Investigating IL-6 Experimental Myasthenia Gravis

研究 IL-6 实验性重症肌无力

基本信息

批准号：
6545705
负责人：
PREMKUMAR CHRISTADOSS
金额：
$ 29.46万
依托单位：
UNIVERSITY OF TEXAS MED BR GALVESTON
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-09-30 至 2003-09-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6545705
关键词：
B lymphocyte T lymphocyte acetylcholine antireceptor antibody autoantibody complement pathway genetically modified animals immunotherapy interleukin 6 laboratory mouse leukocyte activation /transformation molecular pathology myasthenia gravis neurotransmitter receptor recombinant proteins tumor necrosis factor alpha

项目摘要

DESCRIPTION (provided by applicant): Studies suggest a pivotal role for IL-6, TNF, and IL- 18 in development of experimental autoimmune myasthenia gravis (EAMG), because a dramatic suppression of clinical EAMG was observed in IL-6, TNF receptor p55 p75, or IL-18 gene KO mice in the B6 background. The precise cellular and molecular mechanisms by which IL-6, TNF, and IL- 18 contribute to EAMG pathogenesis are not known. The central hypothesis is that IL-6 contributes to EAMG pathogenesis by activating acetylcholine receptor (AChR)-specific T and B cells and germinal center (GC) formation, promoting secondary anti-AChR IgG antibodies and activation of the C3 component of complement. The immunopathological and clinical effects will be evaluated by in-vivo IL-6 administration in B6 and IL-6 KO mice during primary and/or secondary immunizations with AChR. Clinical and immunopathological signs of EAMG will be induced in B6 mice by in vivo administration of IL-6 after priming with AChR. AChR-primed LNC will be exposed to IL-6 and its effect on anti-AChR IgM and IgG isotypes will be evaluated. Also, we will examine whether IL-6 and TNF act in concert or regulate one another in mediating EAMG. B7-1 gene-deficient or B7-1 molecule-blocked mice, and B6 mice will be immunized with AChR, and the effect evaluated of B7-1 deficiency or blocking in EAMG development and production of IL-6 and TNF. To prevent EAMG, antibody to IL-6 will be administered with primary and/or secondary immunizations with AChR. To ameliorate established clinical EAMG, antibody to IL-6 will be administered after clinical signs are established. Finally, combination immunotherapy will be performed with high-dose AChR T cell epitope tolerance and IL-6 neutralization in B6 mice. If IL-6 is involved in activating pathogenic AChR-specific B cells, forming GC, and upregulating and activating C3 and if in vivo blocking of IL-6 function induces remission of established clinical EAMG, then IL-6 antagonist could be used in MG therapy. To avoid non-specific immunosuppression by IL-6 antagonists, high-dose AChR T cell epitope tolerance could be given as maintenance therapy after the first course of combination immunotherapy.

描述（由申请人提供）：研究表明，IL-6，TNF和IL-18在实验自身免疫性肌无力肌无力的GRAVIS（EAMG）中的关键作用，因为在IL-6中观察到了临床EAMG的急剧抑制，TNF受体P75 P75 P75或IL-18 Gene Ko ko ko Mials在IL-6中观察到。 IL-6，TNF和IL-18促成EAMG发病机理的精确细胞和分子机制尚不清楚。中心假设是IL-6通过激活乙酰胆碱受体（ACHR）特异性T和B细胞以及生发中心（GC）形成，从而有助于EAMG发病机理，从而促进次级抗ACHR IgG IgG抗体和补体C3分量的激活。免疫病理和临床效应将通过ACHR初级和/或二次免疫期间的B6和IL-6 KO小鼠的体内IL-6给药进行评估。用ACHR启动后体内给药IL-6，将在B6小鼠中诱导EAMG的临床和免疫病理学迹象。 ACHR结构化的LNC将暴露于IL-6，其对抗ACHR IGM的影响将评估，并评估IgG同型。另外，我们将检查IL-6和TNF在介导EAMG时互相调节还是相互调节。 B7-1基因缺陷型或B7-1分子阻断小鼠，B6小鼠将通过ACHR免疫，并评估B7-1缺乏症或阻断IL-6和TNF的EAMG发育和产生的效果。为了防止EAMG，将使用ACHR进行原始和/或次级免疫来施用IL-6的抗体。为了改善已建立的临床EAMG，建立临床体征后将施用与IL-6的抗体。最后，将使用大剂量ACHR T细胞表位耐受性和B6小鼠中和IL-6中和进行组合进行免疫疗法。如果IL-6参与激活致病性ACHR特异性B细胞，形成GC并上调和激活C3，以及IL-6功能的体内阻断会诱导已建立的临床EAMG的缓解，则IL-6拮抗剂可用于MG治疗。为了避免IL-6拮抗剂非特异性免疫抑制，高剂量的ACHR T细胞表位耐受性可以在第一次结合免疫疗法后作为维持治疗。