INDUCTION OF IMMUNOLGICAL TOLERANCE TO ISLET XENOGRAFTS

我们的实验室最近开发了一种两元素法来测定 诱导小鼠同种异体胰岛移植耐受。这两种技术的结合 小供体淋巴细胞和一种针对共激活的抗体 CD40分子配体(CD40L)使我们能够获得永久性胰岛 同种异体移植物存活率。该项目旨在延长我们最初的 异种胰岛移植系统的观察。我们公布的数据显示 我们的两元素协议可以显著延长 大鼠胰岛和小鼠皮肤异种移植。 在本方案中，我们将1)确定公差的最佳参数 大鼠胰岛和皮肤移植对正常小鼠的诱导作用 人类起源和2)确定宿主免疫反应元件允许 耐受小鼠的异种移植存活(具体目标1)。这些模型 然后，将在收养转移研究中进一步调查这些系统 使用SCID小鼠受体识别细胞机制 允许异种移植在耐受小鼠中存活(具体目标2)。这个 确定的机制将与那些被发现的机制进行比较 负责项目1中的同种异体移植耐受性。这是一个重要的 目标是因为无论是身份还是功能能力 参与异种移植物与同种异体移植物的细胞成分 拒绝是确定无疑的。我们的第三个目标是扩大我们的 人体免疫系统的两要素耐受性诱导方案。我们 已经开发出一种创造完全异种淋巴造血的方法 使用植入人外周血的NOD-SCID小鼠的嵌合体 淋巴细胞(Hu-PBL-NOD-SCID小鼠)。HU-PBL-NOD-SCID小鼠将用于 诱导移植的人体免疫系统对异种病毒的耐受性 胰岛和皮肤(具体目标3)。虽然主要是针对 为此目的而开发的嵌合体技术--异种胰岛移植的研究 这也将允许我们1)研究对人类胰岛的耐受诱导 小动物模型系统中的同种异体移植，以及2)在本实验中的比较 正常人的系统外周血淋巴细胞与慢性阻塞性肺疾病患者的外周血淋巴细胞 胰岛素依赖性糖尿病(IDDM)。 我们的总体目标是在人类免疫系统中诱导异种耐受 采用可适应临床实践的二元法。我们 我相信，希望这种方法最终能证明 适用于治疗糖尿病。

Our laboratories have recently developed a two element method for the induction of tolerance to murine islet allografts. The combination of small donor lymphocytes and an antibody directed against the co-activation molecule CD40 ligand (CD40L) has enabled us to achieve permanent islet allograft survival. This Project is intended to extend our initial observations to islet xenograft systems. We have published data showing that our two element protocol can substantially prolong the survival of both rat islet and skin xenografts in mice. In this proposal, we will 1) identify the optimal parameters for tolerance induction in normal mice engrafted with islets and skin of both rat and human origin and 2) identify the host immune response elements that permit xenograft survival in tolerized mice (Specific Aim #1). These model systems will then be investigated further in adoptive transfer studies using scid mouse recipients to identify the cellular mechanisms that permit xenograft survival in tolerized mice (Specific Aim #2). The mechanisms identified will be compared with those mechanisms found to be responsible for allograft tolerance in Project 1. This is an important objective because neither the identity nor the functional capabilities of the cellular elements which participate in xenograft vs. allograft rejection are known with certainty. Our third objective is to extend our two element tolerance induction protocol to the human immune system. We have developed a method for creating complete xenogeneic lymphohemopoietic chimeras using the NOD-scid mouse engrafted with human peripheral blood lymphocytes (Hu-PBL-NOD-scid mice). Hu-PBL-NOD-scid mice will be used to induce, tolerance in the engrafted human immune system to xenogeneic islets and skin (Specific Aim #3). Although directed primarily at the study of islet xenografts, the chimera technology developed for this Aim will also permit us 1) to study the induction of tolerance to human islet allografts in a small animal model system, and 2) to compare in this system PBLs from normal individuals with those obtained from patients with insulin-dependent diabetes mellitus (IDDM). Our overall goal is to induce xenotolerance in the human immune system using a two element method that can be adapted to clinical practice. We believe it realistic to hope that this method may eventually prove suitable for curing diabetes mellitus.