Modulation of collagen-induced arthritis by adenovirus-mediated intra-articular expression of modified collagen type II.
Modulation of collagen-induced arthritis by adenovirus-mediated intra-articular expression of modified collagen type II.
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DOI：
10.1186/ar3074
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发表时间：
2010
影响因子：
4.9
通讯作者：
Myers LK
中科院分区：
文献类型：
--
作者：
Tang B;Cullins DL;Zhou J;Zawaski JA;Park H;Brand DD;Hasty KA;Gaber MW;Stuart JM;Kang AH;Myers LK
类风湿性关节炎（RA）是一种全身性疾病，表现为多个关节的慢性炎症，包括膝盖和手脚的小关节。我们开发了一种独特的改良方法，用于临床接受的直接向滑膜输送治疗。我们的疗法是基于我们之前发现的一种类似肽（A9），在260 （I到A）、261 （A到B）和263 （F到N）的位置上进行氨基酸取代，可以在胶原诱导的关节炎模型（CIA）中深刻抑制对II型胶原（CII）和关节炎的免疫。我们设计了一个腺病毒载体来包含重组II型胶原的CB11部分，并使用PCR在（CII124-402, 260A, 261B, 263D）， （rCB11-A9）中的三个位点引入点突变，使得到的分子在野生型序列的确切位置包含A9序列。我们使用这种结构来靶向小鼠关节内组织，并利用胶原诱导的关节炎模型来证明这种治疗策略为个体关节炎关节提供了持续的局部治疗，无论是用于预防关节炎还是作为治疗都有效。我们还开发了一种新的体内生物成像系统，使用萤火虫荧光素酶报告基因，允许连续生物发光成像，显示荧光素酶可以在注射到关节后18天检测到。我们的治疗是独特的，我们针对滑膜细胞最终关闭T细胞介导的炎症。它的有效性是基于它将潜在的炎症T细胞和/或旁观者T细胞转化为分泌白细胞介素(IL)-4的治疗性（调节样）T细胞的能力。我们相信这种方法有潜力以最小的副作用有效地抑制RA。
Rheumatoid arthritis (RA) is a systemic disease manifested by chronic inflammation in multiple articular joints, including the knees and small joints of the hands and feet. We have developed a unique modification to a clinically accepted method for delivering therapies directly to the synovium. Our therapy is based on our previous discovery of an analog peptide (A9) with amino acid substitutions made at positions 260 (I to A), 261 (A to B), and 263 (F to N) that could profoundly suppress immunity to type II collagen (CII) and arthritis in the collagen-induced arthritis model (CIA). We engineered an adenoviral vector to contain the CB11 portion of recombinant type II collagen and used PCR to introduce point mutations at three sites within (CII124-402, 260A, 261B, 263D), (rCB11-A9) so that the resulting molecule contained the A9 sequence at the exact site of the wild-type sequence. We used this construct to target intra-articular tissues of mice and utilized the collagen-induced arthritis model to show that this treatment strategy provided a sustained, local therapy for individual arthritic joints, effective whether given to prevent arthritis or as a treatment. We also developed a novel system for in vivo bioimaging, using the firefly luciferase reporter gene to allow serial bioluminescence imaging to show that luciferase can be detected as late as 18 days post injection into the joint. Our therapy is unique in that we target synovial cells to ultimately shut down T cell-mediated inflammation. Its effectiveness is based on its ability to transform potential inflammatory T cells and/or bystander T cells into therapeutic (regulatory-like) T cells which secrete interleukin (IL)-4. We believe this approach has potential to effectively suppress RA with minimal side effects.
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