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Titel: Identifying New Targets, Developing Novel Models, and Investigating Innovative Strategies for the Treatment of Rejection in Thoracic Transplantation
Sonstige Titel: Identifizierung neuer Ziele, Entwicklung neuartiger Modelle und Erforschung von innovativen Strategien zur Behandlung von Abstoßung bei thorakalen Organtransplantationen
Sprache: Englisch
Autor*in: Hua, Xiaoqin
Schlagwörter: transplantation; rejection; immunosuppression; heart; lung
Erscheinungsdatum: 2012
Tag der mündlichen Prüfung: 2012-11-01
Zusammenfassung: 
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.

在我的博士课题研究中,关于急性排斥,首先探讨了JAK1/3抑制剂在T细胞免疫反应中的作用。结果显示两种抑制剂R507和R545均是有效抑制T细胞免疫反应的新型免疫抑制剂,同时说明了对“第三信号”传导途径的阻断是一种减轻排斥的很有前景的方法。关于慢性排斥,在肺移植方面的研究涉及到阻塞性细支气管炎动物模型的建立与比较。原位和异位气管移植模型都是可行并且可信的。可根据研究的问题有目的的选择不同的模型。使用小鼠异位气管移植模型,另一项课题鉴定出KCa3.1通道是肺移植后阻塞性细支气管炎发生的一个重要因素,并且可以被用作新靶位,来防止此种慢性并发症。特异性的KCa3.1通道阻滞可用作额外的治疗方案。动脉内膜增生是移植相关血管病变的主要表现。研究的结果显示对εPKC的持续性抑制可以通过抑制ERK和Akt途径防止血管平滑肌细胞的活化与增殖。我们亦发明了一种有效的拟人化动物模型来研究支架放置之后的血管再狭窄,其病理特征更接近人体的病变。除了器官移植,我的博士课题也涉及到了干细胞移植的免疫生物学等再生医学的研究。Islet-1被认为是心肌祖细胞的标志物,但它也在心脏一些位于特殊位置的完全分化的细胞所表达。因此Islet-1的潜在的再生性作用受到了质疑。由此我们也更加坚信多能干细胞的同种异体移植将会是发展方向。通过使用基因学技术下调人胚胎干细胞表面的HLA-1表达,证实了在异种移植条件下,HLA-1在人胚胎干细胞免疫识别中的重要作用,并证明此过程主要由T细胞调节。下调人胚胎干细胞表面的HLA-1表达可以使其逃避受体免疫系统的识别和攻击,达到长期生存的目的。在上个世纪,基于临床医生和科研共作者的共同努力,移植成为了临床现实可行的治疗方式,并且挽救了不计其数的生命。但如何提高长期生存率、提高患者的生活质量,仍需要两者的合作与努力。移植的终极梦想是不影响正常免疫功能的移植物存活。我们相信这个梦想终会实现。
URL: https://ediss.sub.uni-hamburg.de/handle/ediss/4692
URN: urn:nbn:de:gbv:18-59224
Dokumenttyp: Dissertation
Betreuer*in: Schrepfer, Sonja (Prof. Dr.)
Enthalten in den Sammlungen:Elektronische Dissertationen und Habilitationen

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