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.

众所周知，具有IL-2受体的T淋巴细胞（CD3+，CD25+，CD122+）诱导I型牛皮癣。 当前建议中解决的假设是：（1）介导牛皮癣的T细胞介导为I类MHC，属于效应子C​​D8+淋巴细胞的TC1子集。 还将讨论有关该机制的以下假设：（2）CD4+ T细胞（或其他IL-2受体受体细胞）是致病性的。 （3）I型牛皮癣是角质形成细胞的原发性疾病，其激活T细胞是第二事件。 （4）活化的Langerhans细胞（或其他树突状抗原细胞类型）是直接致病性的。 IL-2受体T淋巴细胞（CD3+CD25+CD122+）诱导I型牛皮癣。介导牛皮癣的T细胞很可能是MHC I类限制的，并且属于效应子C​​D8+淋巴细胞的TC1子集。 主要的替代假设是其他IL-2受体细胞，尤其是CD4+ T细胞是致病性的。 替代假设较少的假设是1）I型脊柱疾病是角质形成细胞的原发性疾病，其激活T细胞作为第二事件或2）激活Langerhans细胞（或其他树突状抗原细胞类型）是直接致病的。 通过体内给药的三种新型免疫调节药物（靶向免疫反应的激活和/或效应阶段）对牛皮癣患者进行了三种新型免疫调节药物（靶向和/或效应阶段），正在检验该假设。 这些药物中的两种直接靶向在活化的T淋巴细胞上上调的IL-2受体，而另一种药物则间接抑制T淋巴细胞的IL-2受体表达。 所研究的药物是DAB389IL2，这是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-11，一种调节T淋巴细胞激活的抗炎作用，以及与CD25的人源化单克隆抗体，CD25是IL-2受体的亚基，该亚基与IL-2相关的IL-2受体的亚基。 这些研究的主要目标首先是探索新型免疫靶向治疗剂在最常见的人类免疫介导的疾病（牛皮癣的牛皮癣）中的安全性和功效，其次，将这些治疗剂用作特定的免疫探针，以剖析不同免疫机制对疾病病原体病原体病原体的贡献。 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的免疫途径。 拟议的研究包括对调节T细胞激活早期，中期和晚期阶段的（1）分子的分析，包括表达CTLA4，FAS和FAS配体等途径，被认为终止了免疫反应； （2）使用新的基于流式细胞术的技术（定义了一些效应子淋巴细胞），由单个T淋巴细胞合成的I型与II型细胞因子合成； （3）使用多个分子标记物（例如GMP-17（TIA-1），CD27，CD28，CD28，CD57，CD45，同工型和CD29）的记忆与CD8+和CD4+ T细胞子集的效应群体的分化； （4）将T细胞运输到银屑病皮肤病变中，包括表达调节粘附分子，例如CLA，CD11A，ICAM-1，CD29和P/Eselectins； （5）通过诱导T细胞凋亡与诱导T细胞厌食的诱导测量的免疫反应的下调。此外，“成熟”或活化的兰格汉细胞（以及其他类型的树突状抗原细胞）可能会为银屑病皮肤病变中持续的T细胞激活提供刺激。 因此，我们还将研究特异性免疫阻滞对共刺激分子（CD80，CD86，CD54和CD40）表达的影响，这些影响在银屑病皮肤病变中对树突状细胞上调。