IMMUNOSUPPRESSIVE PROPERTIES OF 1,25-DIHYDROXYVITAMIN D3

1,25-二羟基维生素 D3 的免疫抑制特性

• 批准号: 3462955
• 负责人: JACQUES LEMIRE
• 金额: $ 10.02万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-02-01 至 1994-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3462955
• 关键词: 1,25 dihydroxycholecalciferol; DNA replication; clone cells; delayed hypersensitivity; enzyme linked immunosorbent assay; experimental allergic encephalomyelitis; helper T lymphocyte; immunoregulation; immunosuppression; immunosuppressive; interstitial nephritis; leukocyte activation /transformation; nucleic acid inhibitor; nutrition related tag; passive immunization; receptor; suppressor T lymphocyte; vitamin metabolism; vitamin therapy

The active metabolite of vitamin D, 1,25-(OH)2-D3, is a well known modulator of calcium homeostasis in man. In recent years, the discovery of specific 1,25-(OH)2-D3 receptors on a variety of malignant and non-malignant cells has prompted an investigation of the potential effect of the hormone on these cells. The presence of such receptors on activated human lymphocytes led us to the following observations. When peripheral human mononuclear cells were activated with lectins or antigen in vitro, a dose-dependent inhibition of DNA synthesis was observed in cells incubated with 1,25-(OH)2-D3 in concentrations ranging from 10-10 to 10-7 M. Production of IgG and IgM, determined by enzyme-linked immunosorbent assay, was similarly inhibited by increasing concentrations of the hormone. Further studies examining lymphocyte subsets revealed the T helper cell (TH) to be the specific cellular target for the immunoinhibitory effect of 1,25- (OH)2-D3. In two T cell dependent animal models of autoimmunity, experimental allergic encephalomyelitis (EAE) and murine interstitial nephritis, specific T cell clones of the helper phenotype can be isolated and shown to exert biological activities in vitro and in vivo. In humans, T cell clones can be generated from lymphocytes of rejected allografts with HLA-DR specificities. In light of these findings, we propose to further evaluate the immunoregulation role of 1,25-(OH)2-D3 by assessing (1) the ability of 1,25-(OH)2-D3 to interfere with the properties and functional characteristics of the T cell clones: proliferation, lymphokine production, helper or suppressor function, transfer of disease activity and delayed-type hypersensitivity and (2) the ability of 1,25-(OH)2-D3 treated murine recipients to be protected from the active induction of EAE and murine interstitial nephritis or from the passive transfer of the autoimmune diseases by T cell clones. We believe this work will advance our understanding of cellular and humoral mechanisms affected by the active vitamin D metabolite, a potential immunosuppressive agent.

维生素D的活性代谢产物，1,25-（OH）2-D3是一个众所周知的 人类钙稳态调节剂。 近年来， 在多种 恶性和非恶性细胞促使对 激素对这些细胞的潜在影响。 存在 激活的人淋巴细胞上的这种受体导致我们进入 以下观察。 当外周人单核细胞 用凝集素或抗原在体外激活，剂量依赖性 在与细胞中观察到DNA合成的抑制作用 1,25-（OH）2-D3的浓度范围为10-10至10-7M。 通过酶连接确定的IgG和IgM的生产 免疫吸附测定法可以通过增加来抑制 激素的浓度。 进一步研究 淋巴细胞亚群显示T辅助细胞（Th）为 1,25-的免疫抑制作用的特定细胞靶标 （OH）2-D3。 在两个T细胞依赖的自身免疫模型中， 实验性过敏性脑脊髓炎（EAE）和鼠 间质性肾炎，辅助器的特异性T细胞克隆 可以隔离表型并显示出生物活性 体外和体内。 在人类中，可以生成T细胞克隆 来自具有HLA-DR特异性的拒绝同种异体移植物的淋巴细胞。 鉴于这些发现，我们建议进一步评估 通过评估（1）能力，通过评估1,25-（OH）2-D3的免疫调节作用 1,25-（OH）2-d3干扰特性和功能 T细胞克隆的特征：增殖，淋巴因子 生产，助手或抑制功能，疾病转移 活动和延迟型超敏反应，（2） 1,25-（OH）2-D3处理的鼠受体受到保护 主动诱导EAE和鼠的间质性肾炎或 T细胞克隆对自身免疫性疾病的被动转移。 我们认为这项工作将提高我们对细胞和细胞的理解 受活性维生素D代谢产物影响的体液机制，A 潜在的免疫抑制剂。