MICA: Suppressing inflammation to enhance antigen-specific immunity in older humans using p38MAPK inhibitors and vitaminD3

老年人更容易受到感染，即使是那些他们年轻时免疫的疾病。针对许多不同传染因子的疫苗接种在这些个体中也是次优的。为了研究衰老过程中免疫力下降的机制，我们将安全的微生物衍生物注射到老年和年轻志愿者的皮肤中。注射药剂后，我们可以提取积聚在免疫反应部位的白细胞来检测它们的功能。我们一直在调查的一种反应是对水痘带状疱疹病毒（VZV）的反应，该病毒主要在年轻人中引起水痘。受感染的人控制这种持续存在的病毒，直到年龄较大，免疫力下降导致病毒重新激活，导致带状疱疹。老年人也容易受到结核病再激活的影响，我们还可以测试他们对结核病蛋白的反应。老年人对皮肤VZV的反应能力下降，这可能是他们对带状疱疹易感性增加的潜在原因。这些人对结核病相关蛋白的皮肤反应也降低，皮肤中的免疫缺陷可能反映了这些人的总体免疫缺陷。我们发现，这种缺陷反应与该组织中增加的基线炎症有关。虽然清除感染需要炎症反应，但过度的炎症已被证明会干扰特异性免疫的产生。因此，我们将研究通过阻断基础炎症来增强老年人免疫反应的方法。为了扩展我们对皮肤高背景炎症的初步观察，我们将使用第二种人体实验系统来研究该组织中哪些细胞负责炎症介质的产生，该系统测试了对皮肤刺激物（称为斑蝥素）的反应。接下来，我们将阻断皮肤的炎症，以确定这是否能改善抗原攻击时的反应。这将通过使用GSK已经开发的药物（Losmapimod, p38MAPkinase inhibitor）和另一种现成的药物（维生素D3）对老年受试者进行预处理来实现。GSK p38抑制剂目前正在进行测试，以防止不必要的炎症。一个令人惊讶的观察结果是，p38抑制也可以使人类T淋巴细胞恢复活力，并增强其体外增殖能力。因此，抑制p38可以阻断不必要的炎症反应，并增强T淋巴细胞的反应性。维生素D3也被证明具有抗炎作用，部分是通过抑制p38MAPkinase的激活来起作用的。在本项目中使用两种独立的干预措施增加了本研究成功的可能性。虽然Losmapimod的抗炎作用可能更具体，但使用维生素D3更具成本效益，因为它是一种容易获得的廉价化合物。这项研究的理想结果是，这些化合物中的一种或另一种，老年志愿者将接受治疗，将增强他们对皮肤微生物抗原挑战的反应。这将提供概念数据的证明，这将导致通过抑制衰老过程中发现的增加的基线炎症反应来增强免疫力的令人兴奋的可能性。这可能是一种总体上增强免疫反应的策略，特别是增强疫苗接种对各种疾病的效力，而这些疾病在老年受试者中效果较差。

Older humans are more susceptible to infections, even those to which they were immune to in their youth. Vaccination against many different infectious agents is also sub-optimal in these individuals. To investigate the mechanisms involved in the decline in immunity during ageing we inject safe derivatives of microorganisms into the skin of old and young volunteers. After injection of the agent, we can extract the white cells (leucocytes) that accumulate at the site of the immune response to test for their function. One of the responses we have been investigating is that to the varicella zoster virus (VZV) that induces chickenpox mainly in young individuals. Infected subjects control this persistent virus until an older age where reduced immunity leads to viral re-activation to cause shingles. Older humans are also susceptible to re-activation of TB and we can also test their response to tuberculosis (TB) proteins. Elderly subjects have decreased capacity to respond to VZV in the skin that may be an underlying reason for their increased susceptibility to shingles. These individuals also have decreased cutaneous responses to TB related proteins and the immune defect in the skin may reflect the general defect in immunity in these individuals. We have found that this defective response is associated with increased baseline inflammation in this tissue. Although inflammatory responses are required to clear infections, excessive inflammation has previously been shown to interfere with the generation of specific immunity. We will therefore investigate ways of enhancing the immune response of older humans by blocking basal inflammation. To extend our initial observations of high background inflammation in the skin, we will investigate which cells in this tissue are responsible for the production of inflammatory mediators by using a second human experimental system that tests the response to a skin irritant known as cantharadin. Next we will block inflammation in the skin to determine whether this can lead to improved responses upon challenge with antigens. This will be achieved by pre-treating old subjects with a drug that has already been developed by GSK (Losmapimod, p38MAPkinase inhibitor) and another that is available off the shelf (vitamin D3). The GSK p38 inhibitors are currently being tested to prevent unwanted inflammation. A surprising observation we made was that p38 inhibition could also rejuvenate human T lymphocytes and enhance their ability to proliferate in vitro. Therefore the inhibition of p38 may block unwanted inflammatory response as well as enhance T lymphocyte reactivity. Vitamin D3 has also been shown to have anti-inflammatory effects and works in part by inhibiting p38MAPkinase activation. The use of 2 separate interventions in this project increases the likelihood of success in this study. While Losmapimod may be more specific in its anti-inflammatory action, the use of vitamin D3 is more cost effective as it is a cheap compound that is readily available. The desirable outcome of this study is that either one or other of these compounds, that older volunteers will be treated with, will boost their response to microbial antigen challenge in the skin. This will provide proof of concept data that will lead to the exciting possibility of enhancing immunity by inhibiting the increased baseline inflammatory responses that are found during ageing. This may be a strategy to enhance immune responses in general and specifically to enhance vaccination efficacy to various diseases that is less effective in older subjects.