Treatments to expand regulatory T cells and/or deplete autoantibody production in primary membranous nephropathy

Abstract

Primary membranous nephropathy (MN) is the most common cause of nephrotic syndrome in Caucasian adults and left untreated, a third of patients progress to kidney failure. While kidney transplantation is the preferred treatment for people with kidney failure, up to half will experience disease recurrence despite immunosuppression to prevent allograft rejection and half experience allograft loss five years after diagnosis since the optimal treatment of recurrent MN remains uncertain. In chapter 3, we developed models to predict recurrent MN after kidney transplantation using the Australian and New Zealand Dialysis and Transplant registry. The Group LASSO and penalized Cox regression models (AUC-ROC 0.85, 95% confidence interval 0.76-0.94 and 0.91, 0.85-0.96 respectively) outperformed the random forest model (AUC-ROC 0.62, 0.57-0.69) in the derivation cohort. In their validation cohorts, the penalised Cox regression model (AUC-ROC 0.73, 0.59-0.86) performed better than the Group LASSO model (AUC-ROC 0.60, 0.49-0.70). Next, we evaluated T cell stimulatory blockade (CTLA4-Ig) with or without proteasome inhibition (chapter 4), and peptide vaccination to induce CD8+ regulatory T cells (Tregs) (chapter 5) in Heymann nephritis, a rat model of MN, which we hypothesised would deplete autoantibody production and expand Tregs respectively. In chapter 4, we found CTLA4-Ig alone ameliorated experimental MN, potentially through suppression of Th17 cells in the kidney without reducing autoantibody production. In chapter 5, we demonstrated peptide vaccination induces CD8+ Tregs, which reduced autoantibody production and ameliorated the induction of experimental MN. B-cell activating factor (BAFF) is a cytokine which is critical for B cell survival and maturation. In chapter 6 we generated chimeric antigen receptor (CAR) T cells that genetically express BAFF, which eliminated B cells in vitro and may represent a novel treatment for B cell-mediated autoimmunity, which underpins MN.