CHRONIC RELAPSING EAE

描述：本申请阐述了检查慢性病患者的研究 小鼠复发性EAE模型。首席调查员发现 与SJL不同，SJL.B小鼠既不会慢性复发，也不会出现慢性复发 EAE(CREAE)病和SJL一样。这在B10小鼠中是相反的 其中B10.S获得CREAE，而普通B10没有。这表明要 首席研究人员认为在H-2b病毒中有一种基因可能 编码用于抵抗中枢神经系统炎症复发。在这套 他着手进行研究，以找出这一现象的原因。他的 项目分为三个具体目标，其中一些目标有子目标。 在第一个具体目标中，他将研究B10的重组体 MHC部分存在的背景。通过这种方式，他希望 缩小包含可能控制CREAE的基因的区域 表型。虽然存在的基因数量有限，但他将利用这些基因 只有在极端的情况下，他才会尝试创造属于自己的新事物。 第二个具体目标是大目标，有五个子目标。所有人都是定向的 朝着确定非复发表型的细胞基础的方向发展 律政司司长在(A)中会调查律政司司长回应PLP的能力。 多肽和全分子。如果没有复发，这可能是相关的 是由于表位扩散失败所致。在(B)中，他将进一步调查 如果非复发表型是缺乏扩散到其他区域的表位 启动抗原，MBP。在这方面，他将使用他的TY1同源基因小鼠 用MBP免疫，他将测试增殖和ELISPOT检测 定义此鼠标对MBP的不同区域做出反应的能力 分子首先使用切割片段，然后使用合成肽)。在……里面 (C)他会决定深水地铁站没有出现CREAE，是否因为有 最初的脑源性(供体)细胞的丢失，或者如果这些供体细胞 失活或转变为Th2。第四个子目标(D)将寻求 了解SJL.B对CREAE的抵抗力是否可以通过操纵来纠正 通过给予超抗原或抗体来提供的细胞因子 细胞因子。在(E)中，他希望定义对CREAE的抗药性水平 驻留在脑源性细胞本身或受者体内 纸巾。他将通过互惠的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(脑源性)T细胞的管理负责或 与CREAE现象有关的持续和/或激活 主持人。在这一部分的次要目标中，他将(A)给出正常的SJL Thy1 转基因抗MBP多肽的动物致病细胞的标记 TCR。这些细胞将是脑源性的，而且还可以连续检测到 因为它们独特的Thy1分子。在(B)中，他会好像这些细胞 在EAE活动复发期间保留其致病性和Th1表型 或减刑。(C)供体生脑细胞是否确实需要？ 治疗旧病复发。他会用抗体将它们删除 脑源性细胞最初被注入，从而消除了它们。进一步 复发不可能是由于它们的致病影响。最后(D)他 将试图发现最初输注的T细胞是扩张的还是 它们的运输模式(中枢与外周--脾)在 缓解和复发。在这一点上，他将给缓解期的小鼠服用BrdU 寻求发现在复发期间在中枢神经系统中发现的细胞是否为阳性 作为记号笔。

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.