COLLAGEN PEPTIDES AND SUPPRESSION OF COLLAGEN ARTHRITIS

产品说明：（改编自申请人的摘要）-申请人先前在CIA小鼠模型上的工作证明，CB 11胶原II肽在残基245-270中含有用于该诱导的活性位点（A2肽），并模拟了在三个氨基酸中具有取代的类似肽A9，当与胶原蛋白II（CII）共同施用时，其可以下调关节炎的严重程度，或在诱发疾病之后。两个氨基酸，260和263参与肽与MHC分子的结合，残基261与T细胞受体（TCR）相互作用。进一步的初步数据表明，与A2肽相比，当用A9肽攻击时，II型胶原致敏的脾和淋巴结细胞产生增加量的白细胞介素-4（IL-4）和白细胞介素-10（IL-10）。在本申请中待检验的假设是，A9对CIA的作用是通过特异性免疫应答极化至主要的Th 2谱来介导的，并且这种极化是由MHC和肽之间的亲和力的变化或MHC/肽与TCR的相互作用引起的，从而导致改变的T细胞信号传导，并因此产生细胞因子。具体目标是：1）鉴定介导其对CII和CIA的免疫应答的调节的类似肽A9的结构特征; 2）确定编码三螺旋CII内的A9取代是否增加抑制CIA中的自身免疫应答的功效; 3）确定A9给药产生的CIA抑制是否依赖于IL-10或IL-4分泌，和4）通过分析参与T细胞活化的信号通路来确定A9改变T细胞功能的机制。

DESCRIPTION: (Adapted from the applicant's abstract) - Prior work of the applicant on the CIA mouse model demonstrated that the CB11 collagen II peptide contained the active site for this induction in residues 245-270 (A2 peptide), and modeled an analog peptide, A9, with substitutions in three amino acids, which can downregulate the severity of arthritis when co-administered with Collagen II(CII), or after induction of the disease. Two of the amino acids, 260 and 263 participate in peptide binding to the MHC molecule and residue 261 interacts with the T-cell receptor (TCR). Further preliminary data indicate that Collagen II-sensitized spleen and lymph node cells produce increased amounts of Interleukin-4 (IL-4) and Interleukin-10 (IL-10) when challenged with the A9 peptide as compared to the A2 peptide. The hypothesis to be tested in this application is that the A9 effect on CIA is mediated through polarization of the specific immune response to a predominant Th2 profile, and that this polarization is caused by changes in the affinity between either MHC and peptide or MHC/peptide interaction with the TCR leading to altered T cell signaling and, consequently, the production of cytokines. The specific aims are: 1) To identify the structural characteristics of the analog peptide A9 that mediate its modulation of the immune response to CII and CIA; 2) determine whether encoding the A9 substitutions within the triple helical CII increases the efficacy in inhibiting the autoimmune response in CIA; 3) determine whether the suppression of CIA produced by A9 administration is dependent on IL-10 or IL-4 secretion, and 4) determine the mechanism by which A9 alters T cell function by analyzing signaling pathways involved in T cell activation.