IDIOTYPES AND INFLAMMATORY DEMYELINATION

独特型和炎症性脱髓鞘

• 批准号: 6302803
• 负责人: JOHN N WHITAKER
• 金额: $ 22.61万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-04-01 至 2002-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6302803
• 关键词: B lymphocyte; CD4 molecule; T cell receptor; T lymphocyte; anergy; antiidiotype antibody; cerebrospinal fluid; clinical research; epitope mapping; experimental allergic encephalomyelitis; helper T lymphocyte; human subject; immunocytochemistry; immunoglobulin genes; immunoglobulin idiotypes; in situ hybridization; laboratory mouse; mass spectrometry; monoclonal antibody; multiple sclerosis; myelin basic proteins; myelinopathy; neuroimmunomodulation

This proposal is based on the premise that idiotype (ld) and anti-ld networks are involved in the inflammatory demyelination of the central nervous system which occurs in multiple sclerosis and experimental allergic encephalomyelitis. It is hypothesized that there is a sharing of lds between the T cell receptor found on encephalitogenic T cells and antibody to the dame myelin basic protein (MBP) peptide. Through immunization with a complementary peptide, i.e., a peptide encoded by RNA complementary to the mRNA of the peptide or epitope of interest, an anti-ld with selective specificity can be produced. These anti-lds are capable of modulating humoral and cellular immune activities in vitro. The further characterization of the in vitro effects of these anti-lds and the analysis of their in vivo impact on immunopathological processes are the goals of this proposal. The specific aims will be: (1) to define the mechanism through which monoclonal anti-ld inhibits the synthesis by murine hybridomas of ld-bearing monoclonal antibodies to MBP peptides. (2) to characterize the effect of anti-ld on T cell lines and clones expressing a T cell receptor whose clonotype recognizes the same MBP peptide as does the ld-bearing monoclonal antibody. (3) to determine the effect of anti-ld reacting with the ld against the encephalitogenic MBP peptide acetyl 1-9 on the development of experimental allergic encephalomyelitis in PL/J mice. (4) to determine the effect of immunization with a peptide complementary to MBP peptide acetyl 1-9 on the induction of experimental allergic encephalomyelitis in PL/J mice. (5) to determine if peripheral blood B cells, Epstein-Barr virus transformed B cells, serum or cerebrospinal fluid from normals, persons with multiple sclerosis or other neurological disease secrete or contain ld-bearing antibody reactive with selected human MBP peptides. The results of this investigation will furnish information relevant to the natural or therapeutically induced modulation of a systemic or in situ immune response in inflammatory demyelination as occurs in multiple sclerosis. With the knowledge of an encephalitogenic sequence of MBP or another molecule, the use of complementary peptides or anti-lds may permit the development of non-encephalitogenic, clinically feasible therapeutic agents.

这一建议的前提是独特型(LD)和抗LD 神经网络参与了中枢神经系统的炎性脱髓鞘 多发性硬化症和实验性变态反应的神经系统 脑脊髓炎。假设存在LDS共享 脑源性T细胞上的T细胞受体与抗体之间的关系 到Dame髓鞘碱性蛋白(MBP)肽。通过免疫接种 互补肽，即由互补的RNA编码的肽 目的多肽或表位的信使核糖核酸，是一种具有选择性的抗LD 可以产生特异性。这些抗LDS能够调制 体外体液免疫和细胞免疫活性。越远 这些抗乳酸脱氢酶体外作用的表征和分析 它们对免疫病理过程的体内影响的目标是 这项提议。具体目标是：(1)明确机制 抗LD单抗通过其抑制小鼠体内合成 抗MBP多肽的含LD单抗杂交瘤。(2)至 抗LD对表达A基因的T细胞系和克隆的影响 T细胞受体，其克隆型识别相同的MBP多肽 携带LD的单抗。(3)确定抗LD的效果。 与抗脑源性MBP多肽乙酰基1-9的LD反应 实验性变态反应性脑脊髓炎的发生发展 (4)测定补体多肽的免疫效果 MBP多肽乙酰基1-9对实验性变态反应的诱导作用 PL/J小鼠的脑脊髓炎。(5)测定外周血B EB病毒转化的B细胞、血清或脑脊液 来自正常人、多发性硬化症患者或其他神经系统疾病患者 分泌或含有与选定的人MBP反应的携带ID的抗体 多肽。这项调查的结果将提供信息 与自然的或治疗诱导的全身性的 或在炎性脱髓鞘中的原位免疫反应 多发性硬化症。在知道一个脑部致病序列的情况下 MBP或另一分子，使用互补多肽或抗LDS可 允许开发非脑源性，临床可行 治疗剂。