Composite Tissue Transplantation

描述：这项建议的长期目标是推进临床 减少手部及复合组织移植面积在临床中的应用 免疫抑制治疗的不良反应。复合组织的作用 移植的基础是功能和美观重建 创伤、先天缺陷或癌症切除。同种异体药物的应用 重建可以避免供区发病率的限制和 可获得性，并为重建 专门的结构，如四肢和头面部部件。 已经建立了一种可靠的小鼠模型来研究小鼠的免疫学。 复合组织移植及利用新近获得的抗体 疗法和基因操纵的动物。封锁CD40 共刺激通路是已有的策略的重要组成部分 成功延长啮齿动物同种异体皮肤和器官移植的存活时间 以及大型动物模型。这一策略尚未在肢体模型中进行研究。 移植。免疫诱导的作用机制 作为单一药物使用时的无反应性和耐受性 在器官移植方面的研究仍在继续。CD40封锁出现 与包括供骨在内的其他疗法相结合时最成功 骨髓输注。同种异体肢体移植的骨髓成分 区别于同种异体器官移植，因此可能有更大的 具有诱导耐受性的潜力。这项建议的具体目的 目的：1)确定同种异体肢体移植耐受的机制。 经CD40阻断治疗后。2)开发一种综合疗法，用于治疗 CD40共刺激诱导同种异体肢体移植耐受 封锁。3)确定供体特异性免疫机制 以CD40阻断为基础的联合方案无反应。评估 技术包括混合淋巴细胞培养、流式细胞术和ELISPOT 检测，结合组织学和免疫组织化学评估 同种异体移植的存活率和排斥反应。这项提议的总体目标是 改善重建选择的质量和生活质量 患有严重畸形的病人。

DESCRIPTION: The long-term goal of this proposal is to advance the clinical application of hand and composite tissue transplantation by reducing the adverse effects of immunosuppressive therapy. The role of composite tissue transplantation is based on functional and aesthetic reconstruction following trauma, congenital defect or cancer resection. The application of allogeneic reconstruction could avoid the limitations of donor-site morbidity and availability, and offer greater potential for the reconstruction of specialized structures such as limb and craniofacial components. A reliable murine model has been developed to study the immunology of composite tissue transplantation and to utilize recently available antibody therapies and genetically manipulated animals. Blockade of the CD40 costimulatory pathway is an important component of strategies that have been successful in prolonging the survival of skin and organ allografts in rodent and large animal models. This strategy has not been studied in a model of limb transplantation. The mechanism of action for the induction of immune unresponsiveness and the resistance to tolerance when used as a single agent in organ transplantation continues to be investigated. CD40 blockade appears to be most successful when combined with other therapies including donor bone marrow transfusion. The bone marrow component of a limb allograft distinguishes it from organ allografts, and may therefore have a greater potential for the induction of tolerance. The specific aims of this proposal are: 1) To determine the mechanism of resistance to limb allograft tolerance after treatment with CD40 blockade. 2) To develop a combined regimen for the induction of tolerance to limb allografts based on CD40 costimulation blockade. 3) To determine the mechanism of donor-specific immune unresponsiveness by a combined regimen based on CD40 blockade. Assessment techniques include mixed lymphocyte culture, flow cytometry, and the ELISPOT assay, in conjunction with histological and immunohistochemical assessment of allograft viability and rejection. The broad objective of this proposal is to improve the quality of reconstructive options and the quality of life for patients with devastating deformities.