Tolerance induction to vascularized skin allografts

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。我们已经确定了一种可以实现耐受性的治疗方法，即在移植时对同种异体皮肤移植进行血管化时，在没有免疫抑制的情况下接受移植物。这项建议的目的是确定血管形成影响同种异体皮肤移植物免疫反应的机制，并促进这些移植物的长期存活。为了解决这些问题，我们提出了以下目标：1.研究血管化如何影响皮肤移植免疫反应的生理学我们将研究皮肤移植血管化对T细胞反应(由CD4+和CD8+T细胞直接和间接同种异体反应)、B细胞反应(同种抗体产生)、移植物供体APC(乘客白细胞)向受者淋巴器官的运输以及包括FoxP3+调节性T细胞在内的受者T细胞向皮片移植物的迁移的影响。具体目的2.通过共刺激阻断研究带血管同种异体皮肤移植物长期存活的机制。我们将研究调节性T细胞在抗CD40L抗体治疗的同种异体皮肤移植物长期存活中的作用。我们将调查移植了带血管皮肤并接受抗CD40L抗体治疗的小鼠是否会产生“真正的”供者特异性耐受。如果成功，这项研究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手术(包括面部移植)存储和成功移植大片同种异体皮肤。此外，在肾、心脏或肺等实体器官移植前，成功的皮肤移植耐受性可用于实现对供体抗原的全身耐受性。除了在移植生物学方面的意义外，这项研究还可能有助于更好地理解肿瘤血管形成影响免疫反应的机制。 公共卫生相关性：在美国，每年大约有240万人报告烧伤，许多严重烧伤的患者至少占其总体表的25%死亡。通过移植时同种异体皮肤的血管化，有可能实现耐受性(即在没有免疫抑制的情况下接受移植物)。我们希望确定血管化影响同种异体皮肤移植免疫反应的机制，并促进这些移植物的长期存活，如果成功，将为基于免疫的策略的开发铺平道路，从而为烧伤患者和重建手术(包括面部移植)患者储存和成功移植大片同种异体皮肤奠定基础。

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. We have identified a treatment that can achieve tolerance i.e. graft acceptance in the absence of immunosuppression to skin allografts when they are vascularized at the time of transplantation. The objective of this proposal is to identify the mechanisms by which vascularization affects the immune response to skin allografts and promote long-term survival of these transplants. To address these issues, we propose the following aims: Specific aim 1. Investigate how vascularization affects the physiology of the immune response to skin allografts We will study the effects of skin graft vascularization of the T cell response (direct and indirect alloresponses by CD4+ and CD8+ T cells), the B cell response (alloantibody production), the trafficking of graft donor APCs (passenger leukocytes) to recipient's lymphoid organs and the migration of recipient's T cells including FoxP3+ regulatory T cells to the skin graft. Specific aim 2. Investigate the mechanisms underlying long-term survival of vascularized skin allografts via costimulation blockade. We will investigate the role of regulatory T cells in long-term survival of vascularized skin allografts in recipients treated with anti-CD40L antibodies. We will investigate whether mice transplanted with a vascularized skin and treated with anti-CD40L antibodies develop "true" donor-specific tolerance. If successful, this research will set the path for the development of immune-based strategies allowing the storage and successful transplantation of large patches of allogeneic skin for patients with burns and for reconstructive surgery (including face transplants). In addition, successful tolerance to skin allografts could be used to achieve systemic tolerance to donor antigens prior to transplantation with solid organ transplants such as kidneys, hearts or lungs. In addition to its implications in transplantation biology, this research may lead to a better understanding on the mechanisms by which vascularization of tumors affects the immune response. PUBLIC HEALTH RELEVANCE: In the United States, where 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. Through vascularization of skin allografts at the time of transplantation, it possible to achieve tolerance (i.e. graft acceptance in the absence of immunosuppression). We hope to identify the mechanisms by which vascularization affects the immune response to skin allografts and promote long-term survival of these transplants and, if successful, set the path for the development of immune-based strategies allowing the storage and successful transplantation of large patches of allogeneic skin for patients with burns and for reconstructive surgery (including face transplants).