2016-08-012024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/645111摘要：心臟同種移植(cardiac allogeneic transplantation)為心臟衰竭末期病患的重要治療方式，但移植接受者(recipients)的長期存活率卻受限於移植性動脈硬化（transplant arteriosclerosis, TA），又稱為心臟同種植體血管病變(cardiac allograft vasculopathy, CAV)。TA是一種加速性動脈硬化，其特徵為心臟植體之冠狀動脈產生瀰漫性內膜增生，導致管腔狹窄，心肌缺氧和植體失效(graft failure)。TA的主要致病機轉為異體免疫反應(allogeneic immune response)。儘管臨床上積極的使用免疫抑制劑能有效的阻止急性心肌排斥(acute myocardial rejection)，但仍無法防範冠脈TA的發生，是以發展新的免疫調控策略實屬迫切。間葉幹細胞(mesenchymal stem cells, MSCs)可藉由產生調節性T細胞（regulatory T cell）或免疫抑制因子，如前列腺素E2（prostaglandin E2）、IL-10和TGF- β等，以調控免疫反應。本實驗室利用豬隻股動脈(femoral artery)同種異體移植模式，已證實並發表骨髓間葉幹細胞（bone marrow mesenchymal stem cells, BM-MSC） 可有效抑制TA，並增加植體血管組織中的類第一型調節性T細胞（T regulatory type 1-like cells, TR1-like cells）.骨髓幹細胞的遷移是受到趨化因子受體4（CXCR4）與其配體基質細胞衍生因子1（stromal cell derived factor-1, SDF-1, 又名CXCL12）的相互作用所支配。阻斷CXCR4和SDF-1之間的交互作用，則可將幹細胞從骨髓驅動至周邊血液中。本實驗室近期發現，CXCR4拮抗劑TG-0054可減輕局部和全身發炎反應並保持心肌梗塞後左心室功能免於惡化。我們也証實此免疫調節功能是由被驅動至周邊血液（peripheral blood，PB ）的CD271+ MSCs所完成。目前已有嚙齒類動物心臟移植模式研究MSCs延長植體存活的療效。但受限於人類與嚙齒類動物免疫與心血管系統的差異性，MSCs是否能減緩大動物與人類心臟移植模式TA的發生，仍屬未知。本實驗室已建立豬隻異位心臟移植（heterotopic heart transplantation）模式，以傳統免疫抑制劑抑制急性心肌排斥，觀察TA發展之時程。本研究計畫為期兩年，我們將（1）利用豬隻異位心臟移植模式，探討MSCs及CXCR4拮抗劑延長心臟植體存活率與預防TA之潛能；（2）探討CXCR4拮抗劑於接受移植動物體內是否經由驅動CD271+ MSCs至周邊血液，並誘導出類TR1細胞而達成免疫耐受性，以闡明調控TA之機制。此研究成果將有助於改善目前植體血管病變之治療困境，為心臟移植病人之長期存活開展契機。<br> Abstract: Heart transplantation is one of the standard treatment modalities for end-stage heart failure. However, the long-term survival of recipients is limited by the presence of transplant arteriosclerosis (TA, also named cardiac allograft vasculopathy, CAV). TA is an accelerated, obliterative form of arteriosclerosis characterized by the diffuse, concentric intimal hyperplasia, leading to severe myocardial ischemia and graft failure. It has been well accepted that allogeneic immune response plays a critical role in the pathogenesis of TA. However, classical immunosuppressive drugs (ISDs) that successfully control acute rejection do not prevent TA. This unmet clinic need suggests exploration of new immunomodulatory strategies is warranted.Mesenchymal stem cells (MSCs) have the ability to suppress immune reactions via regulatory T cells and producing immune suppressive factors such as, prostaglandin E2 and IL-10. We previously reported that bone marrow-derived MSCs effectively control TA by inducing T regulatory type 1 (TR1)-like cells in a porcine femoral artery transplantation model.Interaction between the CXC chemokine receptor 4 (CXCR4) and chemokine stromal-cell-derived factor 1 (SDF-1) governs the sequestration and mobilization of bone marrow stem cells. CXCR4 antagonists can disrupt CXCR4-mediated stem cell adhesion to stromal cells and mobilize BM stem cells to peripheral blood (PB). Our recent work demonstrates that TG-0054, a novel CXCR4 antagonist, attenuates local as well as systemic inflammation, and preserves left ventricular function after myocardial infarction (MI). This immunomodulation function is accomplished by the CD271+ MSCs mobilized into PB.Although the efficacy of MSCs in the treatment of cardiac allografts rejections has been documented in rodent models, differences exist between human beings and rodents in the immune and cardiovascular systems and the susceptibility to arteriosclerosis. Therefore, further studies are warranted to elucidate the therapeutic potential of MSCs in large animals.In this two-year proposal, we aim to (1) evaluate the therapeutic potential of MSCs and CXCR4 antagonists on the allograft survival and prevention of TA in a porcine model of heterotopic heart transplantation; (2) determine whether CXCR4 antagonists mobilize CD271+ MSCs which, in turn, induce TR1-like cells in conferring immune tolerance in TA. The findings in this project may shed light on the treatment of TA and improve the long-term survival of heart transplantation recipients.心臟移植植體動脈硬化間葉幹細胞免疫耐受性趨化因子受體4拮抗劑heart transplantationtransplant arteriosclerosismesenchymal stem cellimmune toleranceCXC chemokine receptor 4 antagonist