PEPTIDE MEDIATED IMMUNOTHERAPY FOR AUTOIMMUNE DISEASE

该基金资助了改变肽配体（APL）治疗自身免疫性疾病，特别是多发性硬化症（MS）的研究。在过去的五年里开展的工作为复发缓解型多发性硬化症患者的首次临床试验提供了框架。在下一个拨款期，我们建议开展临床前实验，以优化多发性硬化症动物模型中的APL治疗，并利用裸DNA疫苗接种技术开发下一代APL治疗。我们还将展示微生物如何通过与自身分子的结构模仿来调节自身免疫性疾病。这笔拨款的具体目的是：1)破坏APL的表位扩散。在这个目的中，我们将看到在分子间表位扩散发生后，如果靶向单个髓磷脂分子上的单个表位的APL能够抑制正在进行的EAE，并逆转瘫痪。这是一个严格的要求，但将是一个有用的范例，以优化治疗方案的II期临床试验复发缓解型MS患者。在Aim 2中，我们将分析APL脉冲树突状细胞如何用于逆转EAE。在Aim 3中，我们将尝试通过接种编码髓磷脂表位的DNA小基因来治疗APL。我们已经成功地利用编码髓鞘PLP表位的小基因通过DNA疫苗预防了EAE。我们将利用髓鞘微小基因与细胞因子和趋化因子构建体配对来优化这种方法。最后，在Aim 4中，我们将研究APL作为调节EAE的微生物模拟物。我们已经成功地进行了初步研究，用微生物序列模拟髓磷脂表位，证明了表位扩散的颠覆。本文将对微生物源APL的优化进行研究。APL的这项工作可能不仅适用于多发性硬化症，也适用于其他自身免疫性疾病，包括青少年糖尿病、类风湿性关节炎和炎症性肠病。

This grant has funded work on altered peptide ligands (APL) for therapy of autoimmune disease, specifically multiple sclerosis (MS). Work undertaken during the previous five years has provided a framework for the first clinical trials on patients with relapsing remitting MS. In the next grant period we propose to carry out pre-clinical experiments that will optimize APL therapy in animal models of MS, and to develop the next generation of APL therapy utilizing techniques involving vaccination with naked DNA. We will also demonstrate how microbes have the capacity to modulate autoimmune disease via structural mimicry with self-molecules. The specific aims of this grant are to 1) subvert epitope spreading with APL. In this aim we will see whether after intermolecular epitope spreading has occurred, if an APL which targets a single epitope on a single myelin molecule, would be able to suppress ongoing EAE, and reverse paralysis. This is a stringent demand, but will be a useful paradigm to optimize therapeutic regimens in Phase II clinical trials with relapsing remitting MS patients. In Aim 2 we will analyse how APL pulsed dendritic cells will serve to reverse EAE. In Aim 3 we will attempt APL therapy via vaccination with DNA minigenes encoding myelin epitopes. We have succeeded in preventing EAE with DNA vaccination using a minigene encoding a myelin PLP epitope. We will optimize this approach utilizing myelin minigenes paired in tandem with cytokine and chemokine constructs. Finally in Aim 4 we will study APL as microbial mimics that modulate EAE. We have succeeded with preliminary studies, in demonstrating subversion of epitope spreading, with microbial sequences that mimic myelin epitopes. The optimization of such APL derived from microbes will be studied here. This work with APL may be applicable not only to MS, but to other autoimmune diseases including juvenile diabetes, rheumatoid arthritis, and inflammatory bowel disease.