Dr TOM LEA-HENRY1,2,3, Dr VICKI ATHANASOPOULOS2,3, Ms JEAN CAPELLO2,3, Ms THUY HUYNH2,3, Ms AYLA LORENZO2,3, Ms SOMASUNDHARI SHANMUGANANDAM2,3, Prof CAROLA VINUESA1, A/Prof CHIRSTOPH NITSCHE1, Dr GILES WALTERS1,2,3, A/Prof. Simon Jiang1,2,3
1Canberra Health Services, Canberra, Australia, 2Australian National University, Canberra, Australia, 3Centre for Personalised Medicine, Canberra, Australia
Biography:
A/Prof Jiang is a consultant nephrologist at The Canberra Hospital and Head of the Personalised Medicine and Autoimmunity (PMA) Laboratory at the Australian National University. A/Prof Jiang is the founding Director of the Australian National University (ANU)-Canberra Health Service (CHS) Centre for Personalised Medicine, a nationwide program using personalised medicine to diagnose and treat refractory autoimmunity and kidney disease. He leads a 20+ member laboratory and has successfully managed over $10 million in grant funded projects including NHMRC and MRFF as CIA, leading to major discoveries in the underlying causes of human autoimmunity
Aim:
Determine how inactivation of Monk prevents glomerulonephritis.
Background:
Glomerulonephritis (GN) is a leading cause of end-stage kidney disease globally. Current treatments for GN have variable efficacy and significant side-effect profiles, largely due to a paucity of insights into the underlying mechanisms of GN. However, activity of proinflammatory M1 macrophages is thought to be central to development of GN.
Methods:
A loss-of-function Monk variant was introduced in C57BL/6 mice using CRISPR-Cas9 (Monkvar) and crossed to Lyn-/-, FasLpr and nephrotoxic serum models of glomerulonephritis. We combine systemic immune phenotyping and kidney histopathologic and immunofluorescent staining to assess the impact of Monkvar on GN.
Results:
Monkvar/var have modest B cell lymphopaenia but are otherwise immunologically normal. When crossed to SLE-prone Lyn-/- mice however, Monkvar/var prevents development of glomerulonephritis. Tail vein injection of nephrotoxic serum, a model of anti-GBM disease, induces GN in wildtype but not Monkvar/var mice. Further, Monkvar/var ameliorates development of GN in FasLpr model of autoimmunity. Together this suggests a universal nephroprotective effect of Monkvar/var. As macrophages are key mediators of GN, we hypothesise Monvar/var nephroprotection is myeloid mediated and confirm novel expression of Monk in monocytes. Further, we demonstrate Monkvar/var restricts formation of pro-inflammatory M1 macrophages. We generate preliminary first-in-class Monk inhibitors as potential novel therapeutic agents to treat GN.
Conclusions:
We show that Monk is not a redundant gene and is required to enable GN in three separate models of GN. Monk is expressed in monocytes and influences M1 and M2 macrophage differentiation, and we hypothesise that Monkvar/var prevents GN by preventing inflammatory M1 macrophage formation. We therefore identify Monk as a novel therapeutic target for the treatment of GN.