Effects of Lymphangiogenesis Blockade on Skin Allograft Rejection

描述（由申请人提供）：在美国，每年报告约240万例烧伤。许多严重烧伤的病人至少有25%的体表面积会死亡。大片皮肤的移植可以挽救他们的生命。然而，同种异体皮肤移植物总是以急性方式排斥。Barker和比灵厄姆在20世纪60年代进行的精液研究已经证明了传入淋巴管在皮肤同种异体移植排斥中的关键作用。然而，皮肤移植物的这一特征在努力实现对这些移植物的耐受性方面一直难以利用。近年来，一系列能够阻断淋巴管生成过程的药物被开发出来，用于预防癌细胞转移。这些药剂（抗VEGFR 3抗体，mF 4 - 31 C和α 5 β 1整联蛋白抑制剂，JSM 6427）已显示在体内预防淋巴管生成3周而无副作用。使用这些药物的初步研究已证明其在角膜和胰岛移植中的有效性。最重要的是，我们已经获得了初步数据，表明使用mF 4 - 31 C mAb阻断淋巴管生成可防止供体乘客白细胞运输，降低抗供体免疫应答，并延长同种异体皮肤移植物存活长达50天（而未治疗的小鼠在10天后排斥其移植物）。我们假设，在皮肤移植时用抗VEGFR 3抗体、mF 4 - 31 C和α 5 β 1整联蛋白抑制剂JSM 6427治疗（全身或局部）受体将破坏来自移植物的细胞运输和可能的细胞向移植物的运输，并影响宿主的抗供体免疫应答的性质，从而促进或诱导皮肤同种异体移植物的长期接受。为了检验这些假设的有效性，我们提出了以下具体目标：具体目标1。研究用F4- 31 C和JSM 6427试剂处理对完全同种异体皮肤移植物的小鼠受体中的淋巴管生成、血管生成和细胞运输的影响。具体目标2。研究使用mF 4 - 31 C和JSM 6427试剂阻断淋巴管生成对完全同种异体移植物的同种免疫应答和排斥的影响。如果成功的话，这项研究将提供新的见解的机制的影响hangiogenesis对免疫细胞的运输和反应在体内。此外，它将为开发基于免疫的策略铺平道路，从而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，每年报告约240万例烧伤，其中许多烧伤面积超过全身面积25%的患者死亡。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，这项研究将为生物策略的发展铺平道路，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).