T-Cell Mediated Immunity In Chlamydial Genital Infection

描述(申请人提供)：沙眼衣原体感染 仍然是盆腔炎的主要原因，并经常导致 输卵管损伤和不孕症。虽然有效的抗生素是 可用的、无症状的感染可能会上升到上生殖道(GT) 并在被发现之前造成不可逆转的组织损伤。其中一个策略是 通过预防性接种疫苗可避免损伤上腹部GT。然而， 抗衣原体CD4T辅助细胞1型(Th1)反应发展为 根除感染也被认为会损害上GT。初步数据 来自我们实验室的研究人员发现，CD4细胞主要被招募到 感染开始的地方是上而不是下GT。我们还发现， 前列腺素E2(PGE2)是在感染过程中在上尿路诱导产生的。这些 数据表明，上下GT在免疫学上是两个截然不同的 并在衣原体感染期间做出不同的反应。我们假设 Th1、CD4效应细胞向低GT的募集不足 用于彻底根除导致高GT感染的衣原体。上端GT 感染导致局部产生前列腺素E，这是一种有效的IL-10诱导剂，它 阻碍抗衣原体Th1CD4反应，从而促进上部GT损伤。 为了验证这一假说，我们将1)确定控制 Th1、CD4细胞向上下GT的募集决定了其作用 Th1、CD4细胞募集改变对抗衣原体感染免疫的影响 确定IL-10阻碍抗衣原体Th1CD4的机制(S) 上位GT的反应和4)确定PGE2是否影响 上部GT中抗衣原体Th1的CD4反应。为了实现这些目标，我们 将用衣原体生殖器感染的小鼠模型来操纵 BALB/c和各种转基因小鼠品系的免疫应答。结果是 这一提议将决定是否改变Th1CD4免疫反应 防止衣原体感染从上到下GT可以增加保护 增强免疫力，减少输卵管病变。此外，监管机构的作用 因素，如PGE2/IL-I0将被表征。通过瞄准不同的 这一过程中的免疫调节机制在上下GT WE内 希望增强保护性免疫，减少上肢GT损伤。如果成功， 这种方法将有助于疫苗的开发，并促进针对 对粘膜表面离散部位的免疫反应。

DESCRIPTION (provided by the applicant): Chlamydia trachomatis infection remains a major cause of pelvic inflammatory disease, and often leads to fallopian tube injury and infertility. While effective antibiotics are available, asymptomatic infection may ascend to the upper genital tract (GT) and cause irreversible tissue damage before it is discovered. One strategy for avoiding injury to the upper GT is through preventative vaccination. However, the anti-chlamydial CD4 T helper type 1 (Th1) response that develops to eradicate infection is also thought to damage the upper GT. Preliminary data from our laboratory has found that CD4 cells are primarily recruited to the upper but not the lower GT where infection begins. We have also found that prostaglandin E2 (PGE2) is induced in the upper tract during infection. These date indicate that the upper and lower GT are two immunologically distinct compartments and respond differently during Chlamydia infection. We hypothesize that the recruitment of Th1 CD4 effector cells to the lower GT is insufficient for completely eradicating chlamydiae resulting in upper GT infection. Upper GT infection causes the local production of PGE, a potent inducer of IL- 10, which impedes the antichlamydial Th1 CD4 response, thereby promoting upper GT injury. To test this hypothesis we will 1) Identify chemokines that control the recruitment of Th1 CD4 cells to the upper and lower GT 2) Determine the effect of altered Th1 CD4 cell recruitment on immunity against Chlamydia infection 3) Identify mechanism(s) whereby IL- 10 hampers an anti-chlamydial Th1 CD4 response in the upper GT and 4) Determine if PGE2 influences the anti-chlamydial Th1 CD4 response in the upper GT. To achieve these goals, we will use the mouse model of chlamydial genital infection to manipulate the immune response in BALB/c and various transgenic mouse strains. The results from this proposal will determine if shifting the Th1 CD4 immune response against Chlamydia from the upper to the lower GT can increase protective immunity and reduce tubal pathology. In addition, the role of regulatory factors, such as PGE2/IL-I0 will be characterized. By targeting different immune regulatory mechanisms in this process within the upper and lower GT we hope to enhance protective immunity and reduce upper GT injury. If successful, this approach will aid vaccine development and promote strategies that target immune responses to discrete sites within mucosal surfaces.