T CELL MEDIATED PATHOLOGIC RESPONSES TO MURINE MALARIA

拟议的研究验证了这样的假设，即特定的T细胞亚群 对约氏疟原虫的反应介导了免疫反应， 降低保护性免疫，对宿主没有好处。 与这一假设一致的是，一对同基因小鼠，BALB/c和 BALB.D2.mls/a已被鉴定为在它们的 抵抗约氏疟原虫感染的能力。BALB.D2.mls/a小鼠有一个 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编码的超抗原缺失T 表达T细胞受体链Vbeta6、7、8.1或9的细胞。何时 感染约氏杆菌的BALB/c小鼠出现贫血和显著的 外周寄生虫血症的程度(高达60%)，有时死于 感染。BALB.D2.mls/a贫血减轻，外周血流量降低 寄生虫血症(低于30%)，消退更快。这些老鼠就是这样 而不是死于感染。因此，Vbeta6、7、8.1和/或 BALB/c小鼠体内9个T细胞与易感性增加相关 疾病。我们推测这些T细胞可能对人体有害 以两种方式寄主；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 通过特定的自身免疫破坏红细胞前体 反应或通过产生抑制红血球的细胞因子 细胞生成。在提出的实验中，我们将确认和推广 携带Vbeta的T细胞对宿主有害的观察 采用过继转移和体内耗竭研究。然后我们将测试 上述假说通过分析细胞因子的产生和生成 这些T细胞的自身免疫反应。

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.