Vitamin A-Mediated Protection in Measles

描述（由申请人提供）：麻疹仍然是全球儿童发病和死亡的最重要原因之一，最年幼儿童的负担最大。大多数麻疹死亡是由于对麻疹引起的对其他病原体的免疫反应抑制知之甚少而引起的继发感染。虽然感染性病毒在皮疹消退后不再能恢复，但可在呼吸道分泌物、尿液和血液中检测到麻疹病毒（MV）RNA，持续数月，这种持续性可能与麻疹诱导的免疫抑制有关。除了急性感染的风险外，2岁以下儿童和免疫受损（例如HIV感染）的儿童和成人由于未能清除病毒和神经系统感染，容易发展为致命的进行性神经系统疾病。虽然通过开展大规模疫苗接种运动在控制麻疹方面取得了进展，但这些运动难以持续。因此，麻疹再次蔓延，预计今后死亡人数将继续增加而不是减少。麻疹唯一可用的“治疗”是维生素A。在疾病急性期给予维生素A可降低死亡率，但这种保护作用的机制尚不清楚，许多儿童没有得到这种补充。了解维生素A如何改善麻疹的康复可能会导致更广泛地使用这种简单廉价的干预措施，更有效地预防MV感染的严重并发症，并可能确定麻疹或发展中国家其他儿童高死亡率感染的相关治疗方法。 目前还没有令人满意的麻疹小动物模型，但恒河猴对野生型MV感染易感，并发生与人类麻疹相似的皮疹疾病，包括淋巴细胞增殖的长期抑制。与人类一样，在感染后几个月内可以检测到MV RNA。皮疹期间出现抗体和T细胞反应。对维生素作用的认识 麻疹的补充剂只能来自猕猴的研究，因为出于伦理考虑，不可能在人类中进行对照研究。我们推测维生素A可以提高免疫介导的MV清除率，缩短免疫抑制期。由于所有反式维甲酸的实验效果是促进Th 2，Treg和CD 8 + T细胞反应，抑制Th 1和Th 17反应，我们预测补充维生素A的猴子将具有改善的抗体，CD 8 + T细胞和CD 4 + Th 2对麻疹的反应，这将与改善的病毒清除和减少的免疫抑制相关。我们计划以下具体目标：（1）确定补充维生素A对感染性病毒和病毒RNA清除的影响;（2）确定补充维生素A对感染后MV特异性抗体和T细胞应答的影响;（3）确定补充维生素A是否降低MV诱导的淋巴细胞增殖抑制的幅度或持续时间。

DESCRIPTION (provided by applicant): Measles remains one of the most important causes of child morbidity and mortality worldwide with the greatest burden in the youngest children. Most measles deaths are due to secondary infections that result from a poorly understood measles-induced suppression of immune responses to other pathogens. Although infectious virus can no longer be recovered after the rash fades, measles virus (MV) RNA can be detected in respiratory secretions, urine and blood for several months and this persistence may be causally related to measles-induced immunosuppression. In addition to the risks of acute infection, children under the age of 2 yrs and immune-compromised (e.g. HIV-infected) children and adults are vulnerable to development of fatal progressive neurologic disease due to failure to clear virus and infection of the nervous system. Although gains have been made in measles control by implementing mass vaccination campaigns, these campaigns have been difficult to sustain. As a result, measles has again become widespread and deaths are predicted to continue to increase, rather than decrease, in the future. The only available "treatment" for measles is vitamin A. Vitamin A given during the acute phase of disease decreases mortality, but the mechanism for this protective effect is not known and many children do not receive this supplementation. An understanding of how vitamin A improves recovery from measles could result in more widespread use of this simple inexpensive intervention, more effective prevention of the severe complications of MV infection and perhaps identification of related treatments for measles or other childhood infections with high mortality in developing countries. There are no satisfactory small animal models for measles, but rhesus macaques are susceptible to wild type MV infection and develop a rash disease that faithfully mimics measles in humans, including prolonged suppression of lymphocyte proliferation. As in humans, MV RNA can be detected for several months after infection. Antibody and T cell responses appear during the rash. An understanding of the effect of vitamin A supplementation on measles will only come from studies of macaques because controlled studies in humans are not possible due to ethical considerations. We hypothesize that vitamin A improves the immune-mediated clearance of MV and shortens the period of immune suppression. Because the experimental effects of all trans-retinoic acid are to boost Th2, Treg and CD8+ T cell responses and to suppress Th1 and Th17 responses, we predict that vitamin A-supplemented monkeys will have improved antibody, CD8+ T cell and CD4+ Th2 responses to measles that will correlate with improved virus clearance and reduced immune suppression. We plan the following specific aims: (1) Determine the effect of supplemental vitamin A on clearance of infectious virus and viral RNA; (2) Identify the effect of supplemental vitamin A on MV-specific antibody and T cell responses after infection; (3) Determine whether supplemental vitamin A decreases the magnitude or duration of MV-induced suppression of lymphocyte proliferation.