Effects of Lymphangiogenesis Blockade on Skin Allograft Rejection

淋巴管生成阻断对皮肤同种异体移植排斥的影响

基本信息

批准号：
8302693
负责人：
GILLES A BENICHOU
金额：
$ 16.9万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-03-01 至 2014-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8302693
关键词：
Acute Adverse effects Affect Allogenic Allografting Antibodies Antigens Artificial skin B-Lymphocytes Bees Biological Body Surface Burn injury CD8B1 gene Cells Clinical Collaborations Data Development Engineering Frequencies Graft Survival Heart Image Imaging technology Immune Immune response Immunosuppression Immunosuppressive Agents In Vitro Individual Integrins Islets of Langerhans Transplantation Isoantibodies Keratoplasty Kidney Laboratories Leukocyte Trafficking Leukocytes Lung Lymphangiogenesis Lymphatic vessel Lymphoid Modeling Mus Nature Neoplasm Metastasis Optics Organ Organ Transplantation Patients Process Production Protocols documentation Reconstructive Surgical Procedures Reporting Research Seminal Series Site Skin Skin Tissue Skin Transplantation Skin graft Solid T cell response T-Lymphocyte Testing Time Transplantation United States Vascular Endothelial Growth Factor Receptor-3 allograft rejection base cancer cell effective therapy facial transplantation in vivo inhibitor/antagonist insight intravital microscopy lymph nodes migration prevent response skin allograft skin patch trafficking treatment effect two-photon

项目摘要

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).

描述（由申请人提供）：在美国，每年约有 240 万烧伤报告。许多全身面积至少 25% 严重烧伤的患者死亡。大块皮肤的移植将挽救他们的生命。然而，同种异体皮肤移植总是会受到严重排斥。 Barker 和 Billingham 在 1960 年代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，很难利用皮肤移植的这一特征来努力实现对这些移植的耐受性。最近，已经开发出一系列能够破坏淋巴管生成过程的药物来预防癌细胞转移。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预防淋巴管生成 3 周，且无副作用。使用这些药物的初步研究已证明它们在角膜和胰岛移植中的功效。最重要的是，我们获得的初步数据表明，使用 mF4-31C mAb 阻断淋巴管生成可防止供体过客白细胞贩运，降低抗供体免疫反应，并延长同种异体皮移植物的存活时间长达 50 天（而未经治疗的小鼠在使用后排斥其移植物） 10 天）。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 对受者（全身或局部）进行治疗将破坏来自移植物的细胞运输以及可能到达移植物的细胞运输，并影响移植物的性质宿主的抗供体免疫反应，从而促进或诱导皮肤同种异体移植物的长期接受。为了测试这些假设的有效性，我们提出以下具体目标：具体目标 1. 研究 F4-31C 和 JSM6427 药物治疗对完全同种异体皮肤移植小鼠接受者的淋巴管生成、血管生成和细胞运输的影响。具体目标 2. 研究使用 mF4-31C 和 JSM6427 药物阻断淋巴管生成对完全同种异体移植物的同种免疫反应和排斥的影响。如果成功，这项研究将为淋巴管生成对体内免疫细胞运输和反应的影响机制提供新的见解。此外，它将为基于免疫的策略的开发铺平道路，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 万起烧伤报告，其中许多烧伤面积超过全身表面 25% 的受害者死亡。我们计划测试一系列已知可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，从而防止皮肤移植物的免疫排斥。如果成功，这项研究将为开发生物策略开辟道路，允许为烧伤患者和重建手术（包括面部移植）存储和成功移植大块同种异体皮肤。