Human Tubular Epithelial Cells and T-cell Alloreactivity

__Abstract__ Kidney transplantation is the treatment of choice for patients with end-stage renal disease. The first successful transplantation was performed in 1954 and acceptable renal allograft survival was achieved after introduction of azathioporine in combination with high dose of corticosteroids in the mid sixties of the 20th century. Introduction of the immunosuppressant calcineurin inhibitor (CNI) cyclosporin A and later on tacrolimus significantly improved the outcome of kidney graft survival. Tacrolimus compared to cyclosporin diminished the acute rejection rate by 31% during the first year after transplantation, and this percentage was even more reduced using anti-CD25 mAb as induction treatment [5]. This success have shifted the problem of transplantation from short term graft survival to how to improve the long term graft survival. The 5-year allograft survival rate in the Netherlands is 83% for deceased donor kidneys and 92% for living donor kidney transplants (Nederlandse Transplantatie Stichting, 12th August 2013). In contrast, the overall European 5-year graft survival is 77% and the USA 5-year graft survival is even worse, representing only 71% graft survival

FoxP3 T cells and the pathophysiologic effects of brain death and warm ischemia in donor kidneys

Background and objectives Forkhead box P3 regulatory T cells control inflammatory responses, but it remains unclear whether they inhibit brain death-initiated inflammation and tissue injury in deceased kidney donors. Design, setting, participants, & measurement To study the actions of regulatory T cells at various stages of the donation and transplantation procedure, forkhead box P3, regulatory and inflammatory cytokine expression, and tissue injury markers were determined in time 0 kidney biopsies from deceased and living donors. Additionally, the interaction between forkhead box P3+ T cells and kidney injury molecule-1 by activated primary tubular epithelial cells was studied. Results After cold storage, the deceased donor kidneys expressed the higher mRNA levels of kidney injury molecule-1 and CD3ε. In these samples, the inflammatory cytokines IL-8 and IFN-γ and markers associated with regulation (forkhead box P3, TGF-β, and IL-10) were highly expressed compared with living donor kidneys. Correlations were found between mRNA expression levels of forkhead box P3 and kidney injury molecule-1 and forkhead box P3 and IFN-γ. Immunohistochemical analysis confirmed the presence of forkhead box P3+ T cells in donor kidneys. Renal function (analyzed by serum creatinine levels) at the first week posttransplantation correlated with kidney injury molecule-1 and forkhead box P3 mRNA levels. In vitro studies showed that kidney injury molecule-1 expression by primary tubular epithelial cells was 63% (mean) lower when cocultured with regulatory T cells compared with control T cells. Conclusions These results show that donor forkhead box P3+ T cells infiltrate the deceased donor kidney, where they may control inflammatory and injury responses