PEPTIDE MEDIATED IMMUNOTHERAPY FOR AUTOIMMUNE DISEASE

这笔赠款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。过去五年开展的工作为首次针对复发缓解期多发性硬化症患者的临床试验提供了框架。在下一个资助期，我们建议开展临床前试验，以优化多发性硬化症动物模型的APL治疗，并利用裸露DNA疫苗接种技术开发下一代APL治疗方法。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。这项资助的具体目的是：1)颠覆APL表位的传播。在这个目标中，我们将看看分子间表位扩散发生后，靶向单个髓鞘分子上的单个表位的APL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，但将是在复发缓解多发性硬化症患者的第二阶段临床试验中优化治疗方案的有用范例。在目标2中，我们将分析APL冲击的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鞘表位的DNA微型基因来治疗APL。我们已经成功地用编码髓鞘PLP表位的微型基因接种DNA疫苗来预防EAE。我们将利用髓鞘微基因结合细胞因子和趋化因子构建来优化这一方法。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，用模仿髓鞘表位的微生物序列证明了表位传播的颠覆性。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，还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.