ASSESSMENT OF SAFETY, CLINICAL EFFICACY & CELLULAR MECHANISM OF RHIL 11

安全性、临床疗效评估

• 批准号: 6115901
• 负责人: JAMES G KRUEGER
• 金额: $ 4.54万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-12-01 至 1999-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6115901
• 关键词: CD antigens; biopsy; clinical research; cytotoxic T lymphocyte; drug screening /evaluation; helper T lymphocyte; human subject; immunotherapy; interleukin 11; leukocyte activation /transformation; photography; psoriasis; recombinant proteins; serology /serodiagnosis; skin disorder chemotherapy

It is known that IL-2 receptor-bearing T-lymphocytes (CD3+, CD25+, CD122+) induce type I psoriasis. The hypothesis addressed in the current proposal is: (1) T-cell mediating psoriasis are MHC class I restricted and belong to the Tc1 subset of effector CD8+ lymphocytes. The following hypotheses regarding the mechanism will also be discussed: (2) CD4+ T cells (or other IL-2 receptor-bearing cells) are pathogenic. (3) Type I psoriasis is a primary disorder of keratinocytes with activation of T cells as a secondary event. (4) Activated Langerhans cells (or other dendritic antigen-presenting cell types) are directly pathogenic. IL-2 receptor-bearing T-lymphocytes (CD3+CD25+CD122+) induce type I psoriasis. T-cells mediating psoriasis are most likely MHC class I restricted and belong to the Tc1 subset of effector CD8+ lymphocytes. The major alternative hypothesis is that other IL-2 receptor-bearing cells, especially CD4+ T-cells, are pathogenic. Less likely alternative hypotheses are 1) that type I psoriasis is a primary disorder of keratinocytes with activation of T cells as a secondary event or 2) that activated Langerhans cells (or other dendritic antigen-presenting cell types) are directly pathogenic. This hypothesis is being tested by the in vivo administration of three novel immune-modulating drugs (which target activation and/or effector phases of immune responses) to patients with psoriasis vulgaris. Two of these agents directly target IL-2 receptors that are up-regulated on activated T-lymphocytes, and the other agent indirectly suppresses IL-2 receptor expression by T-lymphocytes. The agents being studied are DAB389IL2, a rationally engineered fusion toxin which binds selectively to activated T-lymphocytes; rh Interleukin-11, an anti-inflammatory that modulates T-lymphocyte activation, and a humanized monoclonal antibody to CD25, the subunit of the IL-2 receptor that confers high-affinity interaction with IL-2. The major objectives of these studies are, first, to explore the safety and efficacy of novel immune-targeted therapeutic agents in the most common human immune-mediated disease (psoriasis vulgaris) and, secondly, to use these therapeutic agents as specific immune probes to dissect the contribution of different immune mechanisms to disease pathogenesis. Hence, our analysis plan is geared to investigate a broad range of immune pathways that might be affected by each agent. Proposed studies include analysis of (1) Molecules regulating early, mid, and late stages of T-cell activation, including expression of pathways such as CTLA4, Fas, and Fas ligand, believed to terminate immune responses; (2) Type I vs. type II cytokines synthesized by individual T-lymphocytes using new flow cytometry-based techniques (defines some subsets of effector lymphocytes); (3) Differentiation of memory vs. effector populations of CD8+ and CD4+ T-cell subsets using multiple molecular markers such as GMP-17 (TIA-1), CD27, CD28, CD57, CD45 isoforms, and CD29; (4) Trafficking of T-cells into psoriatic skin lesions, including expression of regulatory adhesion molecules such as CLA, CD11a, ICAM-1, CD29, and P/Eselectins; (5) Down-regulation of immune responses as measured by induction of T-cell apoptosis vs. induction of T-cell anergy. Furthermore, "mature" or activated Langerhans cells (as well as other types of dendritic antigen-presenting cells) may provide the stimulus for ongoing T-cell activation in psoriatic skin lesions. Hence, we will also study the effects of specific immune-blockade on the expression of co-stimulatory molecules (CD80, CD86, CD54, and CD40) that are up-regulated on dendritic cells in psoriatic skin lesions.

已知携带 IL-2 受体的 T 淋巴细胞（CD3+、CD25+、CD122+）可诱发 I 型银屑病。 当前提案中提出的假设是：(1) 介导银屑病的 T 细胞受到 MHC I 类限制，属于效应 CD8+ 淋巴细胞的 Tc1 子集。 还将讨论有关其机制的以下假设：（2）CD4+T细胞（或其他携带IL-2受体的细胞）是致病性的。 (3) I 型银屑病是角质形成细胞的原发性疾病，继发性是 T 细胞的活化。 (4) 活化的朗格汉斯细胞（或其他树突状抗原呈递细胞类型）具有直接致病性。 携带 IL-2 受体的 T 淋巴细胞 (CD3+CD25+CD122+) 诱导 I 型银屑病。介导银屑病的 T 细胞很可能受 MHC I 类限制，属于效应 CD8+ 淋巴细胞的 Tc1 子集。 主要的替代假设是其他携带 IL-2 受体的细胞，尤其是 CD4+ T 细胞，是致病性的。 不太可能的替代假设是 1) I 型银屑病是角质形成细胞的原发性疾病，T 细胞激活是继发事件，或 2) 激活的朗格汉斯细胞（或其他树突状抗原呈递细胞类型）具有直接致病性。 这一假设正在通过对寻常型银屑病患者体内施用三种新型免疫调节药物（针对免疫反应的激活和/或效应阶段）进行测试。 其中两种药物直接靶向活化 T 淋巴细胞上调的 IL-2 受体，另一种药物间接抑制 T 淋巴细胞表达 IL-2 受体。 正在研究的药物是 DAB389IL2，一种合理设计的融合毒素，可选择性地与活化的 T 淋巴细胞结合； rh Interleukin-11 是一种调节 T 淋巴细胞活化的抗炎药，也是一种针对 CD25 的人源化单克隆抗体，CD25 是 IL-2 受体的亚基，可与 IL-2 产生高亲和力相互作用。 这些研究的主要目的是，首先，探索新型免疫靶向治疗药物在最常见的人类免疫介导疾病（寻常型银屑病）中的安全性和有效性，其次，使用这些治疗药物作为特异性免疫探针剖析不同免疫机制对疾病发病机制的贡献。 因此，我们的分析计划旨在研究可能受每种药物影响的广泛免疫途径。 拟议的研究包括分析 (1) 调节 T 细胞激活早期、中期和晚期的分子，包括 CTLA4、Fas 和 Fas 配体等途径的表达，据信可以终止免疫反应； (2) 使用基于流式细胞术的新技术，由单个 T 淋巴细胞合成 I 型与 II 型细胞因子（定义了效应淋巴细胞的一些子集）； (3) 使用多种分子标记，例如 GMP-17 (TIA-1)、CD27、CD28、CD57、CD45 亚型和 CD29，区分 CD8+ 和 CD4+ T 细胞亚群的记忆与效应细胞群； (4) T细胞贩运到银屑病皮损中，包括表达调节性粘附分子，例如CLA、CD11a、ICAM-1、CD29和P/E选择素； (5) 通过诱导 T 细胞凋亡与诱导 T 细胞无反应性来测量免疫反应的下调。此外，“成熟”或激活的朗格汉斯细胞（以及其他类型的树突状抗原呈递细胞）可能会刺激银屑病皮肤病变中持续的 T 细胞激活。 因此，我们还将研究特异性免疫阻断对银屑病皮损中树突状细胞上调的共刺激分子（CD80、CD86、CD54 和 CD40）表达的影响。