MECHANISMS OF IMMUNE TOLERANCE INDUCED IN MURINE LUPUS

小鼠狼疮诱导的免疫耐受机制

基本信息

批准号：
7340468
负责人：
BEVRA H HAHN
金额：
$ 44.42万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
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/7340468
关键词：
Affinity Age Algorithms Amino Acid Sequence Amino Acids Antibodies Apoptosis Appearance Autoantibodies Autoantigens Autoimmune Diseases Autoimmune Process B-Lymphocytes Binding CD4 Positive T Lymphocytes Cell Survival Cells Characteristics Class Clinical Complex Consensus DNA Data Disease Dissociation Dose Female Helper-Inducer T-Lymphocyte Histocompatibility Antigens Class II Immune Immune Complex Glomerulonephritis Immune Tolerance Immunization Immunoglobulin G In Vitro Inbred BALB C Mice Individual Induction of Apoptosis Injection of therapeutic agent Interferons Interleukin-4 Interruption Kidney Lead Life Location Lupus MHC Class II Genes Measures Mediating Monoclonal Antibodies Mus Nephritis Numbers Pathogenesis Patients Pattern Peptide/MHC Complex Peptides Plasma Play Population Population Study Positioning Attribute Production Property Purpose Rate Reaction Research Personnel Role Saline Spleen Splenic Tissue Staging Surface Systemic Lupus Erythematosus T-Cell Proliferation T-Lymphocyte Testing Therapeutic Tolerogen Treatment Protocols Variant Week anti-IgG base clinical effect clinical efficacy cytokine ds-DNA in vivo lymph nodes novel novel therapeutics prevent programs research study response synthetic peptide

项目摘要

This proposal aims to define mechanisms of T cell tolerance induced in vivo in NZB/NZW Fl 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 withpCONS, 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 n 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 humanmonoclonal antibodies to DNA, the information from these experiments may suggest a novel therapeutic approach to this disease.

该提案旨在定义 NZB/NZW Fl 狼疮样小鼠狼疮体内诱导的 T 细胞耐受机制施用新型人工肽（共有肽，pCONS）。宽容导致戏剧性的延迟出现高滴度抗dsDNA IgG和肾炎，延长生命7个月以上。 PCONS 的构造是基于 BWF1 T 细胞自发增殖至 BWF1 VH 区域野生肽的算法 DNA 单克隆抗体。该算法预测可能刺激 BWF1 T 细胞的氨基酸序列。一个野生肽 (p33B) 与 pCONS 共享 15 个氨基酸中的 10 个，代表 VH 区 (CDR1/FR2) 中的序列 mAb BWF1 IgG2a 抗 dsDNA 的抗体也具有类似的效果。用违反算法的人工肽进行治疗， pNEG 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，其 T 细胞增殖以耐受肽免疫，并减少 T 细胞有助于产生 IgG 抗体体外双链DNA。他们也未能产生高血浆水平的 IFN（和 IL-4），这是盐水处理的特征 BWF1 女子。我们假设这些耐受原的巨大影响是由于诱导细胞凋亡、细胞因子偏差，或两者都存在于大量辅助 T 细胞中——可能是识别来自不同来源的不同肽的群体。多种自身抗原，无论是在生命早期还是在决定性传播之后。这些影响可能与亲和力相关以及肽/MHC n 类结合的稳定性。该假设将通过确定肽/II 类结合来检验亲和力和稳定性（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 的效果 TCR 对 T 细胞存活和细胞因子的参与，并在体内测试肽变体的临床效果。 BWF1 和表达 MHC 的正常小鼠中 T 细胞对肽/MHC 复合物的反应之间的差异限制这些肽的 II 类分子将识别 Th 激活的新特征，这些特征表征了自身免疫小鼠。由于 SLE 患者的 T 细胞能够识别来自人单克隆抗体的 Ig 衍生肽 DNA 抗体，这些实验的信息可能会提出一种治疗这种疾病的新方法。