Tolerance induction to vascularized skin allografts

描述（由申请人提供）：在美国，每年大约有240万例烧伤报告。许多烧伤面积至少占体表总面积25%的患者死亡。大块皮肤的移植可以挽救他们的生命。然而，同种异体皮肤移植总是急性排斥。我们已经确定了一种治疗方法，可以在移植时血管化的皮肤同种异体移植物没有免疫抑制的情况下实现耐受性，即移植物接受。本建议的目的是确定血管化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。针对这些问题，我们提出以下目标：我们将研究皮肤移植物血管化对T细胞反应（CD4+和CD8+ T细胞的直接和间接同种异体反应）、B细胞反应（同种异体抗体的产生）、移植物供体apc（乘客白细胞）向受体淋巴器官的运输以及受体T细胞（包括FoxP3+调节性T细胞）向移植物的迁移的影响。具体目标2。探讨同种异体皮肤血管化移植物通过共刺激阻断长期存活的机制。我们将研究调节性T细胞在接受抗cd40l抗体治疗的血管化皮肤同种异体移植物长期存活中的作用。我们将研究移植血管化皮肤并接受抗cd40l抗体治疗的小鼠是否会产生“真正的”供体特异性耐受性。如果成功，这项研究将为基于免疫的策略的发展开辟道路，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异体皮肤。此外，对同种异体皮肤移植的成功耐受可用于在与肾、心或肺等实体器官移植前实现对供体抗原的全身耐受。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化影响免疫反应的机制。

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).