PEPTIDE MEDIATED IMMUNOTHERAPY FOR AUTOIMMUNE DISEASE

该基金资助了用于治疗自身免疫性疾病，特别是多发性硬化症（MS）的改变肽配体（APL）的工作。 在过去的五年中进行的工作提供了一个框架，复发缓解型MS患者的第一次临床试验。在下一个赠款期间，我们建议进行临床前实验，将优化APL治疗MS的动物模型，并开发下一代APL治疗利用技术，涉及裸DNA疫苗接种。 我们还将展示微生物如何通过自身分子的结构模拟来调节自身免疫性疾病。 这项资助的具体目标是：1）颠覆APL的表位扩散。 在这个目标中，我们将看到在分子间表位扩散发生后，如果APL靶向单个髓鞘分子上的单个表位，是否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，以优化复发缓解型MS患者的II期临床试验的治疗方案。 在目标2中，我们将分析APL脉冲树突状细胞将如何逆转EAE。 在目标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。 我们已经成功地预防EAE与DNA疫苗接种使用编码髓鞘PLP表位的小基因。 我们将优化这种方法，利用髓磷脂minigenes配对串联细胞因子和趋化因子的结构。 最后，在目标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，证明了表位扩散的颠覆，与微生物序列模拟髓鞘表位。本文将对微生物来源的APL的优化进行研究。APL的这项工作可能不仅适用于MS，而且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.