Kidney Week

Abstract: PO1773

An Inducible Model of Early Lupus Nephritis

Session Information

• Glomerular Diseases: Lupus and Membranous
  October 22, 2020 | Location: On-Demand
  Abstract Time: 10:00 AM - 12:00 PM

Category: Glomerular Diseases

• 1202 Glomerular Diseases: Immunology and Inflammation

Authors

• Bhandari, Aneesha, University of Oxford, Oxford, Oxfordshire, United Kingdom

Aneesha Bhandari,

• Bull, Katherine R., University of Oxford, Oxford, Oxfordshire, United Kingdom

Katherine R. Bull,

• Cornall, Richard John, University of Oxford, Oxford, Oxfordshire, United Kingdom

Richard John Cornall,

• Soares, Maria F., University of Oxford, Oxford, Oxfordshire, United Kingdom

Maria F. Soares,

• Roberts, Ian, University of Oxford, Oxford, Oxfordshire, United Kingdom

Ian Roberts,

Background

Lupus nephritis (LN) is characterised by polyreactive antibodies targeting 'planted' glomerular autoantigens. But how these deposits recruit inflammatory mediators and the roles of resident and recruited cells is unclear. Distinguishing damaging pathways from protective tissue responses is a major challenge. With disease progression, non-specific signals of fibrosis become dominant and human tissue comparisons are confounded by genetic and environmental heterogeneity. A way to separate these early and late pathological events is to use murine models of nephritis. Topical treatment with toll like receptor-7(TLR7) agonist Imiquimod(IMQ) for 8 weeks has been shown to induce glomerulonephritis(GN), significant weight loss and mortality. Using detailed renal and immune phenotyping we explored the suitability of this model to study the very early, active stages of LN.

Methods

6-week female BALB/c mice were treated 3 times weekly for 5 weeks with topical IMQ or Vaseline control(n=6/group). Immune profiling of spleen, bone marrow and mesenteric lymph node was by flow cytometry. Kidneys were fixed and processed for Period Acid Schiff, immunofluorescence and TEM. Serum was assayed for creatinine, urea and albumin.

Results

Treated mice had increased numbers of activated splenic CD4 and CD8 T cells(CD44^hiCD62L^low,P<0.001), Tregs(CD4⁺CD25⁺FOXP3⁺,P<0.01) and activated B cells(B220⁺CD19⁺CD86⁺CD69⁺,P<0.001). IMQ did not result in weight loss, mortality or significant changes in serum creatinine or urinary protein creatinine ratio but kidney histology showed mild mesangial hypercellularity with strong glomerular positivity for IgG, C1q and C3. TEM showed early basement membrane duplication, focal subendothelial and mesangial deposits and mild podocyte effacement.

Conclusion

This study characterises the IMQ model of LN revealing CD44^hi T cell activation and TEM evidence of immune deposits reminiscent of human class II lupus. Treatment for 5 weeks is well tolerated without overt renal failure and creates a model for studying the early pathways involved in immune complex GN and associated therapeutic targets.