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

• 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
• 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

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240万次烧伤受伤。许多大烧伤的患者至少涉及其全身表面死亡的25％。大片皮肤的移植将挽救他们的生命。但是，同种异性皮肤移植物总是以急性的方式被拒绝。 Barker和Billingham在1960年代进行的开创性研究表明，传入淋巴管在拒绝皮肤同种异体移植物中的关键作用。但是，皮肤移植物的这一特征很难利用，以实现对这些移植的耐受性。最近，已经开发了一系列能够破坏淋巴管生成过程的药物，以防止癌细胞转移。这些药物（抗VEGFR3抗体，MF4-31C和A5SS1整联蛋白抑制剂，JSM6427）已证明可以防止体内3周的淋巴管生成，没有副作用。使用这些药物的初步研究证明了它们在角膜和胰岛移植中的功效。最重要的是，我们获得了初步数据，表明使用MF4-31C MAB阻断淋巴管生成可阻止供体乘客白细胞运输，减少了抗抑制剂免疫反应并延长了延长的异肌移植物存活，并最多拒绝了50天（而未培养的小鼠在10天后拒绝其植物）。我们假设使用抗VEGFR3抗体，MF4-31C和A5SSS1整联蛋白抑制剂对受体（全身或局部）的治疗方法JSM6427在使用皮肤移植时，JSM6427将破坏细胞的运输，并大概会促进宿主的抗抑制作用的性质，并影响宿主的抗抑制作用的性质，从而促进抗抑制作用的性质，从而促进抗抑制作用的性质，从而促进抗抑制作用的自由或促进。为了测试这些假设的有效性，我们提出了以下特定目的：具体目的1。研究F4-31C和JSM6427药物治疗对小鼠受益者的淋巴管生成，血管生成和细胞运输的影响。具体目标2。使用MF4-31C和JSM6427药物对淋巴管生成阻滞的影响对完全同种异体同种异体移植物的同种异体免疫反应和排斥。如果成功，这项研究将为淋巴管发生对免疫细胞运输和体内反应的影响的机制提供新的见解。此外，它将为制定基于免疫的策略铺平道路，从而允许燃烧患者的大量同种异体皮肤储存和成功移植，并重建 手术（包括面部移植）。 公共卫生相关性：在美国，每年约有240万次烧伤受伤，其中许多受害者烧伤的受害者占其全身表面死亡的25％以上。我们计划测试一系列已知的化合物，这些化合物已知可以防止淋巴管的形成。我们假设这些治疗将防止供体细胞迁移到宿主的淋巴器官，从而防止免疫排斥皮肤移植物。如果成功的话，这项研究将为生物策略的发展树立道路，允许在烧伤患者和重建手术（包括面部移植）的患者中储存和成功移植大量同种异体皮肤。