MECHANISMS OF IMMUNE TOLERANCE INDUCED IN MURINE LUPUS

小鼠狼疮诱导的免疫耐受机制

• 批准号: 7059463
• 负责人: BEVRA H HAHN
• 金额: $ 44.54万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-02-15 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7059463
• 关键词: MECHANISMS; IMMUNE; TOLERANCE; INDUCED; MURINE

This proposal aims to define mechanisms of T cell tolerance induced in vivo in NZB/NZW F1 lupus-like mice lupus by administration of a novel, artificial peptide (consensus peptide, pCONS). Tolerance results in dramatic delay in appearance of high titer IgG anti-dsDNA and nephritis, and prolongs life 7 months or more. PCONS is constructed from an algorithm based on spontaneous proliferation of BWF1 T cells to wild peptides from the VH regions of BWF1 monoclonal antibodies to DNA. The algorithm predicts amino acid sequences likely to stimulate BWF1 T cells. A wild peptide (p33B) sharing 10 of 15 amino acids with pCONS, representing a sequence in the VH region (CDR1/FR2) of a mAb BWF1 IgG2a anti-dsDNA, has similar effects. Treatment with an artificial peptide that violates the algorithm, pNEG, produces no clinical benefits. Mice treated with pCONS or p33B, but not saline or pNEG, have reduced proliferation of T cells to immunization with the tolerizing peptide, and reduced T cell help for production of IgG anti-dsDNA in vitro. They also fail to develop the high plasma levels of IFN (and IL-4 that characterize saline-treated BWF1 females. We hypothesize that the large effects of these tolerogens result from induction of apotosis, cytokine deviation, or both in a large population of helper T cells - possibly a population that recognizes different peptides from multiple autoantigens, either early in life or later, after determinant spreading. These effects may correlate with affinity and stability of peptide/MHC Class II binding. The hypothesis will be tested by determining peptide/Class II binding affinities and stability (including peptide variants), developing surrogate rapid measures of effects on BWF1 T cells that predict clinical efficacy of peptides with different MHC binding characteristics, determining the effect of peptide/MHC engagement of TCR on T cell survival and cytokines, and testing peptide variants in vivo for clinical effects. Differences between the T cell responses to peptide/MHC complexes in BWF1 and normal mice expressing the MHC Class II molecules restricting these peptides, will identify novel characteristics of Th activation that characterize the autoimmune mice. Since patients with SLE have T cells that recognize Ig-derived peptides from human monoclonal antibodies to DNA, the information from these experiments may suggest a novel therapeutic approach to this disease.

该提案旨在明确通过施用新型人工肽（共有肽，pCONS）在 NZB/NZW F1 狼疮样小鼠狼疮体内诱导 T 细胞耐受的机制。 耐受性会导致高滴度 IgG 抗 dsDNA 和肾炎的出现显着延迟，并延长生命 7 个月或更长时间。 PCONS 是根据 BWF1 T 细胞自发增殖到 BWF1 单克隆抗体 VH 区域的野生肽的算法构建的。 该算法预测可能刺激 BWF1 T 细胞的氨基酸序列。 与 pCONS 共享 15 个氨基酸中的 10 个的野生肽 (p33B)，代表 mAb BWF1 IgG2a 抗 dsDNA 的 VH 区 (CDR1/FR2) 中的序列，具有类似的效果。 使用违反 pNEG 算法的人工肽进行治疗不会产生任何临床益处。 用pCONS或p33B（而不是盐水或pNEG）治疗的小鼠，减少了T细胞对耐受肽免疫的增殖，并减少了T细胞在体外产生IgG抗dsDNA的帮助。 它们也未能产生高血浆水平的 IFN（和 IL-4，这是经盐水处理的 BWF1 雌性的特征）。我们假设这些耐受原的巨大影响是由于在大量辅助细胞中诱导细胞凋亡、细胞因子偏差或两者兼而有之。 T 细胞 - 可能是在生命早期或晚期在决定簇扩散后识别来自多种自身抗原的不同肽的群体。这些效应可能与肽/MHC II 类结合的亲和力和稳定性相关。将通过以下方式进行测试：确定肽/II类结合亲和力和稳定性（包括肽变体），开发对BWF1 T细胞影响的替代快速测量方法，预测具有不同MHC结合特征的肽的临床功效，确定肽/MHC结合的影响TCR 对 T 细胞存活和细胞因子的影响，以及体内测试肽变体的临床效果，BWF1 和表达限制这些肽的 MHC II 类分子的正常小鼠的 T 细胞反应之间的差异。自身免疫小鼠的 Th 激活特征。 由于 SLE 患者的 T 细胞能够识别来自 DNA 人类单克隆抗体的 Ig 衍生肽，因此这些实验的信息可能会为这种疾病提供一种新的治疗方法。