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。目前正在人体中测试的一种有前途的实验性耐受性策略是诱导混合造血嵌合。阻碍混合造血嵌合临床成功的主要障碍是需要对受体进行毒性调节（骨髓消融、淋巴细胞消耗和/或免疫抑制），以确保供体干细胞的植入和稳定的嵌合。在缺乏这种条件的情况下，嵌合和容忍很少实现。因此，需要更好地了解是什么阻止混合造血嵌合，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，阻止成功的嵌合。为了做到这一点，我们建议研究一种无脊椎模式生物，Hydractinia symbiolongicarpus，它缺乏适应性免疫系统，但表现出高度特异性的先天异体识别反应。水螅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。鉴定和表征水螅同种异体识别位点。2. 表征同种异体水螅嵌合体的稳定性。揭示无脊椎动物模式生物（如水螅虫）的先天免疫识别系统，对脊椎动物免疫学具有潜在的重大意义，最近在果蝇中发现Toll受体就说明了这一点。哺乳动物中toll样受体（TLR）的鉴定为免疫系统如何识别和反应非自身微生物提供了令人信服的解释。了解先天免疫系统如何识别异体细胞（非微生物非自体）可能对移植领域具有同等重要的生物医学意义。摘要：人体移植的成功受到移植器官排斥反应的阻碍。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，我们建议使用一种简单的海洋生物，被赋予了拒绝不相关个体的能力，以揭示启动拒绝过程的最基本事件。

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.