Negative regulation of Plasma cells by CD28 and B7 molecules

描述（由申请人提供）：暴露于病原体会导致终生持续产生血清抗体。例如，接种天花疫苗的人在其血清中表现出稳定的中和抗体水平超过75年。抗体是由浆细胞产生的，这些细胞是体液免疫系统在健康（对病原体的反应）和疾病（自身免疫）中的关键效应器，因此，更好地了解这些细胞是如何被调节和维持的很重要。CD28是一种细胞表面蛋白，对激活na - ve T细胞至关重要。有趣的是，cd28也在浆细胞和多发性骨髓瘤细胞上表达。在这里，我们提供的证据表明CD28在短寿命和长寿命的骨髓浆细胞上都表达。我们对CD28在浆细胞上的功能知之甚少。我们还证明了短寿命和长寿命浆细胞也表达CD28、B7.1和B7.2的配体。基于我们令人信服的初步数据，我们的中心假设是CD28/B7分子对浆细胞功能的调节至关重要，使用可溶性CD28或B7分子调节这种相互作用将增强体内的免疫反应。我们将通过追求三个具体目标来检验我们的中心假设。我们将确定CD28 （Aim 1）和B7的作用程度。/B7.2（目标2）影响浆细胞功能和寿命，并确定可溶性CD28或B7是否可用于增强宿主对低免疫原性H5N1禽流感疫苗的免疫应答（目标3）。这项工作意义重大，因为一旦完成，我们将更好地了解CD28和/或B7分子如何调节浆细胞的功能和寿命。这可能潜在地用于(a)增强疫苗诱导的Ab反应或(b)下调自身免疫性疾病中的自身反应性浆细胞。

DESCRIPTION (provided by applicant): Exposure to pathogens leads to the sustained production of serum antibodies for a life-time. For instance, humans immunized with smallpox vaccine exhibit stable levels of neutralizing antibodies in their serum for over 75 years. Antibodies are produced by plasma cells and these cells are critical effectors of the humoral immune system both in health (responses to pathogens) and in disease (autoimmunity) and hence, it is important to better understand how these cells are regulated and maintained. CD28 is a cell surface protein that is critical for the activation of na¿ve T cells. Interestingly, CD28is expressed also on plasma cells and multiple myeloma cells. Here we provide evidence that CD28 is expressed on both short-lived as well as long-lived plasma cells in the bone marrow. Very little is known about the function of CD28 on plasma cells. We also demonstrate that short- and long-lived plasma cells also express the ligands for CD28, B7.1 and B7.2. Based upon our compelling preliminary data, our central hypothesis is that CD28/B7 molecules are critical for the regulation of plasma cell function and modulation of this interaction using soluble CD28 or B7 molecules will enhance immune responses in vivo. We will test our central hypothesis by pursuing three specific aims. We will determine the extent to which CD28 (Aim 1) and B7. /B7.2 (Aim 2) affects plasma cell function and longevity and determine whether soluble CD28 or B7 can be used to enhance host immune responses to poorly-immunogenic H5N1 avian influenza vaccine (Aim 3). The proposed work is significant, because upon completion, we will have a better understanding of how CD28 and or B7 molecules modulate function and longevity of plasma cells. This could potentially be used to (a) enhance vaccine-induced Ab responses or (b) down modulate self-reactive plasma cells in autoimmune disorders.