Novel MHC Class II Constructs For Treatment of EAE

描述（由申请人提供）：本研究的目的是了解和控制致病性T细胞的活化。MHC/肽抗原复合物与T细胞受体（TCR）之间的相互作用对于抗原特异性T细胞活化至关重要。抗原类似物可以作为T细胞活化的强大和特异性抑制剂，为过敏和自身免疫性疾病的抗原特异性免疫干预提供了合理的途径。最近的研究导致了MHC II类分子结构域衍生的平台分子重组ttcr配体（RTL）技术的发展。这些蛋白质疗法已经证明直接抗原特异性结合和抑制致病性T细胞。此外，这些分子可用于预防和治疗实验性自身免疫性脑脊髓炎（EAE），这是一种CD4+、Th1细胞介导的中枢神经系统（CMS）脱髓鞘疾病，被用作人类疾病多发性硬化症（MS）的模型。在本提案的任期内，RTLs将使用复发-缓解和慢性EAE模型进行表征，使我们能够探索RTLs在体内控制致病性T细胞的分子和系统机制。我们提出以下具体目标：l-As和l- ab衍生的重组TCR配体（RTLs）的生化和生物物理特性。具体目标2。RTLs影响体外T细胞活化的分子机制的表征。具体目标3。评价rtl对复发缓解型和慢性EAE模型的体内作用。这项工作将为CD4+ T细胞介导的自身免疫性疾病的药物干预提供坚实的基础。

DESCRIPTION (provided by applicant): The goal of this research is to understand and control the activation of pathogenic T cells. The interaction between the MHC/peptide-antigen complex and the T cell receptor (TCR) is essential for antigen-specific T cell activation. Antigen analogs can act as powerful and specific inhibitors of T cell activation and provide a rational approach to antigen-specific immuno-intervention in allergies and autoimmune diseases. Recent studies have lead to the development of a platform molecular RecombinantTCR Ligand (RTL) technology derived from domains of MHC Class II molecules. These protein therapeutics have demonstrated direct antigen-specific binding and inhibition of pathogenic T cells. Furthermore, these molecules could be used to prevent and treat experimental autoimmune encephalomyelitis (EAE), a CD4+, Th1 cell-mediated demyelinating disease of the central nervous system (CMS) that is used as a model for the human disease multiple sclerosis (MS). During the tenure of this proposal RTLs will be characterized using relapsing- remitting and chronic models of EAE, allowing us to explore the molecular and systemic mechanism(s) by which RTLs control pathogenic T cells in vivo. We propose the following specific aims: SPECIFIC AIM 1. Biochemical and biophysical characterization of l-As- and l-AB-derived Recombinant TCR Ligands (RTLs). SPECIFIC AIM 2. Characterization of the molecular mechanism(s) by which RTLs effect T cell activation in vitro. SPECIFIC AIM 3. Evaluation of the in vivo effects RTLs have on relapsing-remitting and chronic models of EAE. The work proposed will provide a solid base for pharmacological intervention in CD4+ T cell mediated autoimmune diseases.