Impact of hormonal status on the induction of an immune response in the pig upper reproductive tract

我们的研究兴趣包括开发一个有效的粘膜疫苗接种平台，与目前的畜牧业实践工作，以保护猪对传染病。由于加拿大的大多数猪都是用人工授精繁殖的，我们推测在繁殖时将疫苗注入子宫可能是一种有吸引力的免疫途径。我们已经证实，我们的宫内疫苗配方不会影响精子功能，不会影响生育能力，也不会对仔猪出生体重或健康产生负面影响，所有这些都将是畜牧行业接受这种免疫途径的关键。我们的研究还表明，给猪子宫注射疫苗可以触发强大的抗体介导免疫，但如何实现这一机制尚不清楚，因为上生殖道缺乏粘膜相关淋巴组织，这被认为是诱导粘膜免疫反应所必需的。在这项研究中，我们将研究子宫如何作为免疫的诱导部位。我们将在发情期（当它们处于性接受期和子宫颈允许期）和发情期（当猪不处于性接受期时黄体酮水平较高）给猪子宫接种疫苗。我们将监测抗原在上皮壁上的运动，以确定激素状态是否影响子宫对抗原的通透性，我们将识别抗原呈递细胞。此外，我们将确定抗原呈递部位是否发生在引流淋巴结或组织内，如在宫颈附近的淋巴样聚集体内。最后，我们将确定在多次免疫后是否可以诱导对宫内疫苗的抗原特异性细胞介导免疫，或者细胞介导的免疫反应是否不能在该组织中轻易诱导。更好地了解抗原在上生殖道和相关细胞中的呈递方式和位置，将使我们能够制定针对这些细胞的疫苗，以促进猪对传染病的保护性免疫。针对所有目标都制定了应急计划。因为受训者可以为他们的研究方向做出贡献，如果这种基于发现的研究导致新的和意想不到的发现，他们将有机会重新定向他们的重点。对于使用人工授精作为繁殖手段的畜牧业来说，宫内疫苗可能具有巨大的经济效益。如果来自牲畜的数据显示出极好的安全性和对疾病的保护作用，这一研究领域将来可能会进一步发展，以调查宫内免疫是否可以通过保护妇女免受性传播传染病的侵害而使她们受益。

Our research interests include developing an effective mucosal vaccination platform that works with current husbandry practices to protect pigs against infectious diseases. Because the majority of pigs in Canada are bred using artificial insemination, we speculated that delivering a vaccine into the uterus at the time of breeding may be an attractive immunization route for the industry. We have already confirmed that our intrauterine vaccine formulation does not affect sperm function, it does not affect fertility, and it does not negatively impact piglet birth weight or health, all of which will be critical for acceptance of this route of immunization by the livestock industry. Our research also shows that vaccines administered to the pig uterus can trigger robust antibody-mediated immunity but the mechanism for how this is achieved is not clear as the upper reproductive tract lacks mucosal-associated lymphoid tissue which was thought to be necessary to induce a mucosal immune response. In this Discovery Grant, we will investigate how the uterus can act as an inductive site for immunization. We will vaccinate the pig uterus during estrus (when they are sexually receptive and when the cervix is permissive) and in diestrus (a progesterone-high state when pigs are not sexually receptive). We will monitor antigen movement across the epithelial wall to determine if the hormonal status impacts uterus permeability to the antigen and we will identify the antigen-presenting cells. Further, we will determine if the site of antigen presentation occurs in the draining lymph nodes or within the tissue such as within lymphoid aggregates near the cervix. Finally, we will determine if antigen-specific cell-mediated immunity to the intrauterine vaccine can be induced after multiple immunizations or whether the cell-mediated immune response cannot be readily induced in this tissue. A greater understanding of how and where antigen presentation occurs in the upper reproductive tract and the cells involved will allow us to formulate vaccines that target these cells to promote protective immunity against infectious diseases in pigs. Contingency plans are in place for all aims. Because trainees can contribute to the direction of their research, they will have the opportunity to redirect their focus should this discovery-based research lead to new and unanticipated findings. Intrauterine vaccines may be of tremendous economic benefit to livestock industries that use artificial insemination as a means of breeding. Should the data from livestock show excellent safety and protection against disease, this area of research may evolve in the future to investigate whether intrauterine immunization could benefit women by protecting them against sexually-transmitted infectious diseases.