Novel MHC Class II Constructs For Treatment of EAE

描述(申请人提供)：本研究的目标是了解和控制致病T细胞的激活。MHC/多肽-抗原复合体与T细胞受体(TCR)之间的相互作用是抗原特异性T细胞激活所必需的。抗原类似物可以作为T细胞激活的有效和特异的抑制物，并为过敏和自身免疫性疾病的抗原特异性免疫干预提供了一种合理的方法。最近的研究导致了平台分子重组TCR配体(RTL)技术的发展，该技术源于MHC II类分子的结构域。这些蛋白质疗法已经证明了对致病T细胞的直接抗原特异性结合和抑制。此外，这些分子还可用于预防和治疗实验性自身免疫性脑脊髓炎(EAE)，这是一种由CD4+、Th1细胞介导的中枢神经系统(CMS)脱髓鞘疾病，被用作人类多发性硬化症(MS)的模型。在本提案的有效期内，将使用复发-缓解和慢性EAE模型来表征RTL，使我们能够探索RTL在体内控制致病T细胞的分子和系统机制(S)。我们提出了以下具体目标：特异性目标1.L-AS和L-AB衍生的重组TCRL的生化和生物物理特性。特异性目的2.研究RTLS影响T细胞体外活化的分子机制(S)具体目的3.评价RTL对复发-缓解和慢性EAE模型的体内影响。这项工作将为药物干预治疗CD4+T细胞介导的自身免疫性疾病提供坚实的基础。

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.