Prostaglandin E2 and programmed cell death 1
signaling coordinately impair CTL function and survival during chronic viral
infection
More than 10% of
the world's population is chronically infected with HIV, hepatitis C virus
(HCV) or hepatitis B virus (HBV), all of which can cause severe disease and
death. These viruses persist in part because continuous antigenic stimulation
causes the deterioration of virus-specific cytotoxic T lymphocyte (CTL)
function and survival. Additionally, antiviral CTLs autonomously suppress their
responses to limit immunopathology by upregulating inhibitory receptors such as
programmed cell death 1 (PD-1). Identification and blockade of the pathways
that induce CTL dysfunction may facilitate the clearance of chronic viral
infections. We found that the prostaglandin E2 (PGE2) receptors EP2 and EP4
were upregulated on virus-specific CTLs during chronic lymphocytic
choriomeningitis virus (LCMV) infection and suppressed CTL survival and
function. We show that the combined blockade of PGE2 and PD-1 signaling was
therapeutic in terms of improving viral control and augmenting the numbers of
functional virus-specific CTLs. Thus, PGE2 inhibition is both an independent
candidate therapeutic target and a promising adjunct therapy to PD-1 blockade
for the treatment of HIV and other chronic viral infections.
Nature：横扫癌症与感染的新免疫疗法
发布时间：2015-03-30 00:00 文章来源： 作者：
由耶鲁大学领导的一个研究小组发现了一种有前景的新联合免疫疗法，可提高机体对抗慢性病毒感染和癌症的能力。他们的研究结果发表在3月23日的《自然医学》（Nature Medicine）杂志上。
尽管面对着来自机体主要抗病原体防线——T细胞的攻击，一些可引起慢性感染的病毒，如HIV和乙肝及丙肝病毒，仍能够在身体内存留。其原因在于，随着时间的推移我们的T细胞会逐渐衰弱，最终导致“T细胞耗尽”。为了战胜这一过程，耶鲁大学医学院免疫生物学副教授Susan Kaech领导研究小组调查了导致T细胞抑制的两个信号通路。
第一个信号通路是由前列腺素E2(PGE2)触发——这一脂质已知抑制了免疫系统的抗肿瘤反应。为了探究PGE2与T细胞之间的关系，研究小组对病毒感染的小鼠展开了研究，观察到尤其是在慢性感染过程中PGE2水平升高。增加的PGE2降低了攻击感染细胞的T细胞数量，以及它们的抗病毒功能。
根据Kaech所说，T细胞有一些受体通过告知它们是停止或前行来维持它们的平衡。Kaech说：“我们发现PGE2是另一类发送停止信号的受体。”事实上，当研究小组研究缺失PGE2受体或是丧失合成正常量PGE2能力的小鼠时，发现T细胞旺盛地生长。
研究人员随后检测了在全身性减少PGE2的同时阻断另一个PD-1信号通路的组合效应。以往的一些研究也证实了PD-1抑制了T细胞。研究人员用抗PD-1抗体处理了无法生成正常PGE2的病毒感染小鼠，观察发现联合阻断PGE2和PD-1可大大提高T细胞功能，增强病毒控制。
Kaech说：“阻断两条信号通路比任一种单一的处理更大程度上提高了抗病毒反应。”
在最后的步骤中，研究人员发现给予一种常用来控制疼痛的非甾体抗炎药：塞来昔布/西乐葆（celecoxib /Celebrex）可以同样地推动T细胞。论文的第一作者、麻省总医院病理学住院医生Jonathan Chen说：“由于这些抑制剂已在普遍使用，我们想知道如果可以利用它们来降低PGE2信号，是否也能提高T细胞反应。”
这项研究的一个重要影响是表明了，有可能可以利用非甾体抗炎药来作为辅助疗法治疗慢性感染和癌症患者。“阻断PD-1正在一些癌症实验中显示出显著的结果，通过给予我们常规服用的药物，我们有可能可以增大阻断PD-1的效应，”Kaech说。
原文摘要：
Prostaglandin E2 and programmed cell death 1 signaling coordinately impair CTL function and survival during chronic viral infection
More than 10% of the world's population is chronically infected with HIV, hepatitis C virus (HCV) or hepatitis B virus (HBV), all of which can cause severe disease and death. These viruses persist in part because continuous antigenic stimulation causes the deterioration of virus-specific cytotoxic T lymphocyte (CTL) function and survival. Additionally, antiviral CTLs autonomously suppress their responses to limit immunopathology by upregulating inhibitory receptors such as programmed cell death 1 (PD-1). Identification and blockade of the pathways that induce CTL dysfunction may facilitate the clearance of chronic viral infections. We found that the prostaglandin E2 (PGE2) receptors EP2 and EP4 were upregulated on virus-specific CTLs during chronic lymphocytic choriomeningitis virus (LCMV) infection and suppressed CTL survival and function. We show that the combined blockade of PGE2 and PD-1 signaling was therapeutic in terms of improving viral control and augmenting the numbers of functional virus-specific CTLs. Thus, PGE2 inhibition is both an independent candidate therapeutic target and a promising adjunct therapy to PD-1 blockade for the treatment of HIV and other chronic viral infections.
原文链接：http://www.nature.com/nm/journal/vaop/ncurrent/full/nm.3831.html
（来源：Medical Research）
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