Immune and Inflammatory Glomerular Injury

It is now over a century since the first animal model of glomerulonephritis was established by Lindemann [1] who injected rabbits with heterologous antiserum to rabbit kidney raised in guinea pigs. In recent years there has been increasing opposition to the use of animals for research with an escalation in damage to property and violent attacks on researchers by those opposed to such research. This has been a major problem in the UK and is an increasing problem in the US [2]. There is therefore a need for scientists who carry out animal research to demonstrate that the inevitable discomfort and harm which is suffered by experimental animals is reduced as far as possible by good experimental design and, most importantly, is justified by the benefits it brings in understanding and treating human disease. In this talk I will discuss models that have been used in studying immune and inflammatory glomerular injury and ask; 1. How representative they are of human disease 2. What are the key insights they have given into pathogenesis 3. How has this been translated into treatment 4. Are we in danger of being misled by reliance on animal models Al h h h i l h bbi d h h b di d i I will discuss the following models which I think are most useful in understanding human glomerular disease: Nephrotoxic nephritis This model is induced by the injection of a heterologous antibody raised against a preparation of glomerular antigen. Classically there is acute injury produced by binding of the heterologous antibody to the glomerular basement membrane followed by a second phase of injury in which there is an autologous immune response to the heterologous antibody which then acts as a planted antigen. This second phase can be accelerated by pre-immunising the animals with heterologous immunoglobulin. Typically the autologous phase is characterised by proliferative glomerulonephritis with crescent formation in susceptible animals. The heterologous phase closely resembles human anti-GBM disease but the autologous phase has more in common with an immune complex glomerulonephritis with the heterologous antibody acting as a planted antigen. Proliferative immune complex glomerulonephritis can also be produced by antigens planted by other mechanisms, for example, on account of their charge [3] Heymann nephritis This is a model of membranous glomerulonephritis originally induced in rats by immunisation with a suspension of renal cortex and adjuvant. Subsequently a passive There are several models of SLE in mice which are characterised by the generation of autoantibodies and the development of glomerulonephritis with immune complex deposition. In my opinion the model that most closely resembles human disease is that produced by crossing NZB and NZW mice but other models include the MRLlpr mouse and the BXSB mouse. These models have been widely studied and have provided insights into genetic susceptibility to SLE, mechanisms by which tolerance is broken and have been used for elucidating the role of mediators of glomerular injury both by examining gene targeted animals and by administration of pharmacological agents. Models of ANCA-mediated glomerulonephritis A major step forward in our ability to model human glomerular disease was the demonstration by Jennette and co-workers that transfer to normal mice of splenocytes or serum from myeloperoxidase (MPO) deficient mice immunized with MPO led to a pauci-immune necrotising glomerulonephritis [4]. This was the first demonstration that anti-MPO antibodies were pathogenic and has led to further insights into the mechanisms of injury in ANCA-mediated glomerular inflammation. Dense deposit disease and thrombotic microangiopathy Pigs with a spontaneous deficiency of factor H and mice in which the factor H gene has been knocked out develop persistent activation of the alternative pathway of