Study of regulatory T cells in transplantation

© 2011 Dr. Wen Xu LinTransplantation has prolonged the survival of patients with terminal organ diseases. However, even with today’s advanced immunosuppressive therapies, graft rejection remains a major concern with significant patient morbidity and mortality still being associated with immunosuppressive medications. Tolerance induction has been a goal in transplantation for many years, although it still remains elusive. Recently, interest has been renewed in a subset of T cells, the regulatory T cells (Treg) and their potential role in tolerance induction. These cells demonstrate immunosuppressive potential in experimental models. This thesis focuses on examining the role of Treg in transplantation. Techniques to characterise and genetically engineer Treg in vitro were developed. Our studies in over 200 transplant recipients (renal and liver) have shown: (1) percentages of CD4+CD25+ (“activated”) cells and CD4+CD25+Foxp3+ cells are significantly lower in RTR compared to controls; (2) percentages of “activated” cells are significantly lower in LTR compared to controls, while the percentages of CD4+CD25+Foxp3+ cells are significantly higher in patients with chronic liver diseases and LTR compared to normal controls; (3) the key finding that the proportion of “activated” cells expressing Foxp3+ cells is higher in RTR and correlates with renal allograft function; (4) the proportion of CD4+CD25+Foxp3+ cells do not alter at different times post-transplant; (5) a higher percentage of CD4+CD25+ cells is observed in recipients with malignancy; (6) incorporation of human Foxp3 in a human T cell line, CEM may induce a Treg-like phenotype. Collectively, the results from this project provide significant insight into the role of Treg in clinical transplantation and the role of the important Treg transcriptional regulator, Foxp3, in Treg induction and developing therapeutic strategies to facilitate graft acceptance by extending the use of Treg in the future. These findings may help to add further information regarding the mechanism of tolerance induction that may lead to graft survival without ongoing drug therapy