T cell repertoires in animal and huma glomerulonephritis

This thesis aims to study the role of T cells in glomerulonephritis and to take a first step towards design of novel T cell based treatments of these conditions. Two animal models, Heymann nephritis (HN) and experimental autoimmune glomerulonephritis (EAG), are studied. Glomerular T cell receptor (TCR) repertoires from each of these models are analysed using polymerase chain reaction, CDR3 spectratyping and DNA sequencing of their CDR3 regions. In HN, a restricted set of T cells defined by their Vbeta J beta and CDR3 regions are identified as potentially pathogenic cells. In EAG, infiltrating T cells are shown to be clearly oligoclonal with restricted TCR repertoires in each animal. The repertoire restriction differs in each animal studied but the entire population carries multiple TCR CDR3 motifs which are absent in control cells.;The data from HN is utilised to design a DNA vaccination based upon the identified PCR products of infiltrating T cells. Vaccinated rats have significantly improved disease with reduced proteinuria. CD8 + and macrophage infiltration and IFN-gamma. The mechanism of action of DNA vaccination is explored, demonstrating specific anti-TCR antibodies in vaccination rats. The antibodies appear to reduce specific T cell infiltration to the kidneys and to reduce IFN-gamma expression.;Oligoclonal T cells are also identified in archival human renal biopsy tissue. Restricted TCR repertoires are variable but CDR3 spectratypes clearly show oligoclonality within multiple TCR Vbeta families. The data suggest that the most frequently represented T cell mRNA species may account for a large proportion of total T cell receptor mRNA signal.