A Model Organism to Study Chimerism

描述(申请人提供)：免疫耐受是临床移植的理想目标，因为它允许移植物在不需要持续免疫抑制的情况下接受。一种有希望的实验性耐受策略目前正在人类身上进行测试，那就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者进行毒性调节(骨髓清除、淋巴滤除和/或免疫抑制)以确保供者干细胞植入和稳定的嵌合体。在没有这种条件的情况下，嵌合体和宽容很少实现。因此，为了开发更安全的临床策略，需要更好地了解是什么防止了混合造血细胞嵌合体。这项探索性拨款提案的目标是确定防止嵌合体成功的先天免疫同种异体识别机制。为此，我们建议研究一种无脊椎动物模式生物--共生水母，它缺乏适应性免疫系统，但表现出高度特异的天然同种异体识别反应。Hydractinia异体识别系统负责防止组织不相容的动物之间的嵌合体。具体目标是：1.鉴定和鉴定水生植物异源识别基因座。2.研究同种异体水生植物嵌合体的稳定性。在无脊椎动物模式生物中发现先天性免疫识别系统，如最近在果蝇中发现的Toll受体，对脊椎动物免疫学具有潜在的重要意义。哺乳动物中Toll样受体(TLR)的识别为免疫系统如何识别和反应微生物非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、非自我)可能对移植领域具有相当重要的生物医学意义。综述：移植器官的排斥反应阻碍了人体移植的成功。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，我们建议使用一种被赋予拒绝无关个体的能力的简单海洋生物来揭示启动排斥过程的最基本的事件。

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.