T CELL MEDIATED PATHOLOGIC RESPONSES TO MURINE MALARIA

T 细胞介导的鼠疟疾病理反应

• 批准号: 2671387
• 负责人: ANNE C AVERY
• 金额: $ 7.5万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-08-01 至 1999-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2671387
• 关键词: Plasmodium; T lymphocyte; athymic mouse; autoimmunity; cellular pathology; cytokine; enzyme linked immunosorbent assay; flow cytometry; humoral immunity; immunoregulation; laboratory mouse; leukocyte activation /transformation; malaria; passive immunization; protein biosynthesis

The proposed studies test the hypothesis that a specific T cell subset responding to Plasmodium yoelii mediates immune responses that downregulate protective immunity and are of no benefit to the host. Consistent with this hypothesis, a pair of congenic mice, BALB/c and BALB.D2.mls/a, have been identified which differ significantly in their ability to resist infection by P. yoelii. BALB.D2.mls/a mice have a BALB/c genetic background but are congenic for the endogenous mouse mammary tumor virus mtv-7. The superantigen encoded by mtv-7 deletes T cells which express T cell receptor chains Vbeta6, 7, 8.1 or 9. When infected with P yoelii, BALB/c mice develop anemia and a significant degree of peripheral parasitemia (up to 60%), and sometimes die of their infection. BALB.D2.mls/a become less anemic, and have a lower peripheral parasitemia (less than 30%) which resolves more quickly. These mice do not die from their infection. Thus the presence of Vbeta6, 7, 8.1 and/or 9 T cells in BALB/c mice correlates with increased susceptibility to disease. We hypothesize that these T cells could be deleterious to the host in two ways; 1) They could preferentially secrete cytokines which inhibit the development of protective immunity, 2) They could mediate the destruction of red blood cell precursors through specific autoimmune responses or through the production of cytokines which inhibit red blood cell generation. In the experiments proposed we will confirm and extend the observation that Vbeta-bearing T cells are deleterious to the host using adoptive transfer and in vivo depletion studies. We will then test the above hypotheses by analyzing cytokine production and the generation of autoimmune responses by these T cells.

这项研究验证了一个假设，即特定的T细胞亚群 对约氏疟原虫的应答介导免疫应答， 下调保护性免疫力，对宿主无益。 与这一假设一致，一对同源小鼠，BALB/c和 BALB.D2.mls/a，它们在免疫学上的差异显著。 抗约氏疟原虫感染的能力。 BALB.D2.mls/a mice have a BALB/c遗传背景，但与内源性小鼠同源 乳腺肿瘤病毒mtv-7。 mtv-7编码的超抗原删除了T 表达T细胞受体链V β 6、7、8.1或9的细胞。 当 感染约氏疟原虫后，BALB/c小鼠出现贫血， 程度的外周寄生虫血症（高达60%），有时死于其 感染 BALB.D2.mls/a变得不那么贫血，并且具有较低的外围设备 寄生虫血症（低于30%），解决得更快。 这些小鼠 而不是死于感染 因此，Vbeta 6、7、8.1和/或 BALB/c小鼠中的9 T细胞与对 疾病 我们假设这些T细胞可能对 它们通过两种方式感染宿主：1）它们可以优先分泌细胞因子， 抑制保护性免疫的发展，2）它们可以介导 通过特异性自身免疫破坏红细胞前体 反应或通过产生抑制红细胞的细胞因子 细胞生成 在提出的实验中，我们将确认和扩展 观察到携带V β的T细胞对宿主有害 使用过继转移和体内消除研究。 然后我们将测试 通过分析细胞因子的产生和产生， 自身免疫反应的信号