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. ? ? ?
