INTERLEUKIN-12 AS IMMUNOTHERAPY IN LEISHMANIASIS

INTERLEUKIN-12 作为利什曼病的免疫疗法

• 批准号: 2071988
• 负责人: FREDERICK P. HEINZEL
• 金额: $ 12.06万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-09-01 至 1998-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2071988
• 关键词: B lymphocyte; combination therapy; cytokine; disease /disorder model; enzyme linked immunosorbent assay; helper T lymphocyte; immunotherapy; interferon gamma; interleukin 4; laboratory mouse; leishmaniasis; lymph nodes; macrophage; microorganism culture; microorganism immunology; monoclonal antibody; nonhuman therapy evaluation; polymerase chain reaction; protozoal antigen; recombinant DNA; transforming growth factors

The long-term goal of these studies is to understand cytokine-based mechanisms responsible for curative and noncurative immune responses during leishmaniasis. A well-characterized model of murine leishmaniasis has already provided important insights into the cytokine pathology of this disease. Progression of L. major infection from cutaneous to visceral sites in susceptible BALB/c mice is mediated by expansion of the Th2 CD4+ lymphocyte subset and production of IL-4. Although IFN-gamma and Th1 CD4+ cell development are necessary for cure in resistant C57BL/6 mice and in BALB/c mice protectively treated with anti-IL-4 antibodies, IFN-gamma therapy does not restore curative immunity in BALB/c mice. Based on our preliminary data, we propose that IL-12 may be a more effective immunotherapeutic agent for Th2-mediated illnesses. IL-12 is a heterodimeric T-cell growth and IFN-gamma stimulatory cytokine that is produced by B-cells and macrophages and that is known to promote Th1 and suppress Th2 cell responses in vitro. Our preliminary studies confirm the ability of IL-12 to cure susceptible BALB/c mice and to durably suppress Th2 immune responses when administered early during infection with L. major. Treatment of resistant C57BL/6 mice with anti-IL-12 antibodies exacerbates disease. We hypothesize that IL-12 strongly inhibits Th2 T cell responses, that suppression of IL-12 synthesis and function during infection causes Th2- mediated progression of disease, and that IL-12 has potential as an immunotherapeutic agent in leishmaniasis and other Th2-mediated parasitic diseases. We propose experiments to explore further the basic biology of IL-12 production and function during leishmaniasis and to identify immunotherapeutic uses in the mouse model that may suggest clinical applications. Specific aims are to: 1) Examine the role of IL-12 in regulating CD4+ subset selection and curative immunity in disease-susceptible BALB/c mice and resistant C57BL/6 mice infected with Leishmania major. 2) Identify differences in the production of IL-12 by BALB/c and C57BL/6 mice during leishmaniasis. 3) Develop uses for IL-12 as a therapeutic modulator of immune responses during established leishmaniasis.

这些研究的长期目标是了解基于尼古丁的 治疗性和非治疗性免疫反应的机制 在利什曼病期间。 一种良好表征的小鼠模型 利什曼病已经提供了重要的见解， 这种疾病的病理。 L.的进展主要感染来自 敏感BALB/c小鼠的皮肤至内脏部位由 Th 2 CD 4+淋巴细胞亚群的扩增和IL-4的产生。 虽然IFN-γ和Th 1 CD 4+细胞的发育是治愈所必需的， 在抗性C57 BL/6小鼠和BALB/c小鼠中， 抗IL-4抗体，IFN-γ治疗不能恢复治愈性 BALB/c小鼠免疫力。 根据我们的初步数据，我们建议， IL-12可能是一种更有效的免疫抑制剂， 疾病。 IL-12是异二聚体T细胞生长因子，IFN-γ是异二聚体T细胞生长因子。 由B细胞和巨噬细胞产生的刺激性细胞因子， 已知其在体外促进Th 1细胞应答并抑制Th 2细胞应答。 我们的初步研究证实了IL-12治疗易感性 BALB/c小鼠和持久抑制Th 2免疫应答时， 在感染L.少校 治疗 具有抗IL-12抗体的抗性C57 BL/6小鼠使疾病恶化。 我们假设IL-12强烈抑制Th 2 T细胞应答， 在感染期间抑制IL-12合成和功能导致Th 2- 介导的疾病进展，并且IL-12具有作为 利什曼病和其它Th 2介导免疫抑制剂 寄生虫病。 我们提出实验来进一步探索基本的 利什曼病期间IL-12产生和功能的生物学， 确定小鼠模型中的免疫功能， 临床应用。 具体目标是： 第一章 检查IL-12在调节CD 4+亚群选择中的作用， 在疾病易感BALB/c小鼠和抗性BALB/c小鼠中的治疗性免疫 感染硕大利什曼原虫的C57 BL/6小鼠。 （二） 确定BALB/c产生IL-12的差异， 利什曼病期间的C57 BL/6小鼠。 第三章 开发IL-12作为免疫调节剂的治疗用途 在建立利什曼病期间的反应。