A Model Organism to Study Chimerism

描述（由申请人提供）：免疫耐受是临床移植的理想目标，因为它允许移植物接受而不需要持续的免疫抑制。目前正在人类中测试的一种有希望的实验耐受性策略是诱导混合造血嵌合体。阻碍混合造血嵌合体临床成功的主要障碍是需要对受体进行毒性调节（骨髓清除、淋巴细胞清除和/或免疫抑制），以确保供体干细胞植入和稳定的嵌合体。在没有这种条件作用的情况下，嵌合体和耐受性很少实现。因此，需要更好地了解是什么阻止了混合造血嵌合体，以制定更安全的临床策略。这项探索性拨款提案的目标是确定先天免疫同种异体识别机制，防止成功的嵌合体。要做到这一点，我们建议研究无脊椎动物的模式生物，Hydractinia symbiolongarpus，它缺乏适应性免疫系统，但表现出高度特异性的先天同种异体识别反应。Hydroactinia同种异体识别系统负责防止组织不相容动物之间的嵌合。具体目标是：1.鉴定和表征海葵的同种识别位点。2.表征异源海葵嵌合体的稳定性。揭示先天性免疫识别系统在无脊椎动物模式生物，如Hydractinia是潜在的脊椎动物免疫学的极大相关性，最近在果蝇Toll受体的发现说明。Toll样受体（TLR）在哺乳动物中的鉴定为免疫系统如何识别和反应微生物非自我提供了一个令人信服的解释。了解先天免疫系统如何识别同种异体细胞（非微生物非自身）可能与移植领域具有相当重要的生物医学相关性。摘要：人体移植的成功受到移植器官排斥的阻碍。了解引发排斥反应的最早事件对于开发有效的治疗方法至关重要。在这里，我们建议使用一个简单的海洋生物被赋予拒绝无关的个人的能力，以揭示最基本的事件，启动拒绝过程。

DESCRIPTION (provided by applicant): Immunological tolerance is a desirable goal in clinical transplantation as it permits graft acceptance without the need for continuous immunosuppression. A promising experimental tolerance strategy that is currently being tested in humans is the induction of mixed hematopoeitic chimerism. The major obstacle impeding the clinical success of mixed hematopoetic chimerism has been the need for toxic conditioning (myeloablation, lymphodepletion, and/or immunosuppression) of the recipient to ensure donor stem cell engraftment and stable chimerism. In the absence of such conditioning, chimerism and tolerance are rarely achieved. Therefore, a better understanding of what prevents mixed hematopoeitic chimerism is needed to develop safer clinical strategies. The goal of this exploratory grant proposal is to identify the innate immune allorecognition mechanisms that prevent successful chimerism. To do so, we propose to study an invertebrate model organism, Hydractinia symbiolongicarpus, which lacks an adaptive immune system yet exhibits a highly specific innate allorecognition response. The Hydractinia allorecognition system is responsible for preventing chimerism between histo-incompatible animals. The specific aims are: 1. To identify and characterize Hydractinia allorecognition loci. 2. To characterize the stability of allogeneic Hydractinia chimeras. Uncovering innate immune recognition systems in an invertebrate model organism such as Hydractinia is potentially of great relevance to vertebrate immunology as recently illustrated by the discovery of Toll receptors in Drosophila. The identification of Toll-like receptors (TLR) in mammals provided a compelling explanation of how the immune system recognizes and reacts to microbial non-self. Understanding how the innate immune system recognizes allogeneic cells (non-microbial non-self) may be of comparable important biomedical relevance to the field of transplantation. Lay Summary: The success of transplantation in humans is hindered by rejection of the transplanted organ. Understanding the earliest events that trigger rejection is essential for developing effective therapies. Here we propose to use a simple marine organism endowed with the ability to reject unrelated individuals to uncover the most basic events that initiate the rejection process.