Role of cyclooxygenase-2 in antibody responses to vaccination

描述(由申请人提供)：如果要保护人类免受潜在的破坏性传染病的侵袭，对疫苗接种的最佳体液(即抗体)反应是必不可少的。其中包括引起天花的天花等病毒。由于天花和其他感染剂可能被用作针对平民和军人的生物恐怖主义武器，因此受到了极大的关注。B淋巴细胞是免疫系统的关键成分，负责合成抗体，这些抗体在宿主防御包括病毒在内的感染微生物方面发挥关键作用。本实验室已经证明，人和小鼠的B淋巴细胞在激活时高度表达前列腺素生成酶环氧合酶-2(COX-2)。重要的是，常用的非类固醇抗炎药(NSAID)，如双重COX-1/COX-2抑制剂(如消炎痛)和较新的COX-2选择性药物(如Celebrex)显著削弱了B细胞在多克隆和抗原特异性刺激下产生抗体的能力。COX-2基因缺陷的小鼠对病毒样颗粒和牛痘病毒(用于接种天花疫苗)感染的抗体效价也会降低。这些观察结果导致了一种假设，即B淋巴细胞对刺激的最佳反应和产生抗体需要COX-2。因此，非甾体抗炎药，特别是那些针对COX-2的药物，可能会削弱体液免疫。如果被证实，对疫苗接种/感染的抗体反应将会降低，特别是在免疫剂弱刺激B细胞免疫的情况下。进一步的影响包括对免疫系统减弱的人类的影响，例如经常使用非类固醇抗炎药的老年人和免疫受损患者(艾滋病毒、癌症等)。在此，提出了两个特定的目标来研究COX-2在牛痘抗体反应中的作用。目的1确定COX-2在小鼠对痘苗病毒感染的抗体应答中的作用。将使用两种互补的方法：一种是使用COX-2基因敲除小鼠的遗传策略，另一种是使用用COX-1/COX-2或COX-2小分子抑制剂治疗的正常小鼠的药理学策略。将评估对牛痘感染的体液反应，包括免疫表型，并确定抗体反应所需的COX-2活性的关键时间框架。目的2确定COX-2在人B细胞产生抗牛痘病毒抗体中的作用。献血者将由1972年前接种天花疫苗的人和参与最近一项评估天花疫苗的临床试验的人组成。多克隆B细胞的激活与非甾体抗炎药COX-1/COX-2或COX-2的抑制剂一起将决定这些药物是否抑制对牛痘的召回抗体反应。这项研究的总体意义在于，在感染或接种疫苗后的关键时间段，可能禁止使用非类固醇抗炎药或其他抑制COX-2活性或表达的药物。这一发现将提高人类对常规疫苗接种以及任何生物恐怖威胁的反应能力。对公共卫生的影响疫苗接种(免疫)的最佳反应对于预防毁灭性的传染病微生物至关重要。拟议的研究将研究非类固醇抗炎药(NSAID)(如Celebrex、布洛芬等)广泛使用的潜在负面影响。关于免疫的抗体反应。这项研究在疫苗供应不足、在诱导保护性反应方面很差或接受者免疫系统减弱的情况下尤其重要。这项研究的总体意义是，在感染或接种疫苗后的关键时间段，可能禁止使用非类固醇抗炎药。这样的发现将提高我们应对常规疫苗接种以及任何生物恐怖威胁的能力。

DESCRIPTION (provided by applicant): Optimal humoral (i.e. antibody) responses to vaccination are essential if humans are to be protected against potentially devastating infectious agents. These include viruses such as variola that cause smallpox. Variola and other infectious agents have received significant attention due to their potential use as weapons for bioterrorism against both the civilian and military populations. B lymphocytes are crucial elements of the immune system responsible for the synthesis of antibodies that play key roles in host defense against infectious microorganisms including viruses. This laboratory has shown that human and mouse B lymphocytes highly express the prostaglandin-generating enzyme cyclooxygenase-2 (Cox-2) when activated. Importantly, commonly used non-steroidal anti-inflammatory drugs (NSAIDs) such as dual Cox-1/Cox-2 inhibitors (e.g. Indomethacin) and newer Cox-2 selective drugs (e.g. Celebrex) significantly blunt the ability of B cells to produce antibody in response to both polyclonal and antigen-specific stimulation. Mice genetically deficient in Cox-2 also respond with reduced antibody titers to virus-like particles and to infection with vaccinia virus (used in vaccination to smallpox). These observations led to the hypothesis that Cox-2 is required for B lymphocytes to optimally respond to stimulation and produce antibody. Thus NSAIDs, especially those that target Cox-2, may blunt humoral immunity. If proven, antibody responses to vaccination/infection would be reduced, especially where the immunizing agent weakly stimulates B cell immunity. Further ramifications include effects on humans with weakened immune systems such as the elderly and immuno-compromised patients (HIV, cancer, etc), who frequently use NSAIDs. Herein, two specific aims are proposed to study the role of Cox-2 in the antibody response to vaccinia. Aim 1 will determine the role of Cox-2 in the antibody response of mice to infection with vaccinia virus. Two complementary approaches will be used: a genetic strategy employing Cox-2 knock out mice and a pharmacologic one using normal mice treated with small molecule inhibitors of either Cox-1/Cox-2 or Cox-2. Humoral responses to vaccinia infection, including immune phenotyping will be evaluated and the critical time frame when Cox-2 activity is required for antibody responses will be determined. Aim 2 will determine the role of Cox-2 in antibody production to vaccinia for human B cells. Blood donors will consist of those vaccinated against smallpox prior to 1972 and those who participated in a recent clinical trial evaluating the smallpox vaccine. Polyclonal B cell activation in concert with NSAID inhibitors of either Cox-1/Cox-2 or Cox-2 will determine if these drugs dampen a recall antibody response to vaccinia. The overall significance of this research is that the use of NSAIDs or other drugs that inhibit Cox-2 activity or expression may be contraindicated during critical time periods after infection or vaccination. Such a finding will improve the ability of humans to respond to routine vaccination, as well as any bioterror threats. Impact on public health Optimal responses to vaccination (immunization) are essential to protect against devastating infectious microorganisms. The proposed research will study the potentially negative impact of the widespread use of non-steroidal anti-inflammatory drugs (NSAIDs) (e.g. Celebrex, Ibuprofen, etc.) on antibody responses to immunization. This research is especially important where vaccines are in short supply, are poor at inducing protective responses or the recipients have weakened immune systems. The overall significance of this research is that the use of NSAIDs may be contraindicated during critical time periods after infection or vaccination. Such a finding would improve our ability to respond to routine vaccination, as well as any bioterror threats.