between piFNGN and more indolent disease and that predicts the response to chemotherapy and eventual outcome in breast cancer treated with adjuvant chemotherapy (Heys et al, 2010. In preparation). However, the autoantibody studies provided some of the most novel data first by linking antibodies to lysosome associated membrane protein-2 (LAMP-2) to the pathogenesis of piFNGN and then by showing that the patients' autoantibodies cross-react with the bacterial protein FimH and can be induced by molecular mimicry to it (Kain et al. 2008. Nature Medicine.14:1088-96). Thus FimH triggered autoimmunity to hLAMP-2 provides a novel molecular mechanism for the initiation and development of injury in piFNGN that will revolutionise understanding of piFNGN if confirmed by others.
Macrorien established a robust training programme based on the close supervision of doctoral students complemented with a small group interactive course that teaches early stage researchers the generic skills they will require. A particular aim of the course was to develop the students' ability to prepare grant applications, manuscripts and theses and to write them clearly in English. The programme also included a series of advanced lectures on different types of glomerulonephritis. The training programme will continue funded by a Marie Curie ITN coordinated by Professor Rees.
Macrorien also had two secondary objectives aimed at the wider European renal community. First Professor Rees organised two international multidisciplinary meetings designed to enhance European research in renal immunology. One was held in September 2008 and was restricted to established investigators; the second was held March 2010 and mixed established and more junior investigators. The second initiative was to develop a public awareness program about the threats posed by on kidney disease. This has been developed collaboratively with the European Kidney Alliance (chaired by Professor Rees) and concentrates on European politicians and opinion formers.