Effects of Lymphangiogenesis Blockade on Skin Allograft Rejection

描述(由申请人提供)：在美国，每年大约有240万人被烧伤。许多严重烧伤的患者至少占其总体表面积的25%会死亡。大片皮肤的移植将挽救他们的生命。然而，异体皮肤移植总是以一种急性的方式被排斥。Barker和Billingham在20世纪60年代对S进行的开创性研究证明了传入淋巴管在同种异体皮肤移植排斥反应中的关键作用。然而，皮肤移植的这一特点很难被利用，以努力实现对这些移植的耐受性。最近，一系列能够干扰淋巴管生成过程的药物已经被开发出来，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)已被证明可在体内阻止淋巴管生成3周，且无副作用。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，我们已经获得的初步数据表明，使用mF4-31C单抗阻断淋巴管生成可以阻止供者载客白细胞的运输，降低抗供者免疫反应，并将同种异体皮肤移植物的存活延长至50天(而未治疗的小鼠在10天后拒绝移植物)。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治疗受者(全身或局部)将扰乱移植物的细胞运输，并影响宿主抗供体免疫反应的性质，从而促进或诱导同种异体皮肤移植的长期接受。为了检验这些假说的有效性，我们提出了以下具体目标：具体目标1.研究F4-31C和JSM6427药物治疗对全异基因皮肤移植小鼠淋巴管生成、血管生成和细胞迁移的影响。具体目的2.研究mF4-31C和JSM6427阻断淋巴管生成对完全同种异体移植物免疫应答和排斥反应的影响。如果成功，这项研究将为淋巴血管生成影响体内免疫细胞运输和反应的潜在机制提供新的见解。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储存和成功移植大片同种异体皮肤。 手术(包括面部移植)。 公共卫生相关性：在美国，每年约有240万人被烧伤，其中许多患者烧伤面积超过其总体表的25%死亡。我们计划测试一系列已知可以防止淋巴管形成的化合物。我们假设这些治疗将阻止供体细胞迁移到宿主的淋巴器官，从而防止皮肤移植的免疫排斥反应。如果成功，这项研究将为开发生物策略铺平道路，允许为烧伤患者和重建手术(包括面部移植)储存和成功移植大片同种异体皮肤。

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). PUBLIC HEALTH RELEVANCE: In the United States, approximately 2.4 million burn injuries are reported per year, and many of these victims with burns to greater than 25% of their total body surface die. We plan to test a series of compounds which are known to prevent the formation of lymphatic vessels. We hypothesize that these treatments will prevent the migration of donor cells to the host's lymphoid organs and thereby prevent immune rejection of skin grafts. If successful, this research will set the path for the development of biological strategies allowin the storage and successful transplantation of large patches of allogeneic skin for patients with burns and for reconstructive surgery (including face transplants).