Immunomodulation of Inflammatory Bone Resorption

宿主对微生物病原体的最佳抵抗力需要选择性地激活特定细胞的体液免疫反应。由Th1细胞介导的迟发性超敏反应是对抗专性细胞内生物感染所必需的，而Th2细胞在感染细胞外生物(包括口腔病原体)时是有益的。我们和其他人开发的新免疫策略在引导对Th1或Th2表型的反应方面显示出巨大的前景。牙髓感染导致牙髓坏死和根尖周骨吸收。在之前的资助期间，我们发现牙髓感染主要引起Th1型促炎反应，根尖周骨吸收被内源性表达的抗炎Th2细胞因子IL-10显著抑制。在拟议的研究中，我们将检验这样一个假设，即这些新的免疫策略可以用于偏向对模式生物P.gigivalis的反应，使其向Th2表型倾斜，从而增加IL-10的表达，减少根尖周骨吸收。在目标1中，将识别在遗传上对牙龈假单胞菌诱导的根尖周骨吸收敏感或耐药的小鼠品系。来自耐药菌株的T细胞株将用于鉴定优先刺激IL-10反应的牙龈假单胞菌抗原，使用表达克隆(AIM 2)。目的3确定牙龈假单胞菌抗原在体内是否能抑制根尖周骨吸收。牙龈假单胞菌抗原诱导IL-10反应的机制(S)将在目标4中描述。这些研究的目的是通过优先诱导IL-10来设计免疫调节促炎通路和骨吸收的新方法。

Optimal host resistance to microbial pathogens requires the selective activation of a particular cellular of humoral immune response. Delayed-type hypersensitivity responses medicated by Th1 cells are required to combat infection with obligate intracellular organisms, whereas Th2 cells are beneficial in infections with extracellular organisms, including oral pathogens. New immunization strategies developed by us and others show great promise in directing responses toward either a Th1 or Th2 phenotype. Infections of the dental pulp result in pulpal necrosis and the resorption of periapical bone. During the prior grant period, we found that pulpal infection elicits predominantly Th1-type pro-inflammatory responses, and that periapical bone resorption is dramatically inhibited by the endogenously expressed anti-inflammatory Th2 cytokine IL-10. In the proposed studies, we will test the hypothesis that these novel immunization strategies can be used to skew responses against the model organism P.gingivalis toward a Th2 phenotype, resulting in increased IL-10 expression and reduced periapical bone resorption. In Aim 1, mouse strains that are genetically susceptible or resistant to P. gingivalis-induced periapical bone resorption will be identified. T cell lines from a resistant strain will be used to identify P.gingivalis antigens that preferentially stimulate IL-10 responses, using expression cloning (Aim 2). Aim 3 will determine if immunization with P. gingivalis antigens can inhibit periapical bone resorption in vivo. The mechanism(s) by which P.gingivalis antigens induce IL-10 responses will be characterized in Aim 4. The goal of these studies is to devise new methods for immunomodulating proinflammatory pathways and bone resorption via preferential induction of IL-10.