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CBI Heymann Nephritis Immune Mediated FX-1-induced Glomerular Nephritis

A TRANSLATIONAL APPROACH TO PRECLINICAL RESEARCH. CBI Heymann Nephritis Immune Mediated FX-1-induced Glomerular Nephritis. Comparative Biosciences, Inc. 786 Lucerne Drive Sunnyvale, CA 94085 Telephone: 408.738.9261 www.compbio.com.

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CBI Heymann Nephritis Immune Mediated FX-1-induced Glomerular Nephritis

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  1. A TRANSLATIONAL APPROACH TO PRECLINICAL RESEARCH CBIHeymannNephritisImmune Mediated FX-1-induced Glomerular Nephritis Comparative Biosciences, Inc. 786 Lucerne Drive Sunnyvale, CA 94085 Telephone: 408.738.9261 www.compbio.com

  2. Heymann NephritisImmune mediated FX-1-induced glomerular nephritis • Passive Heymann nephritis in rats resembles membranous nephropathy in man. It is induced by injection of sheep antibody to rat proximal tubular epithelial cell brush border antigen (anti-Fx1A). • This is a robust and validated model at CBI. • Induce with administration of optimal concentrations anti-Fx1A IgG in rats administered as a single systemic dose in CFA • Urine changes-marked increases in urinary protein, creatinine and protein/creatinine ratios due to glomerular damage beginning within one week and increasing over 2-3 weeks • Glomerular histologic changes of glomerular hypercellularity, inflammation and deposition visible by 3 weeks histologically • Positive controls-not well understood, steroids not effective,  mycophenolate mofetil show some activity

  3. Heymann NephritisImmune mediated FX-1-induced glomerular nephritisUrine protein excretion increases beginning about Day 8

  4. Heymann NephritisImmune mediated FX-1-induced glomerular nephritisTotal urine protein (Day 21) is markedly increased

  5. Heymann NephritisImmune mediated FX-1-induced glomerular nephritisUrine protein/creatinine ratio (Day 21) is markedly increased

  6. Heymann NephritisImmune mediated FX-1-induced glomerular nephritisUrinary creatinine (Day 21) is markedly increased

  7. A TRANSLATIONAL APPROACH TO PRECLINICAL RESEARCH HEYMANN NEPHRITISImmune mediated FX-1-induced glomerular nephritis HISTOPATHOLOGY Characteristic Glomerular Lesions • Glomerular hypercellularity with eosinophilic deposition, inflammation, and wire loop lesions • Hyperplasia of the Bowman’s capsule • Proteinic material in tubules and tubular dilation • Interstitial lymphocytic inflammation

  8. A TRANSLATIONAL APPROACH TO PRECLINICAL RESEARCH HEYMANN NEPHRITISImmune mediated FX-1-induced glomerular nephritis HISTOPATHOLOGY • Light microscopic examination • Standard stains-HE, Trichrome, Sirius Red, Periodic acid Schiff, Jones methenamine silver stains • Immunohistochemistry-collagen, SMA, basement membrane, inflammation • Semi-quantitative assessment • Option for histomorphometry

  9. A TRANSLATIONAL APPROACH TO PRECLINICAL RESEARCH HEYMANN NEPHRITISImmune mediated FX-1-induced glomerular nephritis HISTOLOGIC SCORING SYSTEM • Assessment by ACVP Veterinary Pathologist • Entire kidney and subparts of the nephron assessed • Glomerulus, mesangium, basement membrane, Bowman’s capsule, cellular infiltrates, tubules, interstitium • Incidence and severity of the lesions were scored using the accepted industry scoring system of 0-4, corresponding to normal, minimal, mild, moderate, and severe, respectively. • Lesions scored for duration (acute, subacute, and chronic) and distribution (focal, multifocal, diffuse) based on the composition and numbers of cell types present

  10. summary • Heymann Nephritis Immune mediated FX-1-induced glomerular nephritis is an established, robust, reproducible model at CBI • Rats are administered the FX-1 antibody • Urine changes-marked increases in urinary protein, creatinine and protein/creatinine ratios due to glomerular damage beginning within one week and increasing over 2-3 weeks • Glomerular histologic changes of glomerular hypercellularity, inflammation and deposition visible by 3 weeks histologically

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