A unique approach to control the CD40/CD154 inflammatory axis in type 1 diabetes

描述(申请人提供)：CD40/CD154炎症轴已被证明在自身免疫性炎症中起关键作用。控制它的尝试使用了抗体和合成的有机小分子；每一种最终都没有起到治疗作用。用抗CD154抗体控制这一轴被证明是非常有效的，但这种抗体本身在人体试验中造成了致命的问题。我们从已知与CD40相互作用的CD154氨基酸序列中设计了一种小的(15-聚体)治疗性多肽(STP)。我们确定STP直接与细胞表面表达的CD40结合，特别是与CD40+T细胞结合，我们描述的CD40+T细胞在T1D的NOD小鼠模型中是高致病性的，在人类T1D中是高致病性的。糖尿病前期受试者体内对人类胰岛有反应的CD4+CD40+细胞水平升高。仅用该肽治疗T细胞可消除胰岛反应。与杂乱的多肽或较小版本的多肽相比，给予多肽可以预防96%治疗的NOD小鼠的高血糖。重要的是，组成多肽的氨基酸数量对疗效至关重要。在这项应用中，我们将研究这种多肽的作用机制。目的1：假设：STP对致病效应T细胞，特别是CD_4~+CD_(40+)细胞有直接作用：耐受机制探讨(S)。目的2将探讨多肽如何影响整体免疫反应，包括抗原召回，潜在的针对外来抗原的抗体产生，以及多肽治疗诱导CD154抗体的可能性。这项研究计划的最终目标是创造一种控制致病效应T细胞的治疗方法。

DESCRIPTION (provided by applicant): The CD40/CD154 inflammatory axis has proven critical in autoimmune inflammation. Attempts to control it have used antibodies and synthesized organic small molecules; each ultimately has failed to be useful as a therapeutic. Controlling that axis with anti- CD154 proved highly effective, but the antibody itself caused lethal problems in human trials. We designed a small (15-mer) therapeutic peptide (STP) derived from the CD154 amino acid sequence that is known to interact with CD40. We determined that the STP binds directly to cell surface expressed CD40, particularly to CD40+ T cells, a subset that we described as highly pathogenic in the NOD mouse model of T1D, and in human T1D. Pre-diabetic human subjects have elevated levels of CD4+CD40+ cells that respond to human islets. Treating only T cells with the peptide ablates islet response. Administration of the peptid prevents hyperglycemia in 96% of treated NOD mice compared to a scrambled peptide or smaller versions of the peptide. Importantly the number of amino acids comprising the peptide is crucial for efficacy. In this application we will examine the mechanism of action of this peptide. Aim 1: Hypothesis: The STP has direct effects on pathogenic effector T cells, specifically CD4+CD40+ cells: Exploring the mechanism(s) of tolerance. Aim 2 will explore how the peptide affects the overall immune response including antigen recall, potential antibody production to foreign antigens and the possibility that peptide treatment induces antibodies to CD154. The ultimate goals of this research plan are to create a therapeutic to control pathogenic effector T cells.