MIXED XENOGENEIC CHIMERISM FOR ISLET XENOGRAFT TOLERANCE

I型糖尿病是一种全身性自身免疫过程， 破坏产生胰岛素的β细胞和严重的慢性 并发症 胰岛移植是最符合生理的方法 替代I型糖尿病患者的胰腺内分泌功能 糖尿病 这种方法目前受到（1）拒绝和（2） 器官短缺 供体特异性移植的诱导 跨越物种障碍的耐受性被认为可以克服这些障碍。 局限性。 主要研究者最近报告了诱导 供体特异性移植耐受的物种差异 通过制备混合异种嵌合体（小鼠+大鼠产量 小鼠）。 受体在体内（皮肤）对供体特异性耐受 移植）和体外，表现出良好的生存，并抵抗移植 抗宿主（GVH）疾病。 混合异源嵌合体模型将 用于诱导供体特异性移植耐受， 胰岛异种移植物（特定目标I）。 骨髓细胞 确定自身免疫性糖尿病的易感性。 移植 从正常动物的骨髓移植到糖尿病易感的接受者， 疾病的发展。 在Specific Aim II中， 异源嵌合体将应用于 糖尿病NOD小鼠（结合胰岛运输）和TO 预防自身免疫性糖尿病的发展 并发症 SPECIFIC AIM II将扩展这些研究， 混合异种嵌合体的非致死性处理方法， 预期潜在的临床应用。 自身免疫疾病是 认为是由于未能充分区分自我 非自我。 针对可变区的单克隆抗体 T细胞受体的β链的部分（V）（Vbeta-TCR）是T细胞受体的β链的部分（V）（Vbeta-TCR）。 强大的工具来跟踪潜在的自身反应性T细胞的命运， 在胸腺中发育的淋巴细胞。 间接证据显示 积累到强烈牵连肽（超抗原）， 自身免疫性疾病中选定的TCR-V β家族。 具体目标四 将表征促细胞（包括V β）的表型 REPERTOIRE）负责胰岛延迟分析 超抗原效应存在于I型糖尿病中。 的总目标 该项目旨在治疗糖尿病，预防相关并发症， 了解自身免疫的机制

Type I diabetes is a systemic autoimmune process which results in destruction of the insulin-producing beta-cells and severe chronic complications. Islet transplantation is the most physiologic approach to replace pancreatic endocrine function in patients with Type I diabetes. This approach is currently limited by (1) rejection and (2) a shortage of organs. The induction of donor-specific transplantation tolerance across a species barriers has been suggested to overcome these limitations. The Principal Investigator recently reported the induction of donor-specific transplantation tolerance across a species disparity through the preparation of mixed xenogeneic chimeras (mouse + rat yields mouse). Recipients were specifically tolerant to the donor in vivo (skin graft) and in vitro, exhibited excellent survival, and resisted graft versus host (GVH) disease. The model for MIXED XENOGENEIC CHIMERISM will be applied TO INDUCE DONOR-SPECIFIC TRANSPLANTATION TOLERANCE TO PANCREATIC ISLET XENOGRAFTS (Specific Aim I). Bone marrow cells determine the susceptibility to autoimmune diabetes. Transplantation of bone marrow from normal animals into diabetes-prone recipients prevented the development of the disease. In Specific Aim II, the model for MIXED XENOGENEIC CHIMERISM WILL BE APPLIED TO REVERSE AUTOIMMUNE DIABETES IN DIABETIC NOD MICE (in conjunction with islet transportation) AND TO PREVENT THE DEVELOPMENT OF AUTOIMMUNE DIABETES before irreversible complications. SPECIFIC AIM II will extend these studies to achieve mixed xenogeneic chimerism using a nonlethal conditioning approach in anticipation of potential clinical application. Autoimmune disease is believed to result from a failure to adequately discriminate between self and non-self. Monoclonal antibodies directed against the variable portion (V) of the beta-chain of the T-cell receptor (Vbeta-TCR) are a powerful tool to follow the fate of potentially autoreactive T- lymphocytes developing in the thymus. Circumstantial evidence has been accumulating to strongly implicate peptides (SUPERANTIGENS) which bind to selected TCR-Vbeta families in autoimmune disease. Specific Aim IV will CHARACTERIZE THE PHENOTYPE OF EFFECTOR CELLS (INCLUDING VBETA REPERTOIRE) RESPONSIBLE FOR ISLET DESTRUCTION to analyze whether a superantigen effect is present in Type I Diabetes. The overall goals of this project is to treat diabetes, prevent the associated complications, and understand the mechanism underlying the autoimmunity.