CHRONIC RELAPSING EAE

描述：本申请阐述了检查慢性炎症的研究。 复发性EAE小鼠模型。 首席研究员发现 SJL.B小鼠与SJL不同， EAE（CREAE）疾病和SJL一样。 这在B10小鼠中是相反的， B10.S得到CREAE而正常B10没有。 这指示 首席研究员说，在H-2b中有一个基因， 编码对CNS炎症复发的抗性。 的此集合中 他开始研究如何解释这一现象。 他 该项目分为三个具体目标，其中一些还有子目标。 在第一个具体目标，他将研究重组的B10 MHC部分存在的背景。 这样，他希望 缩小可能控制CREAE的基因座区域 表型。 虽然存在有限数量的同类，但他将利用这些同类， 只有在极端的情况下，他才能创造出自己的新生命。 第二个具体目标很大，有五个子目标。 都是针对 为了确定非复发性表型的细胞基础， SJL.B.在（A）中，他将调查SJL.B响应PLP的能力 肽和整个分子。 如果没有复发， 是由于表位扩散失败。 在（B）中，他将进一步调查 如果非复发性表型缺乏扩散到其它区域的表位 的起始抗原MBP 在这一实验中，他将使用他的thy 1同源小鼠 用MBP免疫，他将测试增殖和ELISPOT测定， 定义这只小鼠对MBP不同区域的反应能力 分子首先使用切割片段，然后是合成肽）。 在 (C)他将确定SJL.B中不存在CREAE是否是因为 初始致脑炎（供体）细胞的损失，或者如果这些供体细胞 失活或转移到Th 2。 第四个分目标（D）将力求 了解SJL.B对CREAE的抵抗是否可以通过操作来纠正 通过给予超抗原或抗体， 细胞因子 在（E）中，他希望确定是否对CREAE的抗性水平 存在于致脑炎细胞本身或受体中 组织中 他将通过相互的T细胞转移来做到这一点。 在第三个也是最后一个目标中，他希望确定最初的 供体（致脑炎）T细胞的施用负责或 与CREAE现象相关，在 主持人 在本部分的子目标中，他将（A）给出正常的SJL Thy 1 来自抗MBP肽转基因动物的标记的病原细胞 TcR。 这些细胞将是致脑炎的，并且也是持续可检测的 因为它们独特的Thy 1分子。 在（B）中，他会认为这些细胞 在EAE活动性复发期间保持其致病性和Th 1表型 或缓解。 部分（C）是实际需要的供体致脑炎细胞 治疗复发 他会用抗体删除它们， 最初注入的致脑炎细胞，从而消除它们。 进一步 复发不能归因于它们的致病影响。 （D）他 将试图发现最初注入的T细胞是否扩增， 它们的运输模式（中枢神经系统与外周-脾脏）在 缓解和复发。 在这个实验中，他将给缓解期的小鼠注射BrdU， 试图发现在复发期间在CNS中发现的细胞是否为阳性 为了马克。

DESCRIPTION: This application sets forth studies to examine the chronic relapsing EAE model in the mouse. The principal investigator has discovered that the SJL.B mouse, unlike the SJL, does nor develop a chronic relapsing EAE (CREAE) disease as does the SJL. This is reversed in the B10 mouse in which the B10.S gets CREAE while the normal B10 does not. This indicates to the principal investigator that in the H-2b there is a gene which might encode for resistance to relapses in CNS inflammation. In this set of studies he sets forth to discover the explanation for this phenomenon. His project is divided into three Specific Aims, some of which have subaims. In the first Specific Aim he will investigate recombinants of the B10 background in which the MHC is partially present. In this manner he hopes to narrow the area containing the locus that might control the CREAE phenotype. While a limited number of congenics exist, he will utilize those available and only in the extreme try to generate new ones of his own. The second Specific Aim is large an has five subaims. all are directed toward defining the cellular basis of the non-relapsing phenotype of the SJL.B. In (A) he will investigate the ability of the SJL.B to respond to PLP peptides and whole molecule. This might be relevant if the lack of relapses is due to failure of epitope spreading. In (B) he will further investigate if the non-relapsing phenotype is a lack of epitope spreading to other areas of the initiating antigen, MBP. In this he will use his thy1 congenic mice immunized with MBP and he will test proliferation and ELISPOT assays to define the ability of this mouse to respond to different areas of the MBP molecule first using cleavage fragments followed by synthetic peptides). In (C) he will determine if the absence of CREAE in SJL.B is because there is loss of the initial encephalitogenic (donor) cells or if these donor cells become inactivated or shift to Th2. The fourth subaim (D) will seek to learn if the SJL.B's resistance to CREAE can be corrected by manipulations of cytokines afforded by giving superantigens or antibodies against cytokines. In (E) he hopes to define if the level of resistance to CREAE resides in the encephalitogenic cells themselves or in the recipients tissues. He will do this by reciprocal T cell transfers. In the third and final aim, he hopes to determine if the initial administration of donor (encephalitogenic) T cells is responsible for or related to the CREAE phenomenon by remaining persistent and/or activated in the host. In subaims of this part he will (A) give the normal SJL Thy1 tagged pathogenic cells from an animal transgenic for an anti-MBP peptide TcR. These cells will be encephalitogenic, and also continuously detectable because of their distinct Thy1 molecule. In (B) he will as if these cells retain their pathogenicity and Th1 phenotype during active recurrence of EAE or remission. Part (C) are the donor encephalitogenic cells actually needed for relapses. He will delete them with antibodies against the encephalitogenic cells initially infused, thus eliminating them. Further relapses could not be due to their pathogenic influence. Finally (D) he will seek to discover if the initially infused T cells are expand or if their trafficking patterns (CNS vs. periphery -- spleen) change between remission and relapse. In this he will give BrdU to mice in remission and seek to discover if the cells found in the CNS during relapse are positive for the marker.