Effects of Lymphangiogenesis Blockade on Skin Allograft Rejection

描述（由申请人提供）：在美国，每年大约有240万例烧伤报告。许多烧伤面积至少占体表总面积25%的患者死亡。大块皮肤的移植可以挽救他们的生命。然而，同种异体皮肤移植总是急性排斥。Barker和Billingham在20世纪60年代进行的开创性研究表明，传入淋巴管在同种异体皮肤移植的排斥反应中起着关键作用。然而，很难利用皮肤移植的这一特性来实现对这些移植的耐受性。最近，一系列能够破坏淋巴管生成过程的药物被开发出来，以防止癌细胞转移。这些药物（抗vegfr3抗体，mF4-31C和a5ss1整合素抑制剂，JSM6427）已被证明可以在体内阻止淋巴管生成3周，无副作用。使用这些药物的初步研究已经证明了它们在角膜和胰岛移植中的有效性。最重要的是，我们获得的初步数据显示，使用mF4-31C单克隆抗体阻断淋巴管生成可阻止供体乘客白细胞运输，减少抗供体免疫反应，延长同种异体皮移植物存活长达50天（而未治疗的小鼠在10天后排斥移植物）。我们假设，在皮肤移植时，用抗vegfr3抗体mF4-31C和a5ss1整合素抑制剂JSM6427对受体（全身或局部）进行治疗，会破坏细胞从移植物到移植物的运输，影响宿主抗供体免疫反应的性质，从而促进或诱导对同种异体皮肤移植物的长期接受。为了检验这些假设的有效性，我们提出以下具体目标：研究F4-31C和JSM6427对小鼠完全异体皮肤移植后淋巴管生成、血管生成和细胞运输的影响。具体目标2。探讨mF4-31C和JSM6427阻断淋巴管生成对完全同种异体移植的同种免疫反应和排斥反应的影响。如果成功的话，这项研究将为淋巴细胞发生对体内免疫细胞运输和应答的影响机制提供新的见解。此外，它将为开发基于免疫的策略铺平道路，允许为烧伤患者和重建患者存储和成功移植大块异体皮肤

DESCRIPTION (provided by applicant): In the United States, approximately 2.4 million burn injuries are reported per year. Many patients with major burns involving at least 25% of their total body surface die. The transplantation of large patches of skin would save their lives. However, allogeneic skin grafts are invariably rejected in an acute fashion. Seminal studies performed in the 1960's by Barker and Billingham have demonstrated the key role of afferent lymphatic vessels in the rejection of skin allografts. However, this feature of skin grafts has bee difficult to exploit in an effort to achieve tolerance to these transplants. Recently, a series of agents, capable of disrupting the process of lymphangiogenesis, have been developed to prevent cancer cell metastasis. These agents (anti-VEGFR3 antibody, mF4-31C and a5ss1 integrin inhibitor, JSM6427) have been shown to prevent lymphangiogenesis for 3 weeks in vivo with no side effects. Preliminary studies using these agents have proven their efficacy in corneal and islet transplantation. Most importantly, we have obtained preliminary data showing that blocking lymphangiogenesis using mF4-31C mAbs prevents donor passenger leukocyte trafficking, reduced the anti-donor immune response and prolonged alloskin graft survival for up to 50 days (while non-treated mice rejected their grafts after 10 days). We hypothesize that treatment of recipients (systemic or topical) with anti-VEGFR3 antibody, mF4-31C and a5ss1 integrin inhibitor, JSM6427 at the time of skin transplantation with will disrupt the cell traffickng from and presumably to the graft and affect the nature of the host's anti-donor immune response, thereby promoting or inducing long-term acceptance of skin allografts. To test the validity of these hypotheses, we propose the following specific aims: Specific aim 1. Investigate the effect of treatment with F4-31C and JSM6427 agents on lymphangiogenesis, hemangiogenesis and cell trafficking in mice recipient of a fully allogeneic skin graft. Specific aim 2. Investigate the influence of lymphangiogenesis blockade using mF4-31C and JSM6427 agents on the alloimmune response to and rejection of fully allogeneic allografts. If successful, this research will provide new insights into the mechanisms underlying the influence of lymhangiogenesis on immune cell trafficking and response in vivo. In addition, it will pave the way for the development of immune-based strategies allowing the storage and successful transplantation of large patches of allogeneic skins for patients with burns and for reconstructive surgery (including face transplants).