AL Mushafi A1, Lim R2, Cao Le1 A1, Holdsworth S1, Odobasic D1
1Department of Medicine, Centre for Inflammatory Diseases, Monash University, Melbourne, Australia, 2The Ritchie Centre, Hudson Institute of Medical Research, Melbourne, Australia
Background: Crescentic glomerulonephritis (GN) is an immune-mediated inflammatory disease which causes severe glomerular injury. Current therapies are non-specific, toxic and cause many serious adverse effects. Here, we tested if human amniotic epithelial stem cells (hAECs), obtained from the placenta after birth, can attenuate crescentic GN using a mouse model.
Methods: GN was induced by injection of sheep anti-mouse glomerular basement membrane globulin on day 0. Then, saline or hAECs were administered on day 10, when injury is already present. On day 21, we assessed GN development and immunity against sheep globulin. hAECs were also cultured in vitro and their expression of pro- and anti-inflammatory mediators analysed.
Results: hAECs significantly reduced the development of GN. This was demonstrated by decreased proteinuria and glomerular crescent formation. Furthermore, they significantly decreased leukocyte recruitment in the kidney. In line with diminished injury, hAECs decreased CD4 T cell proliferation and augmented the frequency of CD4+foxp3+ regulatory T cells (Tregs) in the spleen. Assessment of Treg phenotype showed that hAECs specifically induced ICOS-expressing Tregs. Interestingly, hAECs increased IFNγ-producing T cells in the spleen, without affecting IL-17A or IL-4 production. hAECs did not affect levels of mouse anti-sheep globulin antibody in serum. In-vitro studies showed that hAECs expressed anti-inflammatory cytokines, TGF-β and IL-10, but did not express pro-inflammatory molecules including CD40 or CD86.
Conclusion: hAECs suppress crescentic GN in mice. They may exert their effects by producing TGF-βor IL-10, and by inducing ICOS+ Tregs. Therefore, hAECs may be a safer, effective therapy for this disease.
Ahmed AL Mushafi
Autoimmune Kidney Disease and Vasculitis Research Group
Centre for Inflammatory Diseases
Faculty of Medicine, Nursing and Health Science