Identifying New Targets, Developing Novel Models, and Investigating Innovative Strategies for the Treatment of Rejection in Thoracic Transplantation,Identifizierung neuer Ziele, Entwicklung neuartiger Modelle und Erforschung von innovativen Strategien zur Behandlung von Abstoßung bei thorakalen Organtransplantationen
Staats- und Universitätsbibliothek Hamburg Carl von Ossietzky
Erscheinungsjahr:
2012
Medientyp:
Text
Schlagworte:
transplantation
rejection
immunosuppression
heart
lung
610 Medizin, Gesundheit
44.45 Immunologie
44.65 Chirurgie
ddc:610
Beschreibung:
In my doctoral study, a study on acute heart rejection was performed to evaluate the role JAK1/3 inhibitors in T cell immune response. Results showed both R507 and R545 were novel and potent immunosuppressants mainly acting on T cells, and the interruption of “Signal 3” transduction is promising way to diminish rejection. Studies on lung transplant involved establishing and comparing the mice models for OB. Both orthotopic and heterotopic tracheal transplant models are feasible and reliable. The choice of model depends on the question the study focuses on. Using the heterotopic model, we identified KCa3.1 as a crucial contributor in the development of OB and also as a potential new target to prevent the OB. Specific KCa3.1 blockade might be considered as an additional therapeutic strategy. Intimal hyperplasia, as a major manifestation of transplant vasculopathy, was also investigated. It showed the capacity of sustained inhibition on epsilon PKC to prevent the vascular smooth muscle cell activation and proliferation via inhibition of ERK and Akt pathways. A novel and reliable humanized model to study restenosis after stenting was invented and established, in which the disease pattern was very close to that in human. Besides solid organ transplantation, the studies also involved the immunobiology of stem cell transplantation for regenerative therapies. Islet-1, which was thought to be the marker for resident cardiac progenitors, was found to be expressed only in specific areas, all of which are well differentiated. The potential regenerative role of the Islet-1+ cells got questioned. Therefore, we strongly believe that allogeneic pluripotent stem cell sources are needed. The study on the immunogenicity of genetically modified hESC revealed a principal role of HLA-I expression in the hESC recognition in a xenotransplant setting, mainly mediated by T cells. And the HLA-I-knockdown using both the microRNA and intrabody technique could help the modified hESC escape immune attack from recipient and may lead to long-term graft survival. In the past century, with all the endeavors of clinicians and researchers, transplantation became clinical reality and has saved innumerable lives of patients with end-stage organ failure. To improve long-term outcomes and patients’ quality of life after transplantation, clinicians and researchers need to continue working together to reach the ultimate goal of transplantation: graft acceptance without affecting normal immune function. We believe that the achievement of this goal will eventually become reality.