T CELL SUBSETS IN CUTANEOUS LEISHMANIASIS

皮肤利什曼病中的 T 细胞亚群

基本信息

批准号：
2406985
负责人：
JAY P FARRELL
金额：
$ 30.57万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
1991
资助国家：
美国
起止时间：
1991-04-01 至 2001-06-30
项目状态：
已结题

项目摘要

Different inbred strains of mice develop either of two divergent patterns of infection with Leishmania major. Most strains develop healing infections whereas certain strains, such as the BALB/c, develop progressive non-healing disease. The development of resistance to infection occurs when the Th1 subset of CD4plus T cells is activated, while progressive disease occurs in mice in which the Th2 subset of CD4plus is preferentially induced. Although patterns of Th1 or Th2 cell predominance become well established early during infection in specific strains of mice, these patterns are not irreversible since a variety of immunological interventions, including treatment with IL-12 or antibodies to IL-2 and IL-4, will reverse the expected course of disease and immunological phenotype, especially if they are administered at or near the time of infection. These immunological interventions function to influence the initial stages of T cell activation from naive CD4plus cells into full differentiated Th1 or Th2 cells, rather than alter the phenotype of an established response. However, neither IL-12 nor anti-IL-4 treatment, alone, will induce healing in mice with established Th2 type responses. Our laboratory has examined ways to reverse established patterns of Th2 cell predominance in mice with non- healing infections and has shown that immunological interventions designed to either suppress Th2 type responses (anti-IL-4 therapy) or enhance Th1 type responses (IL-12 therapy) will promote healing and resistance in susceptible strains of mice if combined with anti- parasite drug therapy to reduce in vivo levels or parasitization. This proposal will examine how differing levels of infection influence the perpetuation of established populations of Th2 cells or the activation of protective Th1 cells and how drug treatment functions to promote successful immunotherapy. In addition, the source of newly derived populations of Th1 cells and the fate of Th2 type populations will e investigated in mice induced to switch from a Th2 to Th1 type response. Finally, the cellular and biochemical events induced by differing immunotherapeutic protocols will be examined in mice exhibiting varying degrees of polarization toward a Th1 or Th2 type response. These studies should provide a better understanding of how mice with chronic infections respond to therapeutic intervention and provide valuable insight into the development of more innovative treatment regimes for leishmaniasis and other infectious diseases.

不同的近交系小鼠会产生两种不同的特征重大利什曼原虫感染模式。大多数菌株发展治愈感染，而某些菌株，例如 BALB/c，发展为进行性不愈性疾病。的发展当 CD4+ T 的 Th1 子集出现时，就会出现对感染的抵抗力细胞被激活，而小鼠发生进行性疾病，其中 CD4+ 的 Th2 子集优先被诱导。虽然 Th1 或 Th2 细胞优势模式已确立在特定品系小鼠感染的早期，这些模式是由于各种免疫干预措施，这种情况不是不可逆转的，包括使用 IL-12 或 IL-2 和 IL-4 抗体进行治疗，将逆转预期的疾病进程和免疫学表型，特别是如果它们在或接近的时间施用感染。这些免疫干预措施可以影响 T 细胞从初始 CD4+ 细胞活化的初始阶段完全分化的 Th1 或 Th2 细胞，而不是改变表型的既定反应。然而，IL-12 和抗 IL-4 均无作用。单独治疗将诱导已建立 Th2 小鼠的愈合类型回复。我们的实验室已经研究了逆转的方法在非小鼠中建立了 Th2 细胞优势模式治愈感染并表明免疫干预旨在抑制 Th2 型反应（抗 IL-4 疗法）或增强 Th1 型反应（IL-12 疗法）将促进愈合如果与抗- 药物治疗可降低体内寄生虫水平或寄生作用。该提案将研究不同感染水平如何影响已建立的 Th2 细胞群的永久存在或保护性Th1细胞的激活以及如何进行药物治疗促进免疫治疗成功的功能。此外，新衍生的 Th1 细胞群的来源及其命运将在诱导转换的小鼠中研究 Th2 型群体从 Th2 型反应转为 Th1 型反应。最后，蜂窝和不同免疫治疗诱导的生化事件将在表现出不同程度的小鼠中检查方案向 Th1 或 Th2 型反应极化。这些研究应该可以更好地了解患有慢性疾病的小鼠如何感染对治疗干预有反应并提供有价值的深入了解更具创新性的治疗方案的开发用于利什曼病和其他传染病。