Molecular And Gene Therapy For Organ Transplantation: Targeting Of Lymph Angiogenesis As a New Immunomodulatory Approach In Heart Transplantation

心脏移植是晚期心力衰竭患者的最佳选择。器官排斥反应是手术后危险的临床并发症。治疗排斥反应的发生是冠状动脉移植物血管病变和慢性排斥反应发展的危险因素，慢性排斥反应是长期存活的主要限制因素。与排斥反应相关的社会经济后果是严重的：较低的存活率、较长的住院时间和较高的排斥治疗费用。尽管目前使用的免疫抑制药物有效地抑制了同种异体反应性T细胞的增殖，但它们有代谢、感染、肾脏和恶性副作用，仍然不能完全防止心脏移植急性排斥反应的发生，也不能预防慢性排斥反应。出于这个原因，在排斥治疗中寻找进一步的替代方法仍然是有意义的。在同种异体免疫反应的初始步骤中，淋巴网络和趋化因子介导的信号对于白细胞的运输是必不可少的。我们的目标是确定淋巴管及其主要生长信号通路在同种异体免疫排斥反应中的作用。为此，我们打算研究小动物心脏移植后淋巴管激活的细节，并描述同种异体心脏移植淋巴管激活对免疫细胞运输和急性和慢性排斥反应发生的影响。这一新的认识可能为检测同种异体心脏移植物淋巴管激活的治疗靶向性提供理论依据。我们认为，通过干预淋巴管生成和白细胞运输可以为心脏移植物排斥反应提供一种新的淋巴管靶向免疫调节疗法。开发一种通过干预移植后淋巴管激活来治疗心脏移植排斥反应的新的免疫调节治疗方法是该项目的主要目标。

Heart transplantation is the best option for patients with terminal heart failure. The organ rejection represents a dangerous clinical complication after the operation. The occurrence of episodes of treated rejection is a risk factor for coronary allograft vasculopathy and development of chronic rejection, which is the major limitation of long-term survival. The rejection related socio-economic consequences are severe: lower survival rate, prolonged hospitalisation and intensive costs for rejection treatment.Although the currently used immunosuppressive drugs effectively inhibit proliferation of alloreactive T cells, they have metabolic, infectious, renal and malignant side effects and still do not completely prevent the development of acute cardiac allograft rejection and are not able to prevent chronic rejection. For this reason, the search for further alternative approaches in rejection therapy remains relevant.Lymphatic network and chemokine-mediated signals are essential for leukocyte traffic during the initial steps of alloimmune response. We are aiming to determine the role of lymphatic vessels and their principal growth signaling pathway in alloimmune rejection. For this purpose we intent to investigate the details of lymphatic vessel activation after heart transplantation in small animals, and to describe the effect of cardiac allograft lymphatic vessel activation on immune cell traffic and development of acute and chronic rejection. This new knowledge may provide the theoretical basis for testing therapeutic targeting of lymphatic vessel activation in cardiac allografts.We suggest that intervening with lymph angiogenesis and so with leukocyte traffic can represent a novel lymphatic vesseltargeted immunomodulatory therapy for cardiac allograft rejection. Development of a new immunomodulatory therapeutic approach for treating cardiac allograft rejection by intervening with post transplant lymphatic vessel activation is the primary goal of the project.