Kidney Week

Abstract: TH-PO0655

Discovery of a Novel Therapeutic Target That Regulates Autoimmune Responses and Licenses Glomerulonephritis

Session Information

• Glomerular Diseases: Immunopathogenesis and Targeted Therapeutics
  November 06, 2025 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Glomerular Diseases

• 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology

Authors

• Lea-Henry, Tom N, Australian National University The John Curtin School of Medical Research, Canberra, Australian Capital Territory, Australia

Tom N Lea-Henry, MBBS

• Nguyen Huynh, Thuy Xuan, Australian National University The John Curtin School of Medical Research, Canberra, Australian Capital Territory, Australia

Thuy Xuan Nguyen Huynh

• Hart, Gemma, Australian National University The John Curtin School of Medical Research, Canberra, Australian Capital Territory, Australia

Gemma Hart

• Chan Hsian Loon, Justin, Australian National University The John Curtin School of Medical Research, Canberra, Australian Capital Territory, Australia

Justin Chan Hsian Loon

• Walters, Giles, Canberra Hospital, Garran, Australian Capital Territory, Australia

Giles Walters, MD, MBChB

• Athanasopoulos, Vicki, Australian National University The John Curtin School of Medical Research, Canberra, Australian Capital Territory, Australia

Vicki Athanasopoulos, PhD

• Jiang, Simon Hee-Tang, Australian National University The John Curtin School of Medical Research, Canberra, Australian Capital Territory, Australia

Simon Hee-Tang Jiang, MBBS, PhD, MPH

Group or Team Name

• Personalised Medicine and Autoimmunity Laboratory.

Background

Glomerulonephritis (GN) is a major cause of chronic kidney disease worldwide. However, the underlying mechanisms of GN remain poorly understood and no new therapies have been developed in over 20 years. We have identified rare loss-of-function variants in the pseudonymised immune gene MONK among patients with systemic autoimmunity.

Methods

A C57BL/6 mouse model carrying an orthologous loss-of-function Monk variant orthologous was developed using CRISPR-Cas9 (Monk^Var). These mice were crossed to existing mouse models of autoimmune kidney disease and extensively immunophenotyped using flow cytometry, ex vivo stimulation assays, and anti-DNA antibody titres. The development of GN was analysed using histopathology.

Results

Monk^Var/Var ameliorates the autoimmune phenotype in Lyn^-/- mice (Monk^Var/Var.Lyn^-/-) with alterations to pathogenic B cell subsets, reduced autoantibody titres, and enhanced B cell receptor editing (Figure 1). However, in the Fas^Lpr mouse model, the Monk^Var allele exacerbates CD8⁺ T cell responses and autoantibody titres. Importantly, the Monk^Var allele ameliorates the development of GN in both of models (Figure 2). Infiltrating monocytes are central to disease development in these models, and we find that the Monk^Var allele favours development of anti-inflammatory M2-type macrophages (Figure 2).

Conclusion

We discover that Monk licenses GN across a range of autoimmune mouse models. We hypothesise that Monk^Var prevents GN through altered monocyte/macrophage polarisation. This identifies a novel therapeutic strategy in the treatment of GN, and we have developed two first-in-class Monk inhibitors targeting this.

Funding

• Private Foundation Support

Digital Object Identifier (DOI)

• doi: 10.1681/ASN.2025gty0brj6